Search

Immunocompromised patients with hematologic malignancies are more susceptible to COVID-19 and at higher risk of severe complications and worse outcomes compared with the general population. In this context, we evaluated the humoral response by determining the titers of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with Waldenström macroglobulinemia (WM) after vaccination with the BNT162b2 or AZD1222 vaccine. A US Food and Drug Administration–approved enzyme-linked immunosorbent assay–based methodology was implemented to evaluate NAbs on the day of the first vaccine shot, as well as on days 22 and 50 afterward. A total of 106 patients with WM (43% men; median age, 73 years) and 212 healthy controls (46% men; median age, 66 years) who were vaccinated during the same period at the same center were enrolled in the study (which is registered at www.clinicaltrials.gov as #NCT04743388). Our data indicate that vaccination with either 2 doses of the BNT162b2 or 1 dose of the AZD1222 vaccine leads to lower production of NAbs against SARS-CoV-2 in patients with WM compared with controls on days 22 and 50 (P < .001 for all comparisons). Disease-related immune dysregulation and therapy-related immunosuppression are involved in the low humoral response. Importantly, active treatment with either rituximab or Bruton’s tyrosine kinase inhibitors was proven as an independent prognostic factor for suboptimal antibody response after vaccination. In conclusion, patients with WM have low humoral response after COVID-19 vaccination, which underlines the need for timely vaccination ideally during a treatment-free period and for continuous vigilance on infection control measures.

Introduction: Multiple myeloma (MM) is the second most common haematological malignancy and is characterized by bone marrow infiltration of monoclonal plasma cells and end-organ involvement. Smoldering MM (SMM) is an intermediate clinical entity between MGUS and MM, with a risk of progression to symptomatic disease at 10% per year. Bone disease is the most frequent related symptom of MM, with approximately 90% of patients developing bone lesions throughout their disease course. Therefore, imaging plays a crucial role in diagnosis and management of these patients. Conventional radiography was traditionally considered as the standard of care, however the limited sensitivity in detecting osteolytic bone lesions has led to more advanced imaging modalities. Imaging also is of high importance to discriminate MM from smoldering disease, since the presence of bone lesions establishes the diagnosis of active disease and requires treatment initiation. Computed tomography (CT) was found to be the most sensitive modality in detecting small osteolytic bone lesions less than 5 mm. Ionizing radiation exposure was one of the main limitations of this technique. Technological advances have made possible low dose assessment of the entire skeleton with effective radiation doses comparable to those of a whole-body plain radiographic skeletal survey. Furthermore, the low dose CT is widely available and has a very short scan time. Therefore, whole-body low dose CT (WBLDCT) has been incorporated in the latest diagnostic criteria of the IMWG. The purpose of this study was to evaluate the role of WBLDCT in the early identification of patients with asymptomatic MM who progress with bone disease only and who require immediate antimyeloma treatment. Patients and Methods: Our study was approved by the local IRB and all patients provided informed consent. All patients diagnosed with SMM based on the 2003 International Myeloma Working Group (IMWG) definition of SMM were serially assessed with WBLDCT from July 2013 until March 2020 as part of our institutional workup. The assessments were performed at baseline, 1-year post diagnosis and every 1 year thereafter. The patients enrolled in the study were those who had at least 2 consecutive CT assessments at the above described time points. All WBLDCT exams were performed with a 16-detector CT scanner. The CTs were evaluated by two experienced radiologists, blinded to the clinical and laboratory data. RESULTS We prospectively evaluated 100 patients with SMM (median age at diagnosis 61 years, range 40-86 years, 52 female /48 male) who underwent WBLDCT at the above described time points. Median number of WBLDCTs exams performed was 2.5 (range 2-5). Totally, 31 patients progressed (either with CRAB criteria and/or at least one myeloma defining event). During a median follow up of 57 months 31 patients have progressed (with either CRAB criteria and/or at least one myeloma defininf event). Importantly, 10 of 31 patients progressed only with bone lesions that were identified on the scheduled WBLDCT as per protocol. Median time to progression from asymptomatic to symptomatic disease for all patients has not been reached, while median time for those who actually progressed was 22 months (95% CI:15,6-28,4). For the subgroup of patients who progressed with bone lesions only the median time was also 22 months (95%CI:3,4-40,6). Median time to progression was not statistically different between the two progressor subgroups. All patients were initiated with antimyeloma treatment immediately post evolution to symptomatic disease. PFS for all 31 patients at first line treatment was 52 months (95%CI:34,5-69,5) and median PFS for bone progressors has not yet been reached. Among the patients who progressed 29 were alive at the time of the analysis. The 2 deaths that occurred were one related (progressive disease) and one unrelated to multiple myeloma (cardiovascular event). Neither had progressed with isolated bone involvement. Conclusion: In conclusion, our strategy allowed early detection of bone lesions in 10% of our patients and these patients were immediately initiated with antimyeloma treatment to avoid further myeloma-related complications. Consecutive low-dose WBLDCT studies can identify early myeloma evolution to symptomatic disease and optimize the disease monitoring along with our therapeutic strategy. Disclosures Gavriatopoulou: Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Janssen: Consultancy, Honoraria, Other: Travel/accommodations/expenses, Research Funding; Pfizer: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel/accommodations/expenses. Terpos:Janssen: Honoraria, Other: travel expenses , Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Medison: Honoraria; Amgen: Honoraria, Research Funding; Genesis: Honoraria, Other: travel expenses , Research Funding. Dimopoulos:Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria; Amgen: Honoraria; Takeda: Honoraria.

Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies. Neutralizing antibodies (NAbs) against SARS-CoV-2 were evaluated in 276 patients with plasma cell neoplasms after vaccination with either the BNT162b2 or the AZD1222 vaccine, on days 1 (before the first vaccine shot), 22, and 50. Patients with MM (n = 213), SMM (n = 38), and MGUS (n = 25) and 226 healthy controls were enrolled in the study (NCT04743388). Vaccination with either two doses of the BNT162b2 or one dose of the AZD1222 vaccine leads to lower production of NAbs in patients with MM compared with controls both on day 22 and on day 50 (p p = 0.009) and on day 50 (p = 0.003). Importantly, active treatment with either anti-CD38 monoclonal antibodies (Mabs) or belantamab mafodotin and lymphopenia at the time of vaccination were independent prognostic factors for suboptimal antibody response following vaccination. In conclusion, MM patients have low humoral response following SARS-CoV-2 vaccination, especially under treatment with anti-CD38 or belamaf. This underlines the need for timely vaccination, possibly during a treatment-free period, and for continuous vigilance on infection control measures in non-responders.

Background Waldenstrom's macroglobulinemia (WM) is a rare malignancy characterized by bone marrow infiltration by lymphoplasmacytic cells and the presence of a monoclonal IgM paraprotein. The interactions of lymphoplasmacytic cells with other cells in their microenvironment, including mast cells and endothelial cells, support their survival and proliferation and can induce resistance to therapy. von Willebrand factor (vWF) plays a key role in primary hemostasis but is also a marker of endothelial “stimulation.” High levels of vWF have been associated with an adverse prognosis in patients with symptomatic WM and might reflect the interactions between lymphoplasmacytic cells and other cells of their microenvironment. Materials and Methods Considering vWF and ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) as markers of endothelial dysfunction and activation, we evaluated the prognostic importance of vWF and ADAMTS-13 antigen levels in the serum of patients with previously untreated symptomatic WM to validate vWF as a possible prognostic marker for progression-free and overall survival. We also validated the measurement of vWF in the serum instead of citrated plasma and investigated the possible correlations of ADAMTS-13 antigen levels with disease characteristics. The analysis included 42 patients with symptomatic WM and 19 matched healthy controls. Results The serum levels of vWF antigen provided significant prognostic information, and patients with levels ≥ 200 IU/dL had a very poor prognosis compared with patients with lower levels. The ADAMTS-13 antigen levels were decreased in WM patients and correlated with the IgM levels, β2-microglobulin, and extent of bone marrow infiltration. Conclusion vWF levels measured in the serum could become an important prognostic marker in patients with WM and requires further investigation.

Despite recent advances, Multiple Myeloma (MM) remains an incurable disease with apparent heterogeneity that may explain patients&rsquo, variable clinical outcomes. While the phenotypic, (epi)genetic, and molecular characteristics of myeloma cells have been thoroughly examined, there is limited information regarding the role of the bone marrow (BM) microenvironment in the natural history of the disease. In the present study, we performed deep phenotyping of 32 distinct immune cell subsets in a cohort of 94 MM patients to reveal unique immune profiles in both BM and peripheral blood (PB) that characterize distinct prognostic groups, responses to induction treatment, and minimal residual disease (MRD) status. Our data show that PB cells do not reflect the BM microenvironment and that the two sites should be studied independently. Adverse ISS stage and high-risk cytogenetics were correlated with distinct immune profiles, most importantly, BM signatures comprised decreased tumor-associated macrophages (TAMs) and erythroblasts, whereas the unique Treg signatures in PB could discriminate those patients achieving complete remission after VRd induction therapy. Moreover, MRD negative status was correlated with a more experienced CD4- and CD8-mediated immunity phenotype in both BM and PB, thus highlighting a critical role of by-stander cells linked to MRD biology.

TO THE EDITOR: The survival of myeloma patients has doubled in the past decade, but patients refractory to both proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) still have poor prognosis.[1][1] Immunotherapy with monoclonal antibodies targeting cell-surface antigens is a promising new

Introduction: Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies. Herein, we evaluated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with plasma cell neoplasms (PCNs) after vaccination with either the mRNA BNT162b2 or viral vector AZD1222 vaccine, up to 50 days post their first vaccine dose. Methods: This is an ongoing large prospective study (NCT04743388) evaluating the kinetics of anti-SARS-CoV-2 antibodies after COVID-19 vaccination in healthy subjects and in patients with hematological malignancies or solid tumors. Here we present the data on patients with PCNs in comparison to controls of similar age and gender, who were vaccinated during the same time period (January to March 2021) in Athens (Greece). Major exclusion criteria for both patients and controls included the presence of: (i) autoimmune disorder under immunosuppressive therapy or other active malignant disease; (ii) HIV or active hepatitis B and C infection, (iii) end-stage renal disease and (iv) prior diagnosis of COVID-19. Serum was collected on day 1 (D1; before the first vaccine dose), on day 22 (D22; before the second dose of the BNT162b2 or 3 weeks post the first AZD1222 dose) and on day 50 (D50; 4 weeks post second dose of the BNT162b2 or 7 weeks post the first AZD1222 dose). NAbs against SARS-CoV-2 were measured using an FDA approved-ELISA methodology (cPass™ SARS-CoV-2 NAbs Detection Kit, GenScript, Piscataway, NJ, USA). Results: We evaluated 382 patients with PCNs after vaccination with either the BNT162b2 or the AZD1222 vaccine. Patients with MM (n=213), WM (n=106), SMM (n=38) and MGUS (n=25) and 226 healthy controls were enrolled in the study. Of MM/SMM/MGUS patients, 215 (77.9%) were vaccinated with the BNT162b2 and 61 (22.1%) with the AZD1222 vaccine, while out of 106 WM patients 90 (84.9%) were vaccinated with the BNT162b2 and 16 (15.1%) with the AZD1222 vaccine. Vaccination with either two doses of the BNT162b2 or one dose of the AZD1222 vaccine led to lower production of NAbs against SARS-CoV-2 in patients compared with controls both on day 22 and on day 50 (P After the first dose of the vaccine, on D22, the patient group had lower NAb titers compared with controls: the median NAb inhibition titer was 27% (IQR: 15.3-42%) for MM/SMM/MGUS versus 20.5% (IQR: 10-37%) for WM patients versus 38.7% (IQR: 22-54.3%) for controls (P Conclusion: Patients with MM and WM have a low humoral response following SARS-CoV-2 vaccination, especially those who are under treatment with anti-CD38-, anti-BCMA-, anti-CD20- or BTKIs-based regimens. This result suggest that these patients have to continue the protective measures against SARS-CoV-2 as they are at high risk for COVID-19. Further studies on the kinetics of immune subpopulations following COVID-19 vaccination will elucidate the underlying immune landscape and determine the potential need for additional booster vaccine doses or protective administration of antibodies against SARS-CoV-2 in MM/WM patients with poor response after full vaccination. Disclosures Terpos: Janssen-Cilag: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Gavriatopoulou: Janssen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria; Genesis: Honoraria; GSK: Honoraria; Amgen: Honoraria. Kastritis: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genesis: Honoraria; Takeda: Honoraria; Pfizer: Honoraria. Dimopoulos: Janssen: Honoraria; BeiGene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; BMS: Honoraria.

Despite significant improvements in myeloma (MM) therapies, patients (pts) refractory to immunomodulatory agents (IMiDs), proteasome inhibitors (PIs) and anti-CD38 monoclonal antibodies (mAbs) have poor prognosis and limited treatment options. Daratumumab (DARA), an anti-CD38 mAb, is active in pts with relapsed/refractory MM through mechanisms that include complement-dependent and antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, apoptosis and immunomodulation. DARA + IMiDs have substantial efficacy, probably through the combination of their immune and microenvironmental effects. The mechanisms of resistance are not fully elucidated but resistance to DARA may be reversed by addition of IMiDs and vice versa, as previously shown (Gavriatopoulou Blood 2019, Nooka Cancer 2019). We prospectively evaluated the combination of DARA + IMiD following refractoriness to both agents, to assess clinical activity but also to longitudinally assess immune cell populations in the peripheral blood (PB) in order to understand the resulting immunomodulation. Consecutive PB samples from 35 pts refractory to an IMiD (LEN or POM) and progressing on DARA monotherapy were analyzed. The last IMiD on which each patient was refractory was added without modulating DARA backbone (RESET). In consenting pts, PB samples were collected at the time of DARA initiation, at progression to DARA monotherapy and IMiD addition, at response and at progression to DARA-IMiD. Samples were viably frozen and analyzed using specific two 8-color panels. Panel 1: CD38-FITC, Granzyme B-PE, CD127-PeCy7, CD25-APC, CD4-APCCy7, CD3-BV510, Lag-3-BV421 and 7-AAD as viability dye; panel 2: CD14-FITC, CD56-PE, CD66-b-PeCy7, CD80-APC, CD45-APCCy7, CD3/CD19-BV510, CD16-BV421 and 7-AAD as viability dye. Pts' median age was 73 years (range 52-86; 66% male); median prior treatment lines were 3 (range 1-16); all had prior exposure and refractoriness to at least one PI; all were refractory to LEN and 51% to POM, 40% had prior ASCT. The IMiD added was the last used prior to DARA, i.e., LEN in 49% (17/35) and POM in 51% (18/35). Median duration of DARA monotherapy prior to RESET was 7.9 months (range 1-38) and 64% responded (≥PR) before progression. Median duration of RESET therapy was 5.5 months (range 0.46 to 23.86) and 43% had ≥PR (≥MR: 60%) [including VGPR: 8.6% (n=3), PR: 34.3% (n=12), MR: 17.1% (n=6), SD/NR: 28.6% (n=10), PD: 11.4% (n=4)]. Median PFS was 5 months (95% CI 1.5-8.4) and median OS was 19 months (95% CI 13.5-24.5). Based on response at 3-month landmark, PFS was 9 months for pts who achieved ≥ PR vs 4 months for < PR (p=0.031). PFS and response to RESET were independent of type or dose of IMiD, prior response to DARA monotherapy or IMiD, number of prior treatments, ISS at diagnosis or at time of RESET. Multivariate flow cytometry analysis showed significant heterogeneity between pts (n=20). After DARA monotherapy there was an increase in CD8+ T cells compared to baseline which persisted throughout DARA-containing therapy with CD4+ T remaining at similar levels at all time-points. Total Tregs reduced after DARA start; however, within Tregs the relative proportion of Lag3+ Tregs tended to increase during DARA monotherapy. NK cell levels were significantly reduced after DARA and remained low throughout DARA therapy, with no recovery after IMiD addition; within NKs, we noticed an increase of CD16-/CD56+ immunomodulatory/cytokine producing and, to a lesser extent, of CD56-/CD16+ cytotoxic subsets compared to mature CD56+/CD16+ NK cells which tended to decrease, especially during DARA monotherapy. Although the samples at response to DARA/IMiD combination are few (n=10), CD56-CD16+ NK cell percentages at the time of progression to DARA were associated with response to DARA/IMiD. Finally, there was a noticeable increase in M1- and a decrease in M2-type macrophage subsets at response to DARA/IMiD. In conclusion, retaining DARA backbone therapy may be associated with clinically relevant activity (ORR 43%, 5 months median PFS) among pts refractory toDARA and IMiD, when these drugs are combined. Longitudinal evaluation of PB immune cell composition showed DARA-specific immunomodulation, which was not altered after addition of IMiDs, but may be related to restoration of sensitivity to the DARA/IMiD combination. Further investigation is in progress to reveal potential immune signatures of clinical relevance. Disclosures Krevvata: Janssen: Current Employment. Gavriatopoulou: Genesis: Honoraria; GSK: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Amgen: Honoraria. Terpos: Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BeiGene: Honoraria. Kastritis: Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria.

Background: The combination of lenalidomide with dexamethasone (Rd) represents a preferred treatment backbone for newly diagnosed, transplant-ineligible patients (pts) with multiple myeloma (MM), while the addition of a third drug (i.e., daratumumab, bortezomib, carfilzomib or ixazomib) leads to higher response rates and deeper responses. Belantamab mafodotin (belamaf; GSK2857916) is a multi-modal antibody-drug conjugate that has demonstrated a clinically meaningful anti-myeloma activity with a manageable safety profile in heavily pre-treated pts with relapsed or refractory MM. Preclinical evidence suggest a potential synergy between belamaf and lenalidomide; at the same time, these drugs do not have overlapping toxicities. Thus, there is strong rationale for investigating the clinical activity of upfront belamaf in combination with Rd in transplant-ineligible MM pts. Aims: The present analysis evaluates the safety profile of belamaf in 3 different dosing schemes in combination with Rd in treatment-naïve, transplant-ineligible MM pts. Methods: BelaRd (study short title) is an open-label, single-center, phase 1/2 study conducted in Greece, aiming to enroll 66 newly diagnosed, transplant-ineligible MM pts. The study comprises 2 parts. Part 1 will evaluate 3 doses of belamaf (2.5, 1.9, and 1.4 mg/kg) in combination with Rd, each given in an individual cohort of pts, and will determine the recommended phase 2 dose (RP2D). In this part, belamaf will be administered q8w and, depending on toxicity, dosing may be rescheduled to q4w or q12w. In Part 2, a single cohort of pts will be treated with belamaf in the RP2D in combination with Rd to further evaluate the safety and clinical activity of this regimen. Part 2 will also evaluate 2 different sets of guidelines for ocular adverse events (AEs) in 2 separate groups of pts to identify the optimal method for the management of belamaf-related keratopathy. This is the initial safety analysis of Part 1 and includes pts who received ≥1 belamaf dose and were followed up for ≥8 weeks. Results: Overall, as of 16 July 2021 (cut-off date), 18 pts completed the dose-limiting toxicity (DLT) observation period, defined as specific ≥ grade 3 AEs occurring during the first cycle of study treatment, and were included in the safety analysis. The median age was 72 years (range: 65-82), and the majority of pts were male (55.6%). Lytic bone lesions were present in 12 (66.7%) pts; no pts had extramedullary disease. Most pts (9, 50.0%) had Eastern Cooperative Oncology Group performance status 0 followed by those at 1 (8, 44.4%) and 2 (1, 5.6%). Regarding the revised International Staging System, most pts (13, 72.2%) were at stage II, followed by those at stages III (2, 11.1%) and I (3, 16.7%); 3 (16.7%) pts had high-risk cytogenetics, defined as del17p13, t(4;14) or t(14;16). By the cut-off date, pts had received a median of 4 treatment cycles, with 17 (94.4%) pts still being on treatment; 1 (5.6%) pt died due to pneumonia, unrelated to the study treatment. 16 (88.9%) pts experienced ≥1 treatment emergent adverse event (TEAE). In total, 11 (61.1%) pts had ≥1 TEAE grade 3/4, of which 1 was related to belamaf; 1 (5.6%) pt experienced a serious adverse event (SAE). There were 2 cases of dose reduction and 1 case of dose delay. The most common grade 3/4 TEAEs were fatigue (5 pts, 27.8%) and rash (4 pts, 22.7%), all related to lenalidomide. One SAE was reported: pneumonia grade 5 in the 2.5 mg/kg cohort. DLTs were noted in 3 (16.7%) pts: 1 pt with grade 3 fatigue in the 1.4 mg/kg cohort and 1 pt with grade 3 rash in each of the 1.9 and 1.4 mg/kg cohorts, all related to lenalidomide. Regarding belamaf-related ocular AEs, there were 2 cases of superficial punctuate keratopathy (grade 1 and 2 each, both in the 2.5 mg/kg cohort), 10 cases of decreased visual acuity (grade 1 [8 pts, 44.4%]: 4 in the 1.9 mg/kg cohort and 4 in the 1.4 mg/kg cohort; grade 2 [2 pts, 11.1%] in the 2.5 mg/kg cohort), and 1 case of grade 1 blurred vision in 2.5 mg/kg cohort. Conclusions: In the first safety analysis of the BelaRd study no new safety signals for the belamaf-Rd combination were observed. The frequency of ocular AEs was within the anticipated range. This early analysis shows that the triplet combination can be safely administered in treatment-naïve, transplant-ineligible MM pts. The enrollment in the study is ongoing, and more safety and efficacy data will become available with the inclusion of additional pts in an updated analysis. Disclosures Terpos: Novartis: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria. Gavriatopoulou: Janssen: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; GSK: Honoraria; Genesis: Honoraria; Sanofi: Honoraria; Amgen: Honoraria. Gkolfinopoulos: Health Data Specialists: Current Employment. Manousou: Health Data Specialists: Current Employment. Dimopoulos: Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria; BMS: Honoraria; Amgen: Honoraria.

Introduction: Advances in induction regimens have significantly improved depth of response and duration of remission in multiple myeloma (MM) patients who are eligible for high-dose therapy and autologous stem cell transplantation (ASCT). Proteasome inhibitor-based induction regimens are standard as part of induction and it has been shown not to have any detrimental effect on stem cell (SC) collection and engraftment. Daratumumab (DARA) is an IgG1k monoclonal antibody directed against CD38 with potent antimyeloma activity. Based on the results of prospective studies DARA is now approved as part of induction therapy. Available data indicate a potential impact of DARA on SC collection but there is limited data on engraftment, duration of hospitalization and infection risk. In this retrospective analysis we evaluated the effect of DARA-based induction on ASCT parameters. Methods: The analysis included consecutive newly diagnosed MM patients that received ASCT between 2016 and 2020, as part of their upfront treatment regimen in our institution (Department of Clinical Therapeutics, Athens, Greece). Per institutional protocol, after 4-6 cycles of induction, pts received low dose cyclophosphamide (2.5 g/m2) followed by G-CSF (10 mcg/Kg/day) to mobilize and collect SCs. Plerixafor was administered on-demand in case of poor mobilization and insufficient first day collection. Large volume leukapheresis was performed in pts with low CD34+ counts in order to increase CD34+ yield. Pts received G-CSF 480 μcg once daily from day +4 after SC reinfusion to ANC >1500/mm3. All pts received antiviral and antifungal but no anti-bacterial prophylaxis. Results: 200 eligible pts were included in the analysis; 40 (20%) pts received DARA as part of PI-based upfront treatment and 160 (80%) pts received PI-based upfront treatment without DARA. Baseline demographics (age, gender, performance status) and disease characteristics (ISS and R-ISS stage, cytopenias, eGFR, lytic bone disease etc) were not different between the two groups. Response after induction was also similar (CR+VGPR rate was 93% vs 95% for non-DARA and DARA-containing regimens respectively). Use of DARA at induction was associated with lower total mean number of collected CD 34+ SCs (10.48 x 10^6/kg vs 16.58 x 10^6/kg, p1 day of SC collection (37.5% vs 6.3%, P 500/mm3, p 25x10^9/mm3, p Conclusion: DARA-containing induction before ASCT is associated with poorer mobilization and frequent need for use of plerixafor. However, similar percentage of patients can move to at least a single ASCT. The use of DARA-containing induction was also associated with slightly increased risk of infectious complications, antibiotics use and blood product transfusions but no increase in the risk of D100 mortality. These data point to the need for certain modifications to ASCT protocol for patients treated with DARA-containing regimens at induction, such as preemptive use of plerixafor, and perhaps prophylactic antibiotics. Disclosures Terpos: Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Gavriatopoulou: Takeda: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BeiGene: Honoraria. Kastritis: Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding.

Patients with lymphoproliferative disorders are at high risk for severe COVID-19. For patients with AL amyloidosis, in which there is also critical organ involvement, this risk may be even higher. Vaccination against SARS-CoV-2 is the best strategy to avoid severe COVID-19, but response to vaccines may be compromised in patients with B-cell lymphoproliferative or plasma cell malignancies, as in AL amyloidosis. Although modest in size, the plasma cell clone in AL may cause immunosuppression while anticlonal therapies further compromise immune responses. To evaluate immunization efficacy, we measured the titers of neutralizing antibodies (NAbs) against SARS-CoV-2 after vaccination with BNT162b2 in patients with AL amyloidosis. As a control group we used volunteers, matched (ratio 1:2) for age and gender, who had no autoimmune or active malignant or infectious disease. Serum was separated within 4 hours from blood collection and stored at -80°C until the day of measurement on (A) day 1 (D1; before the first dose of BNT162b2) (B) day 22 (D22; before the 2nd dose) and (C) day 50 (D50; ie 30 days after the 2nd dose). NAbs against SARS-CoV-2 were measured using FDA approved methodology (cPass™ SARS-CoV-2 NAbs Detection Kit; GenScript, Piscataway, NJ, USA). According to the manufacturer of the assay, a titer ≥ 50% is considered a clinically relevant threshold for viral inhibition. The study included 144 patients with AL amyloidosis, of which 120 had NAbs titers assessed on all time points and were included in the final analysis (53% males; median age: 66, IQR: 57-72 years) and 240 matched controls (53% males; median age: 66, IQR: 57-72 years). 66 (55%) AL patients were on active therapy, 17.5% were on daratumumab (DARA)-based therapy, 52 (43%) had discontinued therapy >3 months from the date of the first shot, 19% had prior exposure to DARA and 94 (78%) were in hematologic remission (CR or VGPR). Prior to the 1st dose (D1), NAb titers were similar between patients and controls (median 14.9% (IQR 7.8-23.1%) vs 14% (IQR 6.8-22.9%), p=0.439); 6 AL patients had baseline NAbs >50%, of which 5 reported a history of COVID-19 infection. On D22, there was a significant increase of NAbs titers both in controls and AL patients (both p On D50, there was further increase in NAbs titers both in controls and AL patients (both p Among AL patients, factors associated with NAb titers on D50 included age (p Generalized linear models were used for evaluation of multiple factors associated with D50 NAb titers: at least 3 months since the last dose of anticlonal therapy (p3 months of treatment-free interval (HR:7.75, p In conclusion, patients with AL amyloidosis have an attenuated response to vaccination with BNT162b2 especially among those on active therapy or with less than 3 months since the last dose of treatment. For such patients, an anamnestic dosing strategy could be considered, especially after completion of anticlonal therapy. Figure 1 Figure 1. Disclosures Kastritis: Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Terpos: Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Gavriatopoulou: Sanofi: Honoraria; GSK: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BeiGene: Honoraria.

In 2014, the IMWG updated the diagnostic criteria for symptomatic myeloma and in addition to classical "CRAB", implemented "biomarkers of malignancy" (BoM) (FLC ratio>100, more than 1 focal lesion in MRI and bone marrow infiltration of at least 60%). As a result, a subset of patients previously considered as having "smoldering myeloma" were characterized as symptomatic and were eligible to start therapy; these criteria are also adopted in clinical trials. However, the impact of the 2014 IMWG criteria in the overall clinical presentation of symptomatic myeloma patients who start therapy or in the outcomes of patients who present only with biomarkers of malignancy, has not been fully appreciated. We evaluated the characteristics and outcomes of patients who started therapy in the past 5 years, when the 2014 IMWG criteria were implement in our clinical practice and compare their characteristics and outcomes with those of patients that started in an earlier period. To adjust for advances in diagnosis and especially imaging, the analysis included 1007 consecutive patients who started therapy in the Department of Clinical Therapeutics between 1/1/2010 and 31/12/2020. Our prospectively maintained database includes all consecutive patients who start therapy for myeloma. The patients were divided in two cohorts: those that started therapy after 1/1/2015 (after 2014 IMWG criteria implementation) and those that started therapy between 1/1/2010 and 31/12/2014. In these two chronological periods, methods for the assessment of disease were similar except for wider use of ldWBCT after 2013 and more frequent use of conventional CT before 2013. In the 2010-2014 period, 393 patients started therapy vs 614 that started between 2015-2020. Patients in the two groups had similar age (mean 67 vs 66.3, p=0.399) and similar b2-microglobulin levels (7.39 vs 7.33 mg/L, p=0.907) but hemoglobin (mean 10.2 vs 10.6 gr/dl, p=0.016), platelet counts (mean 230 vs 246 x10 9/L, p=0.021), serum albumin (3.6 vs 3.8 gr/dl, p=0.003) were higher in the 2015-2020 era. Although it did not reach statistical significance, mean bone marrow infiltration in trephine biopsy (60.5% vs 57.3%, p=0.056) and eGFR (mean 66.6 vs 62.3 ml/min/ 1.73 m2, p=0.057) were higher and mean serum calcium levels lower (9.9 vs 10.2 mg/dl, p=0.073) in 2015-2020 group, while, serum LDH >ULN (19.6% vs 21.4%, p=0.513) and high risk cytogenetics (20.4% vs 20.8%) were found in similar rates. Accordingly, ISS and R-ISS stage distribution was similar (p=0.496). Per CRAB criteria, hemoglobin < 10 gr/dl was present in 48.9% of patients in the 2010-14 period vs 43.6% in the 2015-2020 (p=0.1), hypercalcemia in 18.2% vs 15% (p=0.185), serum creatinine ≥2 mg/dl in 22% vs 18% (p=0.124) and lytic bone disease in 76.9% vs 76.8%, p=0.973). At least one CRAB was present in 96.4% vs 94% of patients in the two periods (p=0.603). Even in the era before the publication of the 2014 IMWG criteria, 3.6% of patients that started therapy did not fulfill the CRAB criteria of that time; in retrospect, most had at least one BoM present. In the 2015-2020 period, 6% of new patients were considered as symptomatic based on the presence of BoM only. The median follow-up of the 2010-2014 cohort is 63 months and is 25 months for the 2015-2020 group; the 1- and 2-year OS is 83% vs 90% and 75% vs 79% respectively (p=0.057) for the two groups; early mortality (within 3 months from start of therapy) was 7.4% vs 3.9% (p=0.016) respectively. The OS of patients starting therapy based on the presence of BoM only is not reached (3-year OS 87%) vs 59 months (3 year OS: 65%) for patients presenting with CRAB (p=0.051). Because there may be a lead time bias, we also compare the OS of patients with biomarkers of malignancy only vs those with CRAB and ISS-1 disease: OS was similar although with a trend towards better OS for those with BoM. In conclusion, the implementation of the 2014 IMWG diagnostic criteria has resulted in about 6% of newly diagnosed patients starting therapy based only on the presence of BoM. Although the implementation of the criteria has resulted in slightly better clinical presentation (less severe CRAB) and reduced early mortality, most patients still present with disease complications. These data point to the need to develop tools that can identify myeloma patients earlier during their disease course, before they develop devastating complications, in order to further improve their outcomes and quality of life. Disclosures Kastritis: Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Genesis Pharma: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Gavriatopoulou: Karyopharm: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Genesis: Honoraria; GSK: Honoraria; Amgen: Honoraria. Terpos: Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos: Takeda: Honoraria; BMS: Honoraria; Amgen: Honoraria; Beigene: Honoraria; Janssen: Honoraria.

Introduction Despite the availability of novel agents in treating multiple myeloma (MM), renal impairment (RI) remains a poor prognostic factor, and the median survival of patients (pts) with MM and RI is approximately half of that for MM pts with normal renal function. RI can affect up to 50% of pts with MM at presentation, highlighting the need for effective treatment options for this patient population. Daratumumab, an IgG1 κ human monoclonal antibody that targets CD38, has shown efficacy and a favorable safety profile in pts with relapsed or refractory MM (RRMM). The DARE study assessed the safety and efficacy of daratumumab with dexamethasone in pts with RRMM and severe RI or requiring hemodialysis. Methods DARE is a prospective, open-label, phase 2 study, conducted in eight sites in Greece and Italy. Eligible pts were adults with documented RRMM and severe RI (estimated glomerular filtration rate [eGFR] Results The study has completed accrual and 38 pts were enrolled. The pts' median (range) age was 72 (40-89) years, and most pts were male (29, 76.3%). At baseline, 37 (97.4%) pts had ECOG PS ≤1 and 34 (89.5%) were at International Staging System (ISS) stage III. By revised ISS, 20 (52.6%) and 16 (42.1%) pts were at stages II and III, respectively. Pts had a median (range) of 3 (2-6) prior systemic therapies; thirteen (34.2%) pts had undergone prior autologous stem cell transplantation. The median eGFR at baseline was 13.0 mL/min/1.73m 2 and seventeen (44.7%) pts were on dialysis at the time of enrollment. The median (range) number of cycles given was 8.0 (1.0-38.0), and the median (range) follow-up was 11.3 ( Overall, 19 (50.0%) pts had ≥1 grade 3/4 adverse event (AE), and 10 (26.3%) had ≥1 serious AE (SAE). The most common grade 3/4 AEs were anemia (6 pts, 15.8%), hyperglycemia (5 pts, 13.2%), and hypercalcemia (3 pts, 7.9%). The most common SAE was septic shock (3 pts, 7.9%). Conclusions The administration of daratumumab with dexamethasone in pts with RRMM and severe RI or requiring hemodialysis is safe and effective therapy associated with a median PFS of approximately 12 months; hematologic responses were rapid and observed within one month from treatment initiation and approximately one-fifth of pts achieved a major renal response. Almost half of the pts were on dialysis and the combination was active and safe also for those on dialysis. No new safety signals were observed with daratumumab in pts with RRMM and severe RI or in need of dialysis. Figure 1 Figure 1. Disclosures Kastritis: Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Terpos: Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Janssen-Cilag: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Symeonidis: Demo: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; WinMedica: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GenesisPharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Research Funding; Sanofi/Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Delimpasi: Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Cavo: Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Novartis: Honoraria. Zamagni: Janssen: Honoraria; Bristol-Myers-Squibb: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. Kyrtsonis: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/Genesis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees. Hatjiharissi: Gilead: Honoraria; Genesis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leonidakis: Health Data Specialists: Current Employment. Manousou: Health Data Specialists: Current Employment. Gavriatopoulou: Sanofi: Honoraria; Genesis: Honoraria; Amgen: Honoraria; Janssen: Honoraria; GSK: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria. Dimopoulos: Amgen: Honoraria; Beigene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Takeda: Honoraria.

Introduction: Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with multiple myeloma (MM), especially under treatment. Herein, we evaluated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in non-vaccinated MM patients who were diagnosed with COVID-19 compared to MM patients after full vaccination with the mRNA BNT162b2 vaccine. Methods: The analysis was performed in the context of an ongoing large prospective study (NCT04743388) evaluating the kinetics of anti-SARS-CoV-2 antibodies after COVID-19 vaccination. We evaluated MM patients diagnosed with COVID-19, confirmed by PCR, matched for age, gender, line of treatment, type of myeloma, type of treatment and response with vaccinated MM patients during the same time period (January - May 2021). Major exclusion criteria for both COVID-19 and vaccine MM groups included the presence of: (i) autoimmune disorder under immunosuppressive therapy or other active cancer; (ii) active HIV, hepatitis B and C infection, and (iii) end-stage renal disease . Serum was collected at 4 th week post confirmed diagnosis for the COVID-19 MM group and at 4 th week post the second BNT162b2 dose for the vaccine MM group. NAbs against SARS-CoV-2 were measured using an FDA approved methodology (cPass™ SARS-CoV-2 NAbs Detection Kit, GenScript, Piscataway, NJ, USA). Results: We evaluated 35 patients with MM and COVID-19 (6 had smoldering MM and 29 symptomatic MM), along with 35 matched MM patients who received the BNT162b2 vaccine. Among COVID-19 MM patients, 13 were diagnosed with mild, 12 with moderate and 10 with severe disease; 22/35 patients were hospitalized and 10/35 were intubated. Seven (20%) patients died due to COVID-19. During the disease course 21 patients (60%) were treated with dexamethasone. Type of treatment was not different between COVID-19 positive and vaccinated MM patients. Between the two patient groups, there was no difference in terms of age [median (IQR) 65 (59) for COVID-19 positive versus 66 (74) for COVID-19 vaccinated, respectively, p=0.76], gender [males: 19/35 (54.3%) versus 16/35 (45.7%), respectively, p=0.47), BMI (median 27 versus 26kg/m 2, respectively, p=0.56), asymptomatic disease [6/35 (18.2%) in both groups, p=1], prior lines of treatment [range: 1 to 7 versus 1 to 6, respectively, p=0.99], and type of treatment (p=0.87). Among the COVID-19 MM patients, 6 (20.7%) were in sCR/CR, 6 (20.7%) in VGPR, 12 (41.4%) patients in PR, 2 (6.9%) in MR/SD and one (3.5%) in PD at the time of confirmed infection. Among the vaccinated MM group, 10 (34.5%) patientswere in sCR/CR, 4 (13.8%) in VGPR, 11 (37.9%) in PR, one (3.5%) in MR/SD and one (3.5%) in PD at the time of vaccination (p-value=0.93 for the comparison between COVID-19 and vaccinated MM groups). No differences between COVID-19 and vaccinated MM patients were also noted regarding the median lymphocyte count (1200/μl versus 1400/μl, respectively, p=0.08) and the median immunoglobulin values (IgG 732 mg/dl versus 747 mg/dl, respectively, p=0.29; IgA 9 mg/dl versus 61 mg/dl, respectively, p=0.7; IgM 26 mg/dl versus 25 mg/dl, p=0.97). The incidence of comorbidities was also similar between the two groups (cardiovascular diseases 55.2% versus 44.8%, respectively, p=0.47; diabetes mellitus 66.7% versus 33.3%, p=0.28; chronic pulmonary disease 50% each, p=1.0). Interestingly, patients with MM and COVID-19 showed a superior humoral response compared with vaccinated MM patients. The median (IQR) NAb titers were 87.6% (IQR: 71.6-94) and 58.7% (21.4-91.8) for COVID-19 and for vaccinated MM patients, respectively (p=0.01). In both groups, 27 out of 35 patients were receiving active treatment for MM at the time of NAb evaluation. The median NAb titer was 88% (IQR 71.6%-96.3%) for COVID-19 MM patients and 35.4% (IQR 17.5%-85.5%) for vaccinated MM patients who received anti-myeloma therapy (p=0.001). Importantly, there was no difference in NAb production between COVID-19 and vaccinated MM patients who did not receive any treatment (median NAb titers, 85.1% versus 91.7%, p=0.14). Conclusion: Patients with MM and COVID-19 present a superior NAb response against SARS-CoV-2 compared with fully vaccinated patients with the BNT162b2 vaccine. This finding was more pronounced among patients receiving active treatment for MM. In this context, additional booster doses may be considered for MM patients with poor humoral response after the BNT162b2 vaccine. Figure 1 Figure 1. Disclosures Gavriatopoulou: Genesis: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Amgen: Honoraria. Terpos: BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Novartis: Honoraria; Genesis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BeiGene: Honoraria.

Background Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies, especially under immunosuppressive therapy. Herein, we evaluated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with plasma cell neoplasms after vaccination with either the mRNA BNT162b2 or viral vector AZD1222 vaccine. Methods Serum of both patients and controls was collected on day 1 (D1; before the first BNT162b2 or AZD1222 dose), on day 22 (D22; before the second dose of the BNT162b2 or 3 weeks post the first AZD1222 dose) and on day 50 (D50; 4 weeks post second dose of the BNT162b2 or 7 weeks post the first AZD1222 dose). NAbs against SARS-CoV-2 were measured using FDA approved-ELISA methodology. Results Patients with MM (n=213), SMM (n=38) and MGUS (n=25) and 226 healthy controls, of similar age and gender, were enrolled in the study (NCT04743388). Two hundred and fifteen patients (77.9%) were vaccinated with the BNT162b2 and 61 (22.1%) with the AZD1222 vaccine. Vaccination with either two doses of the BNT162b2 or one dose of the AZD1222 vaccine leads to lower production of NAbs against SARS-CoV-2 in patients compared with controls both on day 22 and on day 50 (P

Introduction: Renal impairment (RI) is common in multiple myeloma (MM), with up to 40% of the patients (pts) experiencing this complication during the course of their disease. RI increases risk of early death and affects disease management in multiple ways, as it may complicate treatment options and dosing, and render pts more susceptible to infections and prolonged hospitalizations. Therefore, there is an urgent need to restore renal function in these pts in order to improve their quality of life and prognosis. Bortezomib-based therapies are the most commonly used in pts with RI, but eventually pts may become refractory to bortezomib and other drug classes such as IMIDs. Thus, new therapeutic options are needed in order to manage pts with MM and RI who fail these drugs. Daratumumab, an IgG1κ human monoclonal antibody that targets CD38, has shown durable responses and a favorable safety profile in heavily pretreated pts with relapsed/refractory MM (RRMM) as monotherapy. Pharmacokinetic analyses suggest that there are no clinically important differences in exposure to daratumumab in pts with normal or impaired renal function, but the available data on safety and efficacy of pts with RRMM and severe RI is scarce. Methods: DARE is a prospective, open-label, multicenter, phase 2 study, which completed the enrolment of 38 adult pts with documented RRMM and severe RI, defined as either eGFR Results: The current analysis includes 35 pts, enrolled in 7 Sites. Median age was 72 years, and 77.1% were male. The median time from diagnosis to first daratumumab dose was 4.2 years. Pts had a median of 3 prior systemic therapies, and 37.1% had a prior autologous stem cell transplantation. At study initiation 8.6% and 91.4% of pts had international staging system (ISS) 2 and 3 disease, respectively, while 51.4% and 48.6% were revised ISS 2 and 3. The median eGFR at baseline was 13 mL/min/1.73 m2.and 17 pts (48.6%) were on dialysis. The median number of cycles administered until the cut-off date was 5 and the median follow-up duration was 5.5 months. The 6-month progression-free survival rate, was 50% (figure). Overall, ORR was 45.7%, with 31.4% of all pts achieving a VGPR and 14.3% a PR. For pts on dialysis (n=17), ORR was 35.3%, equally divided between pts achieving VGPR and PR (17.6%). The median time from the first dose of study treatment until the first response (≥PR) was 0.9 months. RRR was 17.1%. By the cut-off date, 37.1% of the pts were still receiving protocol therapy, 17.1% discontinued treatment due to death, and 31.4% due to disease progression. Overall, 17 pts (48.6%) had at least 1 adverse event (AE) of grade 3 or 4, most frequent being anemia (17.1%) and hyperglycemia (8.6%). Nine (25.7%) pts had at least 1 SAE: Septic shock (fatal, 2 pts), and performance status decreased (fatal), lower respiratory tract infection (fatal), myocardial infarction (fatal), peritonitis (fatal, in a patient receiving peritoneal dialysis), cerebrovascular accident, pneumonia, acute kidney injury, and hyperkalemia (1 pt each). Conclusions: The administration of daratumumab with dexamethasone led to rapid hematologic responses in pts with RRMM and severe RI, including those in dialysis, and at the same time it resulted in a major renal response for 17.1% of the pts. Importantly, new safety signals were not observed, and daratumumab can be safely administered in pts with severe RI or those on dialysis. Figure 1 Disclosures Kastritis: Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Terpos:Celgene: Honoraria; Takeda: Honoraria, Other: travel expenses , Research Funding; Janssen: Honoraria, Research Funding; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; BMS: Honoraria. Symeonidis:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; WinMedica: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Delimpasi:Genesis: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Zamagni:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Katodritou:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genesis Pharma: Honoraria, Other: Expenses, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Theagenion Cancer Hospital: Current Employment; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Other: Expenses, Research Funding. Rivolti:Celgene: Membership on an entity's Board of Directors or advisory committees. Kyrtsonis:Genesis pharma SA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gavriatopoulou:Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Hatjiharissi:Abbvie: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Genesis pharma SA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees.

Gaucher disease (GD) is one of the most frequent lysosomal storage diseases, and it is caused by mutations in the glucocerebrosidase (GBA) gene that are inherited in an autosomal recessive pattern....

INTRODUCTION The survival of myeloma patients has doubled the past decade, however, patients refractory to both proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) still have poor prognosis. Immunotherapy with monoclonal antibodies targeting cell-surface antigens is a promising treatment strategy with different mechanisms of action and has been integrated both in the newly diagnosed and relapsed/refractory setting. The combination of daratumumab, pomalidomide and dexamethasone (DaraPomDex) has demonstrated significant activity even in patients refractory to both drugs and a potential mechanism may be re-sensitization to pomalidomide. Another report showed that daratumumab-refractory patients who previously failed IMiD, responded when the IMiD was added to daratumumab. This provided a proof of principle that anti-CD38 antibodies can alter the underlying pathophysiology, and can potentially overcome refractoriness to IMIDs. Increased CD38 expression after IMiD exposure could be a mechanism of IMiD resistance, and anti-CD38 agents may act by eliminating this effect. Daratumumab induces clonal CD8+ T-cell expansion that may contribute to clinical responses, which is augmented by IMiDs, resulting in synergy.Potential loss of this response in progressing patients may be recaptured after the reintroduction of IMiDs. Another potential mechanism could involve the reemergence of IMiD-sensitive clones after an IMiD-free period. There is data that daratumumab alters the tumor immune microenvironment, and this effect may be long lasting , even after daratumumab discontinuation . The aim of the study was to evaluate the efficacy of re-treatment with IMiD-based therapy in patients refractory both to IMiDs and anti-CD38 antibodies. PATIENTS AND METHODS The study included 38 patients who were refractory to antiCD-38-based therapy and to at least one IMiD. Overall, 26 (68%) patients had received lenalidomide, 11 (29%) pomalidomide and 1 (3%) thalidomide before anti-CD38 treatment. RESULTS Median number of prior lines before IMiD retreatment was 4 (range 2 to 13). The patient distribution per R-ISS was: R-ISS 1: 8, R-ISS 2: 9, R-ISS 3: 4. Overall, 4 (11%) patients received lenalidomide-, 33 (86.5%) pomalidomide-, and 1 (2.5%) thalidomide-based regimens post anti-CD38. The majority of patients were treated with pomalidomide-cyclophosphamide-dexamethasone (PCD) (n=13) and pomalidomide-dexamethasone (PomD) (n=11). The remaining 14 patients were treated with other IMiD-based triplets. Importantly, 10 (26%) patients received the same IMiD as prior to anti-CD38 exposure (lenalidomide n=2, pomalidomide n=8). Median time from diagnosis to IMiD re-treatment was 61.5 months. Overall, 20 patients (53%) achieved a response during IMiD retreatment, including CR=1, VGPR=5, PR=10 and MR=4; 11 patients achieved SD, whereas 7 patients progressed. The disease control rate (DCR=SD+PR+VGPR+CR) was 82%. Among the patients re-exposed to the same IMiD, 5 responded, 3 progressed and 2 remained stable. Among the responders, 1 achieved VGPR with PCD, 2 PR with PCD and DaraPomDex, whereas 2 showed MR with PCD and PCD with Bortezomib. 79% (22/28) of the patients received pomalidomide following previous exposure to lenalidomide; among them, 15/22 (68%) patients responded (1 CR, 4 VGPR, 8 PR, 2 MR), 3 remained stable and 4 progressed. Interestingly, 10 out of 13 (77%) patients who received PCD responded. Median PFS for all patients was 4 months (range 2.9-4.8). Median time to next treatment (TtNT) for the whole study cohort as well as for those who received the same IMiD pre- and post-exposure to anti-CD38 was 4.2 months as well. Median duration of response (DoR) for the responders was 7 months. Median TtNT for those who received pomalidomide after previous exposure to lenalidomide (n=22) was 3.9 months; median DoR among the responders was 6.6 months. Median OS 5.3 range 0.5-35.5. CONCLUSION IMiD retreatment in patients refractory to both an IMiD and an anti-CD38 antibody can induce significant response rates, even among patients re-exposed to the same IMiD. This indicates that after anti-CD38 therapy a long lasting, probably immunomodulatory effect may be associated with some degree of re-sensitization to IMiDs. The subgroup of patients receiving PCD derived the most benefit. In this context, a prospective study evaluating the role of PCD in this population is currently ongoing. Disclosures Gavriatopoulou: Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Terpos:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Sanofi: Honoraria; BMS: Honoraria. Kastritis:Takeda: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Pfizer: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel/accommodations/expenses, Research Funding; Genesis Pharma: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Amgen: Consultancy, Honoraria, Research Funding. Dimopoulos:Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria.

Introduction: Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) is the circulating form of a glycosyl-phosphatidylinositol-anchored three-domain membrane protein. suPAR is expressed on a variety of cells, including immunologically active cells, endothelial cells, and renal podocytes. Both the circulating and membrane-bound forms are directly involved in the regulation of cell adhesion and migration through binding of integrins. Elevated suPAR levels have been associated with poor outcomes in various conditions. suPAR has been implicated in the pathogenesis of kidney disease, specifically Focal Segmental Glomerulosclerosis and Diabetic Nephropathy, through interference with podocyte migration and apoptosis. Elevated plasma suPAR levels were associated with incident Chronic Kidney Disease (CKD) and a more rapid decline in the eGFR in persons with normal kidney function at baseline, and with acute kidney injury in various clinical and experimental contexts. suPAR was a strong and independent predictor of mortality in patients with Chronic Heart Failure (CHF), in a recent study. In patients with AL amyloidosis renal involvement is very common and is associated with a high risk of progression to End Stage Renal Disease (ESRD). Evaluation of renal response is challenging and prognostication is based mainly in serum creatinine and proteinuria; limited data exist about new renal biomarkers. Thus, we evaluated suPAR, as a potential new biomarker for renal outcomes in patients with AL amyloidosis treated with contemporary therapies. Methods: we measured serum suPAR levels in 136 patients with AL amyloidosis, before start of therapy and at 6 months in 98 of them. Serum suPAR levels were determined using a standard commercial enzyme-linked immunosorbent assay (suPARnostic Standard kit; ViroGates A/S, Birkerød, Denmark). Results: The median age was 65, 56% were males, 72% had renal, 71% heart, and 17% liver involvement; Mayo stage disposition was 15%, 56% and 29% and renal stage disposition 39%, 44% and 17%, respectively; 82% received bortezomib-based therapy. Median baseline suPAR levels were 6.6 ng/mL (range 2.7-29.0 ng/mL), which is significantly higher than in other studies in non-amyloidosis patients with CKD or CAD/CHF (median 3.04-3.7 ng/ml). We observed a weak negative correlation of suPAR levels with eGFR, but there was no correlation with proteinuria or serum albumin levels in patients with AL amyloidosis and was not associated with renal stage (as defined by eGFR5 gr/d). suPAR levels were higher in patients with heart involvement and were associated with NT-proBNP (p=0.003), hs-TnT (p Baseline suPAR levels were associated with higher probability of eGFR decline (p=0.008) and with renal progression per consensus criteria (p=0.02), at 6 months. Furthermore, suPAR levels at 6 months were strongly associated with the probability of progression to dialysis (2% vs 20% at 2 years and 2% vs 38% at 4 years, p Conclusion: in patients with AL amyloidosis suPAR levels are prognostic of renal outcomes, especially with progression to ESRD requiring dialysis. Most importantly, suPAR levels and their changes were independently associated with renal progression and progression to dialysis either when measured before start of therapy or at 6 months, independent of baseline renal stage, renal progression by the Palladini criteria and even of the quality of hematologic response. Further evaluation in larger cohorts is required to evaluate suPAR as a biomarker for renal outcomes in AL amyloidosis. Figure 1 Disclosures Kastritis: Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Gavriatopoulou:Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:Sanofi: Honoraria; Janssen: Honoraria, Research Funding; Genesis Pharma SA: Honoraria, Other, Research Funding; Celgene: Honoraria; BMS: Honoraria; Takeda: Honoraria, Other, Research Funding; Amgen: Honoraria, Research Funding. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees.

Introduction: An increased inherited risk for the development of plasma cell dyscrasias (PCDs) has long been suspected, however to date, only a limited number of potential genomic risk loci have been described. To characterize the inherited risk and facilitate identification of additional risk loci it is important to combine detailed pedigrees with extensive genetic analysis. To identify familial PCDs we initiated a prospective study with active recruitment of a large cohort of patients with PCDs and active screening of their relatives combined with tissue banking and subsequent genetic analysis. Methods: All patients in the Department of Clinical Therapeutics diagnosed with PCDs between January 2017 and January 2019, were offered enrollment in the study. Following informed consent, 1st and 2nd degree relatives over the age of 30 were eligible for screening. A detailed family pedigree was created for each index case with special focus on family history of PCDs, B-cell lymphomas, or other hematologic or solid malignancies. As a control, subjects' spouses were also screened. Screening included serum protein electrophoresis with immunofixation. In families where an additional member was identified with a PCD or B-cell malignancy, peripheral blood was collected from consenting family members over the age of 18 for further genetic analysis. Samples from affected individuals were profiled using whole genome sequencing (WGS) and unaffected individuals were genotyped using Axiom Arrays. Data were analyzed using Axion Array Suite and plink and GATK toolkit with BWA. Results: Of 1,084 patients screened for participation in the study; 752 had multiple myeloma (MM), 77 had smoldering MM, 81 a monoclonal gammopathy of undetermined significance, 93 Waldenström's Macroglobulinemia and 81 had AL amyloidosis. 176 (16.2%) patients refused to participate in the study, while 44 (4.1%) patients were ineligible for further screening due to the absence of a living first- or second-degree relative. The median number of screened first or second-degree relatives per index patient was 3 (range 1 to 10). The median age of index cases was 65 years, offspring was 37 years, second-degree relatives was 65 years, and spouses was 65 years. The incidence of a PCD among second-degree relatives was 4.5%, while it was 0.6% among offspring. As a control group, the incidence of PCDs among spouses was 2.6%. Overall at least one additional member (beyond the index patient) with a monoclonal gammopathy was detected in 98 families (11.3%). In 57 families (6.6%) there was a positive history of at least one additional first- or second-degree relative with a PCD or B-cell malignancy. In addition, 41 new cases of monoclonal gammopathy (4.7%) were identified through the screening process associated with this study. To identify genetic loci that could be associated with a predisposition to development of PCDs, genetic analysis was performed on the most heavily affected 18 families, those with at least three affected members or with early onset disease (i.e. PCD diagnosed before age 50). We have evaluated 838,750 SNPs from 103 samples from 18 families. 30 samples were from affected members and 73 from unaffected members. We found eight SNPs (rs13233413, rs11648113, rs59444635, rs148480125, rs113556240, rs11547122, rs671880, rs4726610) that are significantly enriched in affected members with a p-value below the suggestive cut-off of Conclusions: Our active prospective screening approach to identify familial predisposition to PCDs revealed that 11.3% of patients had families with at least one additional affected member and some families had a substantially higher incidence of PCDs with earlier onset. Study of these high-risk families have identified genomewide association markers which in future may help us define familial predisposition to plasma cell dyscrasias. Disclosures Gavriatopoulou: Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:Amgen: Honoraria, Research Funding; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Sanofi: Honoraria; BMS: Honoraria. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria. Munshi:Janssen: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Consultancy; Legend: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; C4: Current equity holder in private company; Adaptive: Consultancy. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau.

Introduction: Treatment options for patients with myeloma (MM) expand but development of refractoriness to major drug classes is inevitable in most patients. Management of disease refractory to proteasome inhibitors, IMiDs and antiCD38 monoclonal antibodies is challenging; but there is data to support that some drug combinations provide benefit even when there is resistance to individual drugs. This has been observed with anti-CD38-IMiD combinations and we have previously reported data in patients who have responded to the daratumumab-IMiD combination post refractoriness to both drug classes. These results may be related to the mechanisms of action of daratumumab, it acts both directly and through antibody mediated cytotoxicity, phagocytosis and immune modulation and of IMiDs which also enhance natural killer cell cytotoxicity and modify the immune microenvironment. Other mechanisms may also be involved but we need more clinical and biological data to understand this phenomenon. We present our experience with consecutive patients who were refractory to IMiD combinations and single agent daratumumab, who were retreated with the IMiD and daratumumab, following development of resistance to daratumumab. Methods: A total of 27 consecutive patients who were refractory to an IMiD (lenalidomide or pomalidomide) and progressed on single agent daratumumab, were enrolled. The more recent IMiD to which the patients were refractory prior to daratumumab treatment was added to daratumumab, without any intensification of either schedule (RESET). All patients were treated in the Department of Clinical Therapeutics, in Athens. Results: The median age was 74 years (range 52-86) and 70% were male. The median number of treatment lines prior to RESET was 4 (range 1-16). Eleven patients (41%) had undergone ASCT/HDM. All patients had previously received bortezomib and 60% were refractory, 37% (n=9) were carfilzomib-exposed and 30% refractory, 30% (n=8) were Ixazomib-exposed and 26% refractory; 82% had alkylating agent exposure and 52% were refractory. All patients had prior exposure and 93% of them were refractory to lenalidomide, while 52% (n=14) were pomalidomide-exposed and 48% refractory. The regimen prior to daratumumab monotherapy was IMiD-based in 48% (n=13), PI-based in 26% (n=7), both IMiD & PI containing in 18.5% (n=5), and other in 7% (n=2). At RESET, the IMiD added was lenalidomide in 48% (n=13) and pomalidomide in 52% (n=14). Median time from diagnosis to RESET was 72 months (25.6-135.3). The median time from the last IMiD dose to RESET was 13.2 months (2.13-41.3). The median duration of daratumumab monotherapy prior to RESET was 7.57 months (range 1.61 to 38.2) and the best response achieved was VGPR in 41% , PR in 33.3% a PR and 25.8% had stable disease, prior to progression. Median duration of treatment in RESET was 5.3 months (0.46 to 22.33) and best response distribution was VGPR in 7.4% (n=2), PR in 33.3% (n=9), for an ORR of 41% (n=11). Currently, 9 (33%) patients still receive treatment at RESET and 18 (67%) have progressed. Median PFS in RESET was 8.9 months (95% CI 4-13.7) and the median OS from start of RESET was 20 months (95% CI 6.4-33.6). Both PFS and response to RESET were independent of the type of IMiD added, whether IMiD at most recent line or added at RESET was administered at full or reduced dose, and the dose of dexamethasone at last regimen, Prior response to daratumumab monotherapy or to the most recent IMiD-based regimen and the median number of prior treatment lines also did not affect PFS or response at RESET. Following progression at RESET, 11 patients have received further therapy; the median number of treatment lines post RESET was 2 (1-5). Two patients responded to the subsequent therapy (at least PR). Conclusion: The combination of daratumumab with an IMiD can partly overcome resistance to both agents, even without intensification of either schedule. Importantly, this combination was associated with a 40% ORR and a PFS of 8.9 months, which is quite promising given the advanced refractoriness of these patients to individual treatments. These data also indicate the potential of an anti-CD38 backbone as part of a treatment strategy that extends over multiple lines of therapy, which should be explored in larger prospective trials. Our group is now investigating the impact of individual drugs and their combination to further understand the modulation in the immune environment. Disclosures Gavriatopoulou: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria. Terpos:Celgene: Honoraria; Medison: Honoraria; Janssen: Honoraria, Other: travel expenses , Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Amgen: Honoraria, Research Funding; Genesis: Honoraria, Other: travel expenses , Research Funding. Dimopoulos:Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Honoraria.

A deep and profound hematologic response is associated with substantial improvement in the probability of improvement in organ function and survival in patients with AL amyloidosis or LCDD. Bortezomib-based therapy is the mainstay of anti-clonal therapy for AL amyloidosis and LCDD, however, hemCR is achieved in only 20% of patients. Daratumumab has shown to be active and able to induce rapid responses in patients with AL amyloidosis. Plasma cell clones in AL are small and indolent and further improvement of hematologic response could be achieved by consolidation strategies. Given the activity of daratumumab and the rapid induction of deep responses in AL amyloidosis, we treated patients with AL amyloidosis or LCDD , who had not achieved a hemCR after standard therapy, with a short course of daratumumab. In consenting patients, we evaluated MRD in the bone marrow (BM), before and after consolidation, by means of next generation multiparametric flow cytometry (NGF-MFC), using the Euroflow protocol. Thus, beyond the presence of MRD , we were able to evaluate also other components of the BM microenvironment and their changes before and after daratumumab. All patients were treated in the Department of Clinical Therapeutics, Athens, Greece. The study included patients who had achieved either PR or VGPR after completing standard bortezomib-based primary therapy. Consolidation included 4 weekly infusions of daratumumab 16 mg/kg. Pre-emptive therapy for IRR was given starting two days before the first infusion of daratumumab that included low dose steroids (equivalent of 16 mg of methylprednisolone), H1 & H2 inhibitors and montelukast. Twenty-five patients (20 with AL and 5 with LCDD) received daratumumab consolidation. Among patients with AL amyloidosis, median age is 65, kidneys and heart were involved in 70% and 75% respectively, baseline Mayo stage was 20%, 70% and 10% for stage 1,2 & 3 respectively. Baseline immunofixation in serum or urine was positive in all patients, median baseline dFLC at diagnosis was 125 mg/L (range 60-7228). Median time from start of first line therapy to daratumumab consolidation was 7 months and all patients had completed their planned therapy. At the time of initiation of daratumumab, 24 patients were in VGPR and one in PR and the median dFLC level was 12 mg/L; all had positive serum or urine immunofixation and in all patients MRD was detectable by NGF-MFC. Except for one patient, all the others received the planned 4 daratumumab infusion. Mild IRRs occurred in 3 patients (grade 1 in 2 and grade 2 in one patient); no IRRs occurred after the first infusion. One month after completion of consolidation with daratumumab, median dFLC dropped to 5 mg/L and 10 (40%) of the patients improved their response: 36% from VGPR to hemCR and one patient with PR to VGPR. Among those that achieved a hemCR, 5 (50%) became MRD negative by NGF-MFC. However, even among those that remained MRD-positive there was a decrease in the number of aberrant plasma cells (APCs) by a median of one log. In MRD-positive patients a change in the composition of the remaining phenotypic subclones of APCs was also observed. Regarding the other BM cell populations, we observed statistically significant changes in B-cell precursors (increased from 14.32%+/-11.75% to 34.76% +/-24.11%, p=0.0004), naïve B-cells (decreased from 65.58%+/-17.56% to 47.37%+/-22.66%, p=0.0003), T cells (increased from 6.44% +/- 2.78% to 10.86%+/- 6.407%, p=0.0007), CD27+ NK & NKT cells (increased from 15.65% +/-13.5% to 36.34%+/- 24.43%, p=0.0002), mast cells (increased from 0.0092%+/-0.0123% to 0.011%+/-0.012%, p=0.002) and erythroblasts (increased from 1.82%+/-0.97% to 2.41%+/- 1.03%, p=0.076). Due to the small numbers it was not possible to make meaningful comparison between MRD positive and negative patients. However, the above results indicate that even a short course of daratumumab was able to cause significant changes in the BM microenvironment of these patients. From this small prospective study we conclude that consolidation with a short course of daratumumab can improve the depth of response in patients with AL or LCDD that have not achieved a hemCR after primary therapy, even to the depth of undetected MRD. In addition, daratumumab causes significant changes in the BM environment, which need further investigation in order to understand their implications. Disclosures Kastritis: Genesis Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gavriatopoulou:Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:BMS: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Other: travel expenses , Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding; Sanofi: Honoraria. Dimopoulos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. OffLabel Disclosure: daratumumab for AL amyloidosis

Introduction: Carfilzomib is a second-generation irreversible proteasome inhibitor that has been shown to improve overall survival in patients with relapsed and/or refractory multiple myeloma (RRMM). Carfilzomib may exert cardiovascular adverse events (CVAEs), although related mechanisms, prognostic markers and precipitating factors have not been fully characterized. In the prospective randomized phase 3 CANDOR study, comparing daratumumab in combination with carfilzomib and dexamethasone (DaraKd) versus Kd alone, a lower rate of cardiac failure events was observed in the DaraKd arm. The aim of this study was to assess whether treatment with daratumumab may ameliorate carfilzomib-related cardiovascular toxicity. Patients and Methods: This is an ongoing, prospective, observational study on the effects of Kd with or without daratumumab on cardiac function of patients with RRMM. All patients attended an initial visit, which included recording of medical history and cardiotoxicity risk factors (age ≥65 years, obesity, smoking, hypertension, hypercholesterolemia, diabetes mellitus, previous anthracycline use, previous chest or mediastinum radiotherapy and current myocardial disease). At baseline, cardiac ultrasound was performed and images were acquired for standard echocardiographic analysis and for speckle tracking offline analysis. As in ENDEAVOR study, carfilzomib was administered at 20 mg/m2 on days 1 (C1D1) and 2 (C1D2) of cycle 1 and at 56 mg/m2 thereafter, with dexamethasone 40 mg on days 1, 8 & 15 of 28-day cycles (Kd regimen). In the DaraKd regimen, daratumumab was administered at a weekly dose of 16 mg/kg, iv, for cycles 1-2, every 2 weeks for cycles 3-6 and every 4 weeks thereafter, while Kd was given at the dose described previously. A follow-up cardiac ultrasound study, as described above, was performed on the last day of cycle 6 (C6D16) or earlier if carfilzomib interruption was indicated. Patients were followed for a median of 10 months for carfilzomib-related CVAEs [hypertension (HTN), heart failure (HF) and acute coronary syndrome (ACS)]. Results: In this preliminary report, we evaluated 25 patients with relapsed or refractory MM who received either DaraKd or Kd in the everyday clinical practice; 11 patients received DaraKd and 14 received Kd. Patients' mean (±SD) age was 67.8±7.6 years and 60% were men. The two treatment groups did not significantly differ in baseline characteristics including age, gender and prevalence of hypertension, hyperlipidemia, smoking, diabetes mellitus and cardiovascular disease (p>0.1 for all). In the DaraKd group, we did not observe any significant change of markers of left and right ventricular systolic function; however, these markers deteriorated in the Kd group. Specifically, in the Kd group, among left ventricular (LV) systolic function markers, average LV ejection fraction (LVEF) decreased from 59.6±4.8 to 56.6±5.4% (p=0.026) and LV global longitudinal strain (GLS) from -22.5±2.9 to -19.4±3.1 (p=0.007). Similarly, among right ventricular (RV) function markers, tricuspid annular plane systolic excursion (TAPSE) decreased from 23.8±3.6 to 20.4±2.8 mm (p=0.020) and RV free wall longitudinal strain from -31.9±3.4 to -28.2±4.3 (p=0.012). A significant group interaction (p Conclusion: The combination of daratumumab with Kd is associated with preserved post-treatment cardiac systolic function as compared to the Kd regimen in patients with RRMM, who had received 1-3 prior lines of therapy. This was associated with a lower CVAE rate, even in this small group of patients. The clinical significance and the mechanisms mediating this possible protective cardiovascular action of daratumumab merits further investigation, given the high activity of DaraKd in patients with relapsed or refractory MM. Disclosures Terpos: Amgen: Honoraria, Research Funding; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Sanofi: Honoraria; BMS: Honoraria. Stamatelopoulos:Amgen: Honoraria, Research Funding. Gavriatopoulou:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Dimopoulos:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Kastritis:Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding.

Renal disease in monoclonal gammopathies (MGs) is associated with several different pathologies with prognostic and treatment implications. In symptomatic MM, cast nephropathy is a leading cause of renal dysfunction and acute renal failure (ARF) but in patients with other MGs the diagnoses may be diverse and monoclonal gammopathy of renal significance (MGRS) is well described. Renal biopsy is required in such cases in order to establish the diagnosis, especially if selective Bence Jones proteinuria is absent. MGs are more frequent in the elderly, in which renal diseases are also common, associated with underlying co-morbidities (diabetes, hypertension etc). However, although common, there is limited data on the frequency of monoclonal immunoglobulin (MIg)-unrelated pathologies in patients with a known MG presenting with renal dysfunction. Thus, we evaluated the frequency of non-MIg related renal pathologies in patients with known MGs, in a series of consecutive patients from a single referral center (Department of Clinical Therapeutics, Athens , Greece). We reviewed our database and identified 79 patients with known MGs that had a renal biopsy for evaluation of renal dysfunction, and which was performed after the diagnosis of MG. We excluded patients in which renal biopsy was performed before the diagnosis of the MG. At the time of renal biopsy, median age was 69 years (range 39-84), 63% were males, 28% had diabetes, 72% hypertension, 22.5% CAD, 7% an autoimmune disease ; 45% had known symptomatic MM (N=36) and 55% a prior diagnosis of MGUS or SMM. Median eGFR was 33 ml/min/1.73 m2 (range 4-110), 15% required dialysis, median proteinuria was 3.1 gr/d and was >0.5 gr/d in 93%. Abnormal FLC ratio was present in 69.5%, median dFLC level was 85 mg/L and 62% had dFLC>50 mg/L. In urine protein electrophoresis (PEP), median albumin proportion was 40% (range 3-100%) and median urine monoclonal protein was 2% (range 0-97%) of the total urine protein. Reasons leading to renal biopsy included proteinuria (with Renal pathology revealed a MIg-related diagnosis in 68%, which included cast nephropathy in 13%, MIDD in 25%, AL amyloidosis in 25% and other MGRS in 5%. A non MIg-related diagnosis was established in 32%, and included diabetic nephropathy in 5%, hypertension-associated in 14%, single cases of IgA nephropathy, chinese herb nephropathy, obesity-related GN and in 8% was drug related. Among MM patients, 26/36 were on therapy when renal biopsy was performed, 19/36 (53%) were in hematologic remission. Notably, in 11/19 (58%) of MM patients in remission, renal pathology was not related to MIg vs 6/17 (35%) of those not in remission or at the time of MM diagnosis. Factors that were associated with MIg-related pathology included serum albumin 1.7 gr/d (82% vs 48%, p=0.004), a positive UIFE (75% vs 33%, p=0.039), urine monoclonal protein >100 mg/d (68% vs 25%, p=0.003), dFLC > 50 mg/L (76% vs 37%, p=0.003) and abnormal FLC ratio (78% vs 53%, p=0.044). The presence of other co-morbidities (diabetes, hypertension, history of CAD, history of autoimmune disease) or the presence of hematuria or the reason leading to renal biopsy (proteinuria or ARF) were not associated with a diagnosis of non MIg-related renal pathology. In multivariate analysis, only urine monoclonal protein >100 mg/d (HR:7.95, 95% CI 1.3-47, p=0.024) was independently associated with a diagnosis of MIg-related pathology. If parameters of urine PEP (urine monoclonal protein, urine IFE) were not included in the analysis, then total proteinuria >1.7 gr/d (HR: 4.5, 95% CI 1.1-18, p=0.036) and dFLC>50 mg/L (HR:5.8, 95% CI 1.15-29, p=0.033) were the only independent predictors. By using these two parameters 7% of those without any vs 30% with any of the two vs 63% with both factors had a MIg related renal pathology. In conclusion, among patients with known monoclonal gammopathies and renal dysfunction, 32% had a non MIg-related diagnosis, which had implications in their management. Urine protein electrophoresis can help identify those at higher probability of MIg-related renal disease and should be evaluated in all patients with MGs; otherwise, dFLC > 50 mg/L and proteinuria >1.7 gr/d can be used. Renal dysfunction should not attributed to the underlying MIg without careful consideration of the other parameters and of a renal biopsy. Disclosures Kastritis: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Gavriatopoulou:Genesis: Honoraria, Other: Travel expenses; Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses. Terpos:Medison: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Amgen: Honoraria, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding.

Introduction: About 20-40% of patients (pts) with multiple myeloma (MM) present with moderate or severe renal impairment (RI) and about 25% of pts will also experience RI later during the disease course (Dimopoulos MA, et al; Leukemia 2008; 22:1485-1493). Moderate or severe RI is associated with poorer overall survival (OS) and higher risk of early death but also with challenges in the management and administration of the appropriate treatment. Daratumumab, an IgG1κ human monoclonal antibody that targets CD38, has shown efficacy and a favorable safety profile in pts with relapsed or refractory MM (RRMM) both as a monotherapy (Lonial S, et al; Lancet 2016; 387(10027):1551-1560) and in combination with other anti-myeloma agents (Dimopoulos MA, et al; N Engl J Med 2016; 375:1319-1331, and Palumbo A, et al; N Engl J Med 2016; 375:754-766). In population pharmacokinetic analyses, no clinically important differences in exposure to daratumumab were observed between pts with renal impairment and those with normal renal function. However, there are no prospective data on the safety and efficacy of daratumumab in pts with RRMM and severe renal dysfunction or those requiring dialysis. Methods: DARE is an ongoing multicenter, single arm, open-label, phase 2 study, aiming to enroll ~38 adult pts with documented RRMM and severe renal impairment (estimated glomerular filtration rate [eGFR]< 30 ml/min/1.73m2) or in need for hemodialysis. Pts must previously have had ≥ 2 lines of therapy with both bortezomib- and lenalidomide-based regimens and an Eastern Cooperative Oncology Group performance status (ECOG PS) score of ≤ 2. Exclusion criteria include previous treatment with daratumumab or other anti-CD38 therapy. All pts receive 28-day cycles of treatment with daratumumab given intravenously at 16 mg/kg weekly for Cycles 1-2, every 2 weeks for Cycles 3-6, followed by every 4 weeks thereafter, with dexamethasone 40 mg given weekly for each 4-week cycle. The primary endpoint of the study is the evaluation of progression-free survival (PFS). Key secondary endpoints include overall response rate (ORR; defined as the proportion of pts with partial response or better), renal response rate (RRR; defined as the proportion of pts with best response of renal partial response or better), and the assessment of daratumumab safety and tolerability. All responses were based on investigators' assessment per International Myeloma Working Group criteria. This interim analysis presents study results for pts who received the first dose of study treatment at least 3 months prior to the cut-off date (06/05/2019). Results: Eighteen pts, enrolled in 4 centers, were included in this prespecified analysis. The pts' median age was 74.0 years, and most were males (77.8%). The median time from MM diagnosis to first dose of daratumumab was 3.6 years. The number of pts with baseline ECOG PS 0, 1, and 2 were 4 (22.2%), 13 (72.2%), and 1 (5.6%), respectively. At the start of the study, 22.2% and 77.8% of patients had ISS Stage II and III disease, respectively. Moreover, 44.4%, and 55.6% of pts had a revised ISS stage II and III, respectively. Median number of prior lines of therapy was 3.5, and two (11.1%) pts had previous autologous stem cell transplantation; Median eGFR at baseline was 12 mL/min/1.73m2. The median number of therapy cycles received per patient was 4.5. The median time from first daratumumab dose to first partial response or better was 0.9 months. The median follow-up is 4.4 months and the Kaplan-Meier estimate of the 6-month PFS rate is 51.9% (Figure), ORR was 44.4% (8/18 pts) (including VGPR in 4, and PR in 4 pts), and RRR was 27.8% (5/18 pts). By the cut-off date, 10 (55.6%) pts were still on daratumumab; 7 (38.9%) pts discontinued treatment due to progressive disease and 1 (5.6%) due to a fatal serious adverse event (SAE). Overall, ten (55.6%) pts had ≥ 1 AE of grade 3 or 4. Of all grade 3 or 4 AEs, the most frequent were anemia (4, 25%), hyperglycemia (3, 18.8%), and hypocalcemia (2, 12.5%). Three (16.7%) pts suffered a single SAE each: lung infection, sepsis (fatal), and stroke. Conclusions: The combination of daratumumab with dexamethasone is efficacious and with a favorable safety profile and no new safety signals, in pts with RRMM with severe renal impairment. Importantly, hematologic responses are high in these heavily pretreated patients while about 28% achieved also a renal response. The study is ongoing and updated results will be presented at the meeting. Figure Disclosures Kastritis: Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria. Terpos:Takeda: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Medison: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding. Symeonidis:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Delimpasi:Genesis: Honoraria, Other: Travel grant; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Cavo:Janssen, Celgene: Other: Travel Accommodations; Janssen, Celgene, Amgen, Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen, Celgene: Speakers Bureau; Celgene, Janssen, Amgen, BMS, Abbvie, Takeda: Honoraria. Zamagni:Celgene Corporation: Honoraria, Other: Advisory board, Speakers Bureau; Janssen: Honoraria, Other: Advisory board, Speakers Bureau; Amgen: Honoraria, Other: Advisory board, Speakers Bureau; BMS: Honoraria, Other: Advisory Board, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Sanofi: Honoraria, Other: Advisory Board, Speakers Bureau. Katodritou:Takeda: Honoraria; Janssen: Honoraria; Genesis: Honoraria; Amgen: Honoraria. Gamberi:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gavriatopoulou:Genesis: Honoraria, Other: Travel expenses; Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses. Hatjiharissi:Janssen: Honoraria. Dimopoulos:Sanofi Oncology: Research Funding.

Lung involvement in patients with systemic AL amyloidosis is not very common and consensus criteria require direct biopsy verification with symptoms or typical radiographic changes of diffuse interstitial lung disease. Dyspnea and other symptoms are commonly attributed to cardiac dysfunction and thus, lung dysfunction may go unrecognized while, in some series evidence suggest that lung involvement is probably more frequent than reported. No prospective comprehensive evaluation of lung function has been performed in patients with AL amyloidosis; the aim of our study was to prospectively assess lung function by performing comprehensive pulmonary function tests (PFTs) in consecutive patients with systemic AL amyloidosis. This was a non-interventional prospective study that included consecutive patients with systemic AL amyloidosis treated in the Department of Clinical Therapeutics (Athens, Greece). Patients with localized lung amyloidosis were excluded. PFTs were performed in a Master screen Body (Jaeger, Germany), according to manufacturer's instructions and standard European Respiratory Society / American Thoracic Society guidelines. We performed spirometry, lung volumes measurement, single-breath determination of carbon monoxide uptake in the lung corrected for hemoglobin (carbon monoxide diffusion capacity, DLCO) and maximal expiratory (Pe) and inspiratory (Pi) pressures measurement, in a sitting position. The patient's age, height and weight were recorded for use in the calculation of reference values. We adjusted DLCO for Hb prior to the interpretation of the maneuver in the predicted values. Smoking habits were recorded (smoker or no, pack/years, years of smoking cessation). We report on the first 84 patients with systemic AL amyloidosis that were included in the study. Median age was 63 years (range 44-84), 60% were males, median baseline dFLC was 162 mg/L, median BM infiltration was 15% (range 0-30%). Kidney involvement was present in 73%, median eGFR was 63 ml/min/1.73 m2. Heart was involved in 72% and 12%, 62%, 17% & 8% of patients were Mayo stage 1,2, 3A and 3B respectively. Liver was involved in 25%, peripheral/autonomic nerve in 21% and soft tissue in 12%. Based on imaging and/or lung biopsy, lung involvement was present in 2 (2%) patients; 48% of the patients were current or ex-smokers. Primary treatment was bortezomib-based in 89% of the patients. According to PFTs, breathing pattern was normal in 49%, restrictive in 37%, obstructive in 11% and mixed in 3%. The presence of a restrictive pattern was marginally associated with heart involvement (p=0.056) but not with Mayo stage and was more common in patients with liver (p=0.022) and soft tissue involvement (0.031) and there was no association with renal or nerve involvement or FLC levels. In univariate analysis, restrictive pattern was associated with worse survival (24 months vs not reached for obstructive and normal, p=0.015); 1-year mortality was 42% for restrictive vs 13% for obstructive and 5% for normal breathing patterns. When adjusted for Mayo stage, restrictive pattern (HR 2.63, p=0.033) and Mayo stage 3B (HR: 12, p=0.033) were independently associated with survival. Among individual PFTs indices, corrected DLCO (p=0.02), TLC% (p=0.012) and Pe% (p=0.019) were associated with survival. A DLCO In this comprehensive evaluation of lung function by PFTs we found that restrictive breathing pattern is common among patients with systemic AL, and indices of lung function are associated with prognosis independently of cardiac dysfunction. Our results point to the presence of unrecognized pulmonary involvement, despite the absence of typical imaging findings. Disclosures Kastritis: Genesis: Honoraria; Prothena: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Gavriatopoulou:Janssen: Honoraria, Other: Travel expenses; Amgen: Honoraria; Takeda: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses. Terpos:Medison: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Janssen: Honoraria, Other: Travel expenses, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding.

Introduction: Severe renal impairment (RI) is a common complication of multiple myeloma (MM). Effective anti-MM therapy and supportive care can restore renal function in several patients, but we lack biomarkers that could predict renal outcomes. Neutrophil gelatinase-associated lipocalin (NGAL) is one of the earliest and most robust markers of acute kidney injury while serum Cystatin C (CysC) reflects renal function more accurately than creatinine and correlates with both tumor burden and renal function in MM. GDF-15 is secreted by bone marrow stromal cells and high serum levels indicate a poor treatment prognosis and a high risk of progression to dialysis in AL amyloidosis. Our aim was to evaluate serum NGAL, CysC, and GDF-15 in MM patients with severe RI defined as eGFR Patients & Methods: MM patients who presented with myeloma-related severe RI in the Department of Clinical Therapeutics (Athens, Greece) were included in this study. NGAL, CysC and GDF-15 were measured in the same frozen serum sample collected before the administration of any therapy. Serum NGAL was measured using ELISA (BioPorto Diagnostics A/S, Gentofte, Denmark), while CysC was measured using a latex particle-enhanced nephelometric immunoassay (Dade Behring-Siemens Healthcare Diagnostics, Liederbach, Germany). GDF-15 was measured by a novel immunoassay, the Elecsys GDF-15 assay (Roche Diagnostics International Ltd, Rotkreuz, Switzerland), which is based on the sandwich immunoassay principle using biotin-streptavidin technology. Patients on dialysis received dialysis with regular membranes. IMWG renal response criteria were used. Results: In total, 101 newly diagnosed MM patients with severe RI were included in this analysis. Median creatinine was 4.6 mg/dl (range 2->10 mg/dl), median eGFR (ml/min/1.73 m2) was 11.3 (1.3-29.8) and dialysis was required in 35 (35%) patients. The median age was 71 years; median involved FLC was 4740 mg/L; hypercalcemia was found in 24%, LDH ≥ULN in 44% and high-risk cytogenetics in 25% of patients, while 98% of patients were classified as having ISS-3 and 49% as having R-ISS-3 disease stage. Treatment was bortezomib-based in all patients (in 21% VD and in 79% a triplet: VCD or VTD). Median NGAL levels were 182.3 ng/mL (range 20-550 ng/ml) and of CysC were 3.3 mg/L (0.9-8 mg/L); there was a strong correlation between NGAL and CysC levels (R2=0.653, p Conclusions: Serum levels of NGAL were independent predictors of major renal response in MM patients with severe RI. Thus, serum NGAL could identify MM patients with severe RI who should be treated with more aggressive therapies and more effective and rapidly acting antimyeloma regimens. The absence of any predictive value of GDF-15 in MM-related severe RI in contrast to AL amyloidosis patients reflect the different biology of RI in these plasma cell dyscrasias. Figure Disclosures Dimopoulos: Sanofi Oncology: Research Funding. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genesis: Honoraria; Prothena: Honoraria; Pfizer: Honoraria; Takeda: Honoraria. Papassotiriou:Roche: Employment. Gavriatopoulou:Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses. Terpos:Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria; Takeda: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria.

Consolidation therapy post autologous stem cell transplantation (ASCT) in patients (pts) with multiple myeloma (MM) seems to deepen disease responses. MRD negativity represents a strong prognostic factor for prolonged remission. Carfilzomib is a second-generation proteasome inhibitor, which in combination with lenalidomide has been associated with high rates of deep responses before ASCT in phase 2 studies. In this context, we prospectively evaluated the role of carfilzomib, lenalidomide and dexamethasone (KRd) as consolidation therapy post-ASCT in newly diagnosed MM pts who have not achieved MRD negative complete remission (CR). The primary endpoint was to assess KRd efficacy in terms of improving disease response, whereas secondary endpoints included percentage of minimal residual disease (MRD) (performed by Next Generation Flow Cytometry) negativity post KRd, safety, time to progression (TTP), time to next treatment (TtNT), overall survival (OS) and the effects of KRd on bone metabolism in the absence of bisphosphonate administration. All pts achieving at least partial response and less than MRD negativity post-ASCT were eligible for inclusion in the study. Consolidation consisted of 4 cycles of KRd, starting on day 100 post-ASCT: carfilzomib was given at a dose of 20 mg/m2 iv on day 1 cycle 1 and 56 mg/m2, on days 1, 8, 15 thereafter; lenalidomide was given at 25 mg daily on days 1-21 and dexamethasone at 40mg weekly every 28-days. All pts continued lenalidomide maintenance 10 mg following consolidation until progressive disease. Pts did not receive bisphosphonates during or post-ASCT as well as throughout the period of KRd consolidation. Bone remodeling was evaluated by the following serum indices before and after KRd (2 measurements for each pt): i) osteoclast regulators (soluble receptor activator of nuclear factor kappaB ligand and osteoprotegerin), ii) osteoblast inhibitors (dickkopf-1 and sclerostin) iii) bone resorption markers (CTX and TRACP-5b) and iv) bone formation markers (bone-specific alkaline phosphatase and osteocalcin). Between January 2018 and May 2019, 39 consecutive pts all MRD positive (20M/19F, median age 56 years, range 44-67 years) entered the study. The distribution per revised ISS was 36.1% stage 1, 52.8% stage 2 and 11.1% respectively. After a median follow-up of 16 months (range 1-17) following KRd initiation, 35 (89.7%) pts had received 4 cycles of KRD, whereas two pts continue on treatment and two discontinued treatment due to toxicity. Following ASCT, one (2.6%) pt had achieved stringent CR (sCR), 4 (10.3%) were in CR, 29 (74.4%) were in very good partial remission (VGPR) and 5 pts (12.8%) were in PR. Post KRd consolidation, 30 out of 37 evaluable pts (81%) pts improved their response status with KRd. Overall, 28 (75.7%) pts achieved a sCR, one (2.7%) CR and 8 (21.6%) VGPR, while 25 (67.6%) pts achieved MRD negativity at 10-5. Among the 25 MRD negative pts, 11 (44%) were R-ISS stage 1, 13 (52%) stage 2 and one (4%) stage 3. Positron emission tomography-computed tomography (PET/CT) scans that were performed in 14 MRD (-) pts were negative for all pts except one. The markers of bone metabolism were measured in 22 pts. Only TRACP-5b levels showed a significant reduction (p=0.011) post KRd consolidation, which suggests a beneficial effect on bone resorption that must be further investigated. No new skeletal-related events (SREs) were reported. No patient has progressed whereas 37/39 (95%) are alive. One patient died due to staphylococcal pneumonia and another due to refractory thrombotic thrombocytopenic purpura complicated by brain hemorrhage and in-hospital infection during KRD. 7 (18%) pts experienced ≥grade 3 toxicities (mainly infections, TTP, fatigue, neutropenia, pneumonitis, hypocalcemia and increase of γGT and ALP). There were no new cases of peripheral neuropathy. In conclusion, KRd consolidation with weekly carfilzomib, post ASCT, is highly effective and improves the quality of response by increasing MRD negativity rates. Although it is given for four cycles only, KRD consolidation reduces bone resorption and correlates with no SREs in the absence of bisphosphonates. Infections prophylaxis is strongly encouraged. This triplet combination should be further investigated as a potential consolidation regimen both for standard and high-risk pts. Disclosures Gavriatopoulou: Janssen: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses; Amgen: Honoraria; Takeda: Honoraria, Other: Travel expenses. Terpos:Takeda: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Medison: Honoraria; Celgene: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Dimopoulos:Sanofi Oncology: Research Funding.

A deep and rapid hematologic response is fundamental in order to improve the outcomes (overall survival (OS) and organ responses) of patients with AL amyloidosis. However, the optimal time to assess the efficacy of therapy and make decisions has not been established, with most data based on assessments performed after 3 months of therapy. However, given the toxicity of the circulating free light chains, a delay in response may have detrimental consequences, especially for high risk patients. In patients not optimally responding, early rather than late change in therapy may salvage some of them, but there is limited data. We aimed to evaluate the significance of an early response (i.e at 1 and at 3 months after start of therapy) and of an earlier introduction of salvage therapy, in patients not achieving at least a very good partial response (VGPR). The analysis included consecutive previously untreated patients with AL amyloidosis, who received bortezomib-based primary therapy, in a single center (Department of Clinical Therapeutics, Athens, Greece). The analysis included 198 patients who had evaluable clonal disease (i.e dFLC>20 mg/L with abnormal FLC ratio, or serum monoclonal protein >0.5 gr/dl) and available assessments at 1 and at 3 months from the start of therapy, excluding patients who died early ( The median age was 64 years (range 40-84), 57% were males. Heart was involved in 64%, per Mayo stage 23%, 52%, 18% and 7% were stage 1,2, 3A & 3B. Kidneys were involved in 72%, median eGFR was 71 ml/min/1.73 m2, median proteinuria was 5.3 gr/d; peripheral/autonomic nerve was involved in 18% and liver in 21%. After 1 month of therapy, 38% had not achieved a response (NR), 35% had a VGPR and 27% a PR. Among patients who had We then assessed the impact of the depth of response at 1 and at 3 months. One-year OS of patients with VGPR, PR and NR at 1 month was 85%, 84% and 67% and at 3 years was 78%, 53% and 48% respectively (median OS: 9.5 vs 3.1 vs 2 years, p=0.001). According to the response at 3 months landmark, 1 year OS was 92% vs 69% vs 61% for VGPR, PR and NR respectively ( median OS: 7 vs 3.5 vs 1.2 years respectively, p Patients that after 3 months of therapy had not achieved at least a VGPR were analyzed according to whether they remained on the same treatment or started salvage therapy immediately. Most received salvage therapy with lenalidomide/dexamethasone or with lenalidomide added to bortezomib. Of those with NR, 32% started a new therapy at this timepoint and 68% continued on the same therapy, while among those in PR, 80% continued the same therapy. At 6 months, 37% (10% VGPR, 27% PR) of patients who had NR at 3 months and remained on the same therapy achieved a response vs 44% (20% VGPR, 24% PR) of those that switched to salvage therapy. Among those in PR at 3 months, only 12.5% of those continuing with the same therapy improved their response to VGPR. Patients with In multivariate analysis, at least VGPR after 1 month (p=0.001) or at 3 months (p=0.004) and Mayo stage 1 or 2 (vs stage 3) (p In conclusion, in this cohort of bortezomib-treated patients with AL amyloidosis, a very early (at 1 month) and deep response is associated with better survival. Early introduction of salvage therapy may improve the depth of response and survival for some patients, but, with the available therapies, it may be too late for many patients even if salvage is given early. Based on our results, starting with the most effective therapy to achieve rapidly the deepest response possible, especially in patients at higher risk, is the best strategy. Disclosures Kastritis: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Gavriatopoulou:Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses; Amgen: Honoraria; Genesis: Honoraria, Other: Travel expenses. Terpos:Janssen: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria. Dimopoulos:Sanofi Oncology: Research Funding.

Introduction: Skeletal-related events (SREs) that include pathological fractures, spinal cord compression (SCC) and need for radiotherapy or surgery to the bone are frequent complications of multiple myeloma (MM). Although the incidence of SREs at diagnosis is well-documented, there is limited information for the natural history of SREs during treatment with novel agents. Thus, we evaluated the SRE rate in MM patients who received frontline and second line therapy with proteasome inhibitors (PIs) or immunomodulatory drug (IMiD)-based therapies and explored possible correlations with disease or genetic features and type of treatment. Methods: MM patients who received frontline therapy in our center (Department of Clinical Therapeutics, University of Athens, Greece), between 2007-2017, were included in this analysis. Patients had a whole-body skeletal survey using either conventional radiography (WBXR) or low-dose CT (WBLDCT) at diagnosis and then at the time of relapse or whenever clinically indicated. Magnetic Resonance Imaging (MRI) of the spine and pelvis at diagnosis was recorded when available. SNPs in genes that are involved in bone destruction in osteoporosis were also evaluated: LRP5 (rs4988321), GC vitamin D (rs4588), TNFRSF11A (rs3018362), DKK1 (rs1569198), RANKL (rs9594759), OPG (rs6469804) and ERS1 (rs1038304). Results: In total, 620 consecutive patients with symptomatic MM (316M/304F, median age: 65 years) were studied. The median follow-up was 54 months. At diagnosis, osteolytic disease was present in 408 (66%) patients. MRI was available in 390 patients: 149 (38%) patients had focal, 139 (36%) diffuse, 81 (21%) normal and 21 (5%) variegated pattern of marrow involvement. SREs were observed in 271 (44%) patients at diagnosis: 213 (34%) presented with pathological fractures (183 with vertebral fractures, 18 with rib fractures and 15 with long bone fractures; 32 patients had both vertebral and long bone or rib fractures), while 34 (5.5%) patients needed surgery to bone, 45 (7.2%) radiotherapy and 31 (5%) patients presented with SCC. The incidence of SREs was higher in patients with osteolytic lesions (76.4% vs. 12.4%, p Conclusions: Our data, which constitutes one of the few systematic reports on the incidence and characteristics of SREs in the era of novel agents, indicate that SREs remain a significant complication in MM. Despite high response rates after first line therapy and the broad use of BPs, more than 20% of patients develop a new SRE during the first and second line treatment or at the time of first relapse. Importantly, patients who do not receive BPs due to renal impairment develop very frequently SREs, suggesting an unmet need in this setting. More effective frontline therapies or more potent bone-targeted agents (denosumab or anti-sclerostin drugs) may manage to further reduce the SREs rate in MM patients, especially in those who cannot receive BPs. Disclosures Terpos: Celgene: Honoraria; Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria. Kastritis:Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria. Gavriatopoulou:Amgen: Honoraria; Takeda: Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses. Dimopoulos:Sanofi Oncology: Research Funding.

Multiple myeloma (MM) is a hematologic malignancy characterized by infiltration of the bone marrow (BM) by malignant plasma cells. Multiple myeloma diagnosis is made by the presence of one or more of the CRAB criteria or one of the recently added biomarkers of malignancy. Smoldering MM (SMM) is a plasma cell dyscrasia preceding multiple myeloma, characterized by bone marrow infiltration of 10-60% and/or serum monoclonal protein ≥3g/dL or urinary monoclonal protein ≥500 mg per 24h, along with the absence of myeloma-defining events. MicroRNAs (miRNA) are single-stranded, small non-coding RNA molecules (~21 nt) that regulate protein-coding gene expression at the post-transcriptional level, mainly through interactions with the 3′-untranslated region of target mRNAs. The results of such interactions can be mRNA degradation and/or translational repression, depending on the complementarity of the miRNA seed sequence with the mRNAs 3′-untranslated region. They can function as oncogenes or tumor suppressors, possessing a vital role in several aspects of all stages of tumorigenesis and cancer progression. In the present study, we have investigated the clinical value of a molecular signature consisting of 10 cancer-related miRNAs in MM: miR-15a, miR-16, miR-21, miR-221, miR-222, miR-25, miR-125, miR-155, miR-223, and miR-181a. These molecules were selected due to their well-documented role and clinical significance in numerous human malignancies. More specifically, miR-15a and miR-16 expression levels have been associated with chronic lymphocytic leukemia. The deletion 13q14, the most prevalent alteration in CLL, leads to the deletion of these miRNAs, which act on cell proliferation and in the process of apoptosis. miR-221 and miR-222 form a cluster that has been correlated with tumorigenesis and unfavorable prognosis in human malignancies, while miR-155 is a pro-inflammatory, oncogenic molecule, with a potential role in chronic lymphocytic leukemia. Bone marrow aspiration samples were collected from 94 patients with MM and SMM, and CD138+ plasma cells were positively selected using magnetic beads coated with an anti-CD138 antibody. Total RNA was isolated using TRIZol. Thereafter, 200ng RNA of each sample were polyadenylated at the 3´ end and reversely transcribed. An in-house developed real-time quantitative PCR assay was conducted and the results were biostatistically analyzed. For the normalization of the expression levels of each miRNA, the mean expression of two small nucleolar RNAs (RNU43 and RNU48) was used as reference. Seventy six out of the 94 BM aspiration samples were derived from MM patients and 18 of them from SMM patients, at the time of diagnosis. The MM patients were classified, according to the R-ISS staging system, as follows: 15 patients had stage I disease, 42 patients had stage II, and 19 patients stage III MM. Forty nine myeloma patients presented with osteolytic lesions at diagnosis. The statistical analysis revealed significantly lower expression levels of miR-16 (p=0.036) and miR-155 (p=0.045) in CD138+ cells of MM patients, compared to those from SMM patients, highlighting their potential value to discriminate MM from SMM. Furthermore, miR-221 and miR-222 expression levels were negatively correlated with R-ISS; thus, miR-221 and miR-222 expression was significantly downregulated in MM patients with R-ISS stage III (p=0.004 and 0.034, respectively). This tendency reveals a potential favorable prognostic value of miR-221/222 cluster in MM. Next, miR-15a and miR-16 expression was shown to be associated with the presence of osteolytic lesions. In this regard, the expression levels of miR-15a (p=0.048) and miR-16 (p=0.047) were decreased in MM patients with bone disease, compared to those without bone disease. The observed decreased expression of these two miRNAs in symptomatic MM patients could constitute a predictive biomarker for the occurrence of bone disease and, hence, a putative predictive biomarker of SMM patients at high risk of evolution to symptomatic disease with bone lesions. We conclude that miR-221/222 correlate with more favorable R-ISS stage, while miR-15a and miR-16 correlate with the presence of osteolytic disease in MM. This ongoing study will further reveal the possible prognostic significance of this 10 miRNAs signature studied, when response to therapy, progression-free and overall survival is available. Disclosures Kastritis: Genesis: Honoraria; Prothena: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria. Gavriatopoulou:Takeda: Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Amgen: Honoraria; Genesis: Honoraria, Other: Travel expenses. Dimopoulos:Sanofi Oncology: Research Funding. Terpos:Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding.

Introduction: The apparent heterogeneity of multiple myeloma (MM) constitutes a key challenge in the clinical management and the design of effective therapeutic interventions, while it entails the identification of biomarkers with a strong prognostic value. In this context and taking into account patients' inconvenience to invasive bone marrow (BM) aspiration, the assessment of circulating plasma cells (CPCs) in liquid biopsies, at the time of diagnosis, has been proposed as a useful assay with prognostic value. Different methodologies have been applied for the detection of CPCs; the most common is the use of multicolor flow cytometry (MFC), mainly of 2-, 4-, or 6-color combination panels, which however yielded heterogeneous results due to variations in the detection efficacy of each approach. In the present study, we applied the standardized and highly sensitive Next Generation Flow Cytometry (NGF) approach, to detect CPCs in diagnostic MM peripheral blood (PB) samples, we compared their phenotypic characteristics with the aberrant clonal cells of BM matched samples and we correlated their presence with disease characteristics. Patients and Methods: PB and BM matched samples from 182 consecutive MM patients, at diagnosis, were evaluated for the presence of aberrant plasma cells (APCs) following the standard operating procedures (SOP) of NGF, according to EuroFlow guidelines. All these patients were diagnosed and treated in a single center (Department of Clinical Therapeutics, N.K. University of Athens, Greece). Samples were collected in EDTA-anticoagulated tubes and treated with the bulk-lysis procedure. Recovered cells were stained with antibodies against surface CD19-PEC7, CD27-BV510, CD38-FITC, CD45-PERCP, CD56-PE and CD138-BV421 and the intracellular CyIgκ-APC and CyIgλ-APCC750 to verify clonality. Six to ten million cells were acquired per sample, thus reaching a median Limit of Detection (LOD) of 3.5x10-6. Optimal PMT voltages were set according to the EuroFlow SOP for instrument set-up and daily performance status of FACSCANTOII was monitored with both CS&T (BD) and Rainbow beads (Spherotech Inc, Lake Forest, IL). Results: CPCs were detected in 158/182 (86.8%) MM diagnostic samples within a range of 0.0002% to 63.8% of total PB nucleated cells (PBNCs). The CPCs showed the same aberrant phenotype as the one detected in the BM for all cases, although with a significantly reduced intensity for the markers CD27, CD38, CD138 and CD56. When more than one phenotypically distinct subgroups were detectable in the BM, the same phenotypic subsets were present in the PB with the same relative frequency for >90% of bi/multi-phenotypic cases. The higher number of CPCs (>0.1% of all PBNCs) strongly correlated with an increased BM infiltration rate by myeloma cells (p Conclusions: The NGF approach using the EuroFlow protocol enables the detection of even rare CPCs in diagnostic MM PB samples, due to the high number of cells acquired and the elegantly elaborated 8-color marker combinations which allows for the detection of CPCs with even a non-typical phenotype. Our matched PB and BM analysis revealed that BM APCs and CPCs share very similar characteristics suggesting that liquid biopsy offers a representative alternative for the phenotypic characterization of BM APCs. The correlation of high CPCs with adverse disease characteristics suggests that the quantification of CPCs by standardized NGF may emerge as a valuable surrogate prognostic biomarker which could replace other invasive methods or other less informative assays. Disclosures Terpos: Janssen: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria. Gavriatopoulou:Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses. Kastritis:Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria. Dimopoulos:Sanofi Oncology: Research Funding.

Background - Objectives: Primary Bone non-Hodgkin's Lymphoma (PB-NHL) is a rare disease and constitutes about 3% of the total NHL patient population. We estimated the prevalence of this type of lymphoma in the local lymphoma registry of Western Greece and retrospectively analyzed 102 cases, in an effort to describe the clinical, histological and prognostic features of this tumor. Patients and Methods: Among 1225 patients (pts) with all types of NHL, diagnosed between 1.1.1991 and 31.12.2018 in the area of Western Greece, 32 (2.6%) had PB-NHL. We analyzed the data of these 32 pts, together with those of additional 70 pts, treated in 7 large Hematology Departments in Greece. Pts were 60 males and 42 females (♂/♀ ratio 1.43) with a median age of 62 years (range 20-93 years) and 55% of them were Results: In 81 pts (79.4%) the disease presented with local symptoms only, in 4 (3.9%) with systemic/constitutional symptoms, and in the remaining 17 (16.7%), with both, local and constitutional symptoms. The mainly affected bones were pelvis (iliac-pubertal-sacral, 23 pts), femur (15), lumbar vertebrae (14), thoracic vertebrae (12), mandible, humerus and tibia (7 each), ribs/sternum (5), skull, clavicle and scapula (3 each), maxilla (2) and patella (1). The most common histological type was Diffuse Large B-cell Lymphoma Not Otherwise Specified (DLBCL-NOS: 92 pts), followed by Ki-1+ anaplastic (3), small lymphocytic (3), mantle cell (3) and follicular lymphoma (1). A B-cell phenotype was revealed in 99 cases and non-B/non-T cell CD30+ in 3. One bone site was affected in 68 pts (66.7%), alone in 25, with contiguous extranodal or lateral nodal involvement in 23, and with one additional non-contiguous extranodal or distal nodal involvement in 20. Two bone sites with or without additional nodal or extranodal involvement was found in 12 pts and multiple bone sites with or without additional nodal or extranodal involvement in the remaining 22 pts. Ann-Arbor stage was early (I-II) in 51 pts and advanced (III-IV) in 51, B-symptoms were present in 21 pts (20.6%) and the marrow was involved in 20/87 pts (23%). Anemia was present in 33 pts, leukocytosis in 14, neutrophilia in 22, thrombocytosis in 15 and symptomatic hypercalcemia in 1 patient. Elevated serum LDH was found in 60/101 pts (59.4%), CRP in 35/55 pts (63.6%), alkaline phosphatase in 20/69 pts (29%) and beta2-microglobulin in 24/60 pts (40%). Six out of 51 pts (11.8%) were HBsAg(+), 1/51 anti-HCV(+) and 1/55 anti-HIV(+). Active treatment was administered in 97 pts, which was chemoimmunotherapy (Ch-Im) alone in 58, combined modality [Ch-Im + Radiotherapy (Rx)] in 38 and Rx alone in 1. Anthracycline-based regimens were administered in 93 pts. Five pts were not evaluable for response (lost from follow-up N=4, still on treatment N=1). Seventy-three pts achieved a CR (79.3% or 75.3% on an intention to treat basis) and treatment failed in 20 (20.6%). The median DFS was 29.5 months. Survival analysis was restricted to DLBCL pts who received Ch-Im: After a median follow-up of 33 months (range, 1-207) 58/76 pts were still alive for a 5-year OS of 71%. The 5-year progression free survival (PFS) was 59%. No survival benefit in terms of PFS and OS was found among pts, who received adjuvant Rx compared to pts who received Ch-Im alone, p=0.40). Age >60 yrs, PS ≥2, elevated LDH and tumor burden were all predictive of PFS and OS in univariate analysis. Ann Arbor stage III/IV had only borderline significance restricted on PFS. Only LDH (p=0.04) and tumor burden (intermediate and high versus low; p=0.07) were independent predictors of PFS in backward stepwise multivariate analysis. LDH and poor PS were the only potential independent predictors of OS in multivariate analysis but both had borderline significance. Discussion and Conclusive remarks: PB-NHL is a rare aggressive lymphoma subtype, with a main histology of DLBCL-NOS, which responds favorably to anthracycline-based Ch-Im and response rates are similar to other nodal and extranodal aggressive lymphomas. Radiotherapy appears not to add on survival and should only be used for local palliation. Disclosures Symeonidis: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Pappa:Gilead: Honoraria, Research Funding; Amgen: Research Funding; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Angelopoulou:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene / GenesiaPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hatzimichael:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zikos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria. Pangalis:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vassilakopoulos:WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Monoclonal Gammopathy of Renal significance encompasses a spectrum of different renal pathologies that have a causal relationship with an underlying monoclonal protein produced by a, relatively indolent, plasma or other B-cell clone. These patients require anti-clonal treatment in order to salvage kidney function, however, there are few prognostic biomarkers that can help identify patients at higher risk for progression of renal disease. Increased plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) have been associated with focal segmental glomerulosclerosis and an elevated level of suPAR was independently associated with incident chronic kidney disease and an accelerated decline in the eGFR, in a large study (Hayek S et al, N Engl J Med 2015; 373:1916-1925). Increased Growth Differentiation Factor-15 (GDF-15) has been associated with the deterioration of renal function and progression to ESRD in diabetic patients but also in patients with AL amyloidosis. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is one of the earliest and most robust markers of acute kidney injury while serum Cystatin C (CysC) reflects renal function more accurately than creatinine and correlates with both tumor burden and renal function in MM. We measured serum levels of suPAR, NGAL, GDF-15 and CysC in the same frozen serum sample that was collected before any therapy was given. Measurements of the analytes were performed by means of immunoenzymatic techniques: suPAR (ViroGates A/S, Birkerod, Denmark), NGAL and GDF-15 (R&D Systems, Minneapolis, MN, USA), while CysC was measured with an immunoturbidimetric assay using the Roche Cobas 6000 Clinical Chemistry System. The study included 23 patients with MGRS (MIDD: 18, C3GN: 3, PGNMID: 2), 57% were men, median age was 66 years (range 47-85). Median baseline eGFR (by CKD-EPI) was 30.5 ml/min/1.73 m2 (range 3-102) and at the time of initiation of therapy one (4%) required dialysis. Median baseline proteinuria was 1.7 gr/d (range 0.6-10.2). Median dFLC was 57 mg/L (range 2-2,239) and median BM infiltration was 10% (range 0-50%). At initial presentation 92% had hypertension, requiring a median of 2 different drug classes (range 1-5). Median baseline levels of suPAR were 8.02 ng/ml (range 2.2-21), of CysC were 2.33 mg/L (0.94-7.03), of NGAL were 150.6 ng/ml (range 51.7-573) and of GDF-15 were 2,144 pg/ml (range 548-6,956). A correlation of suPAR levels was found with proteinuria (r=0.691, p=0.001), serum albumin levels (r=-0.706, p0.2 for all). All these biomarkers showed significant correlations with each other (p All patients received bortezomib-based therapy (with cyclophosphamide and dexamethasone); median follow up is 9 months and at 3 month landmark, 55% of evaluable patients had achieved a hematologic response while at 6 months 60% had a hematologic response. At the same time points a renal response (>50% reduction of proteinuria and 50% reduction of proteinuria (p=0.096), which after adjustment for baseline proteinuria and eGFR became clearer (p=0.054). We conclude that suPAR, NGAL, GDF-15 and CysC are markers with significant associations with renal function in patients with MGRS, but, from a clinical standpoint suPAR is probably the most promising marker with potential prognostic significance for renal outcomes. Additional follow up of the cohort and inclusion of additional patients will allow us to further evaluate this biomarker in MGRS. Disclosures Kastritis: Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Amgen: Honoraria, Research Funding; Genesis: Honoraria. Gavriatopoulou:Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses. Papassotiriou:Roche: Employment. Terpos:Janssen: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Takeda: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding.

Background and Methods: Systemic Mastocytosis (SM) is a rare haematologic malignancy characterized by the abnormal growth and accumulation of neoplastic mast cells in one or more organs. The cKIT D816V mutation is a common genetic finding in most cases. A subset of patients appears to be at increased risk for mediator release related symptoms as well as organ dysfunction, including skeletal problems such as osteoporosis, osteolytic lesions and fractures. The diversity of clinical manifestations results in both delayed diagnosis and therapeutic dilemmas. SM cases diagnosed in Greece, between 1987 and 2018, are presented. This project is included in the current activities of Myeloproliferative Neoplasm Working Party of Hellenic Society of Haematology for registry and research development. The medical files of the patients were retrospectively evaluated for disease characteristics, treatment and outcome. Results: Overall 59 patients, median age 52.0 years, with SM were included in the study. Median time of symptoms onset to diagnosis was two years. Twenty-one patients were categorized as indolent SM (ISM), 19 as SM with an associated haematological neoplasm (SM-AHN), 18 as aggressive SM (ASM) and one with mast cell leukaemia (MCL). The main characteristics of the disease are shown in Table 1. Several haematologic neoplasms were associated with SM. Although myeloid malignancies were the most common, including MDS or MDS/MPN (n=9), CMML (n=2), AML (n=1), CML (n=1) and ET (n=1), lymphoid malignancies were also reported and included NHL (n=3), HL (n=1) and B-ALL (n=1). SM and the AHN were diagnosed simultaneously in 12 cases. AHN diagnosis preceded the diagnosis of SM in 4 cases (median time: 22 months), while the opposite occurred in three cases (median time: 7.0 months). Most of the patients with ISM (16/21) did not receive any specific treatment. As far as the remaining five are concerned, one was treated with imatinib, one with hydroxyurea and the rest three received corticosteroids to control the mediators' related symptoms. One of the latter had diarrhoea without infiltration of the gastrointestinal tract and received consecutively Interferon alpha (IFNα), imatinib and corticosteroids without resolution of the syndrome. Eight patients with SM-AHN received treatment for both the SM and the co-existing haematological neoplasm, six only for the AHN, three only for SM, while three did not require treatment yet. The most common treatment for SM was IFNα (n=6), followed by imatinib (n=4), cladribine (2-CdA) (n=3) and dasatinib (n=1). Patients with ASM received either IFNα (n=8) or 2-CdA (n=5) as first line treatment. Second line treatment included imatinib (n=2), 2-CdA due to IFNα intolerance (n=1) and corticosteroids (n=2). Two patients with vertebrae fractures required surgical intervention. All patients with skeletal involvement received additionally biphosphonates. The patient with MCL received consecutively 2-CdA, chemotherapy (FLAG-Ida) and dasatinib achieving partial response and proceeded to allogeneic stem cell transplantation. He died 6 months later due to complications related to graft versus host disease. With a median follow-up of 31 months the median overall survival in the entire cohort is not reached. The median follow-up for patients with ISM and ASM is 33.5 and 18.5 months respectively, and all of them are alive with adequate disease control. Seven deaths were reported only in the group of patients with SM-AHN. Six patients died due to acute leukaemia and one due to infection, indicating that the aggressiveness of the underlying haematological malignancy is the strongest factor that affects survival in this group. Conclusion: Systemic Mastocytosis is a rare disease with variable manifestations and outcome. Nowadays, several therapeutic modalities are available for effective disease management over time. Novel targeted therapies seem to be promising to further improve the outcome, but still early and accurate diagnosis, in accordance to WHO classification, remains important. Table 1. Table 1. Disclosures Gavriilaki: European Hematology Association: Research Funding. Terpos:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria.

Carfilzomib (CFZ) is a proteasome inhibitor associated with cardiovascular (CV) adverse events (AEs) mainly hypertension (HTN) and cardiac dysfunction. Endothelial dysfunction is a major mediating mechanism in cardiovascular diseases and endothelial function may be adversely affected by proteasome inhibition. However, CFZ effects on endothelial and vascular function and associations with inhibition of proteasome activity have not been explored in humans. We prospectively evaluated CFZ effects on endothelial function and underlying mechanisms as well as baseline vascular function and its response to treatment as potential predictors of CFZ-associated CV toxicity. In this prospective study (NCT03543579), 48 relapsed/refractory myeloma patients (median 1 (1-3) lines of therapy, median age: 67.5, 67% men) received Kd [CFZ 20/56 mg/m2 and dexamethasone] in routine practice. A detailed medical history and evaluation of risk factors for cardiotoxicity [age≥65 years, obesity, smoking, HTN, hypercholesterolemia, diabetes mellitus, previous anthracyclin use, chest or mediastinum radiotherapy and current myocardial disease] were recorded. Before CFZ start and at prespecified timepoints cardiac echo, hemodynamic parameters and vascular function that reflect pivotal mechanisms involved in development of HTN and CV events were non-invasively assessed [aortic blood pressure and arterial wave reflections, aortic stiffness and endothelial function using flow-mediated dilatation of the brachial artery (FMD)] along with 24h ambulatory blood pressure monitoring. Proteasome activity (PrA) was measured in peripheral blood mononuclear cells (PBMC) before and 2 hours post CFZ infusion on days 1 (FMDbaseD1 and FMDpostCFZD1) and 2 (FMDbaseD2 and FMDpostCFZD2) of cycle 1 and at prespecified time points concurrently with vascular function assessment. CV AEs were recorded and rated according to CTCAE v4.03. The prevalence of risk factors for cardiotoxicity was high (median 3 factors, IQR 2-4). After first CFZ dose, FMD decreased acutely at 2 hours (FMDbaseD1: 5.2%, IQR: 3.2-7.4 vs FMDpostCFZD1: 3.6%, IQR: 1.5-4.7, p=0.008), which partially recovered before and after second CFZ infusion (FMDbaseD2: 4.1% and FMDpostCFZD2: 4%, as compared to FMDbaseD1) (Figure1A). However, FMD decrease was more pronounced among patients who subsequently had lower recovery rate of PBMC PrA 24 hours after first CFZ administration (FMDbaseD1: 5.1%, vs FMDpostCFZD1: 3%, p=0.002) while FMD was not decreased significantly in those who had higher recovery rates of PrA (FMDbaseD1: 5.3%, vs FMDpost CFZD1: 4.5%, p=0.197, Figure 1B), suggesting that the ability to recover PrA is implicated in CFZ induced endothelial dysfunction. At the time of analysis, enrolment has completed; 35 patients are still receiving therapy, 13 have discontinued Kd and median follow up is 4.73 months. CV AEs were recorded in 17 (35.4%) patients [HTN(Gr3): 20.8%, Gr3 Left Ventricular dysfunction : 8.3%, Gr3 acute coronary syndrome: 4.2%, Gr3 pulmonary embolism: 2.1%] and generally occurred early (median time to CV event 2.9 months). Kd was discontinued in 2 patients (4.2%) due to cardiotoxicity and in 2 patients (4.2%) CFZ dose was reduced due to cardiotoxicity; no CFZ dose reduction or discontinuation was needed for HTN. Among clinical and hemodynamic parameters assessed at baseline, patients with higher aortic SBP (i.e at higher quartile) had a higher risk of HTN even after adjustment for age, gender and baseline HTN (HR=8, 95%CI 2.4-26, p=0.001 and HR=4.9, 95%CI 1.5-15, p=0.007 respectively). Lower PrA recovery rate was associated with increased risk of developing Gr3 HTN (log-rank test p=0.01). Higher post-CFZ reduction of FMD was associated with HTN in patients not receiving statins but not in those receiving statins (a drug class strongly affecting FMD), indicating that statin treatment may exert protective effects against CFZ-related CV toxicity. In conclusion, CFZ causes acute endothelial dysfunction; however, higher recovery of proteasome activity is associated with ameliorated depression of endothelial function. Given that poor proteasome recovery rate and acute deterioration of endothelial function are both associated with development of HTN, these findings may improve our understanding of CFZ-related CV toxicity and its prevention. The study is ongoing and more data will be presented at the meeting. Disclosures Kastritis: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; BMS: Consultancy; Novartis: Consultancy. Dimopoulos:Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria.

Carfilzomib (CFZ) is a non-reversible proteasome inhibitor approved for the treatment of patients with relapsed or refractory myeloma (RRMM), either in combination with dexamethasone (Kd) or with lenalidomide and dexamethasone (KRd). CFZ has been associated with a risk of cardiovascular toxicity but although a signal of clinically significant renal complications has also been identified, renal toxicity is less extensively investigated. Thus, we analyzed the data of 114 consecutive patients who received CFZ for RRMM in our center (Department of Clinical Therapeutics, Athens, Greece) for renal outcomes and complications. Detailed baseline characteristics and medical history (demographics, history of renal and cardiovascular diseases, diabetes, medication use) and detailed data on myeloma status, proteinuria and urine electrophoresis, serum free light chains (sFLC), serum creatinine and cardiovascular complications were available in all patients for the duration of CFZ therapy. Median age was 70 years (range 36-86, 25% were ≥75) and 60.5% were men. Median number of prior therapies was 2 (range 1-7): 78% had prior bortezomib, 73% prior IMiDs, 27% prior anthracyclines and 46.5% prior ASCT. CFZ dose was 20/27 in 30%, 20/36 in 11% and 20/56 in 59%; 75% received Kd, 14% received KRd and 11% other CFZ-based combinations. Median follow up from start of CFZ is 27 months, median duration of CFZ therapy is 5.5 months (IQR 3.2 to 11.5) and 28 (24.5%) patients continue on CFZ therapy at the time of analysis. During CFZ therapy, 19 (17%) patients developed renal complications, not related to MM progression: 6 (5%) developed thrombotic microangiopathy (TMA), 7 (6%) developed albuminuria > 1gr/day (in all with very low amounts of light chains or with negative urine immunofixation) and 6 (5%) developed acute kidney injury/ acute renal failure (AKI/ARF) at least grade 3, which was not otherwise explained. Median time to development of renal complications was 62 days (~2 months) (IQR 35 to 272) and in 15/19 patients CFZ was discontinued due to renal complications. Median time from CFZ start to TMA was 3 months (0.3-19.5). At diagnosis of TMA, median platelet counts were 20x109/L (range 11-30), median hemoglobin 8 gr/dl, median LDH 449 IU/L (ULN1 gr/d was 6 months (range 2-59 months), median proteinuria was 3.7 gr/d (range 1 - 4.5) and in all cases >90% of urine protein was albumin; all patients were in disease remission (VGPR or CR); median eGFR was 53 ml/min/1.73 m2 (range 41-92). Only one patient had proteinuria before CFZ which was mainly Bence Jones proteinuria. Following interruption of CFZ, proteinuria decreased in 2/7 patients and in one patient CFZ was resumed at a reduced dose. A renal biopsy was performed in 5/6 patients with albuminuria and one with AKI: none had immunoglobulin mediated pathology (cast nephropathy, MIDD or amyloidosis) or pathology related to the alternative complement activation pathway. The most constant finding (in all patients with albuminuria), was a pattern of focal segmental glomerulosclerosis (FSGS) of various subtypes. Coexistent with the previous lesions, a pattern of TMA with intraglomerular and/or arteriolar fibrin microthrombi and/or mucoid degeneration of arteriolar/arterial wall and/or reduplication of glomerular basement membranes with endothelial cells' swelling, was seen in 4 biopsies. We found no association between CFZ dose with renal complications or of baseline proteinuria (immunoglobulin or albumin), sFLC or myeloma type, age, prior history of cardiovascular disease or hypertension or baseline eGFR. Among 33 patients with baseline eGFR < 60 ml/min, 18 (54.5%) patients improved their eGFR to >60 ml/minafter CFZ therapy. We conclude that renal complications during CFZ therapy are common, occur mostly early and are essentially unpredictable. Albuminuria associated with FSGS and TMA developed in 6% and 5% of our patients respectively and warrant further investigation. A potential effect of CFZ on the renal endothelium could be implicated in the pathogenesis of these complications and may also share common pathophysiology with cardiovascular effects of CFZ. Figure. Figure. Disclosures Kastritis: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; BMS: Consultancy; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; Novartis: Consultancy. Dimopoulos:Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria.

The aim of therapy in AL amyloidosis is to rapidly eliminate the production of toxic, amyloidogenic light chains by targeting the plasma cell clone. Especially for patients with advanced cardiac involvement, a rapid hematologic response may be critical, while, the depth of response is important in order to maximize the probability of organ response. Bortezomib with the addition of dexamethasone with either cyclophosphamide (CyBorD) or melphalan (BMDex) remain the most commonly used primary treatment. In myeloma multiple (MM) patients the combinations of bortezomib with an IMiD [thalidomide (VTD) or lenalidomide (VRD)] are very effective and widely used in newly diagnosed patients. In AL amyloidosis the tumor clone is usually of low burden without adverse prognostic features ; thus, the VRD regimen should be particularly effective. However, IMiDs have unique toxicity in patients with AL and their tolerability is poorer than in MM patients and lower doses of IMiDs are commonly used in AL patients. Here we report our experience with a VRD light regimen as primary therapy in consecutive patients with AL amyloidosis. From March 2017, 30 consecutive patients (28 evaluable at the day of this report) treated at the Department of Clinical Therapeutics, Athens, Greece, received bortezomib 1.3 mg/m2 on days 1, 8 & 15, with lenalidomide (starting at 5 to 15 mg, according to age, cardiac and renal function) on days 1-21 and dexamethasone 20 mg weekly, every 28 days for 8 cycles (VRD regimen). Standard and updated criteria for organ involvement and response evaluation and for hematologic response were used. A rigorous assessment following standard institutional protocol for efficacy and toxicity was followed. Among the 30 patients, 71% were males, median age was 65 years (range 46-84); 75% had cardiac involvement, median NTproBNP was 3649 pg/ml (81- >30000) and per Mayo stage 14%, 54% , 14% and 18% were stage 1, 2, 3A and 3B respectively; 54% had renal involvement with a median eGFR of 59 ml/min/1.73 m2 (range 10-133), renal stage distribution was 13%, 53% and 33% (stages 1, 2 & 3) and no patient required dialysis at the time of initiation of VRD. So far 14 patients have completed the planned 8 cycles, 7 died prior to completion of planned therapy, 1 discontinued per physician's decision and 8 are still on therapy. The starting dose of lenalidomide was 5 mg in 26 (86%), 10 mg in 2 (7%) and 15 mg in 2 (7%) patients. After the first cycle of VRD, 32% patients achieved a VGPR and 29% a PR; after 3 months 76% of evaluable patients (N=17) had a VGPR and 24% a PR, while after 6 cycles ≥VGPR and PR rates (N=15 evaluable) were 94% and 6% respectively. Overall, on intent to treat, the best hematologic response was CR in 24%, VGPR in 48% and PR in 16%, for an ORR of 88% and ≥VGPR of 72%. Median follow up is 10 months and 6 and 12 month survival is 73% (100%, 85% and 71% for stage 1, 2 & 3A patients respectively, but only 20% for stage 3B). At 6 month landmark, organ responses were documented in 21% of patients (20% renal and 15% cardiac), but the follow up is still short. Hematologic toxicity was mild (≥Gr3 neutropenia: 4%, anemia: 7%, thrombocytopenia: 7%). Among non hematologic toxicities rash was common (Gr2: 29%, Gr3: 11%, Gr4: 4%); median time to development of rash was 118 days, in 2 patients lenalidomide was discontinued due to rash and in the rest it was continued with the addition of anti-histamines, low dose steroids with or without dose reductions of lenalidomide. Other common AEs included infections (≥Gr3: 11%), constipation (≥Gr3: 11%), neuropathy (Gr2: 18%). Thromboprophylaxis with aspirin was given in 46%, LMWH in 25%, NOACs in 14% and coumadin in 15%. A thromboembolic event (pulmonary embolism) occurred in only one patient with heavy nephrotic syndrome who was receiving LMWH prophylaxis. In total, 43% of patients required lenalidomide dose reduction, 28% discontinued lenalidomide before therapy completion, while, 29% required bortezomib dose reduction and 11% discontinued bortezomib before cycle 8. We conclude that VRD with weekly bortezomib and low dose lenalidomide is a very effective and rapidly acting regimen that can induce deep hematologic responses within 3 months of therapy with toxicity that is manageable with appropriate interventions and thromboprophylaxis. Disclosures Kastritis: Prothena: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Genesis Pahrma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Terpos:Novartis: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding. Dimopoulos:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria.

A deep hematologic response (i.e at least a very good partial hematologic response - hemVGPR or a complete hematologic response- hemCR) is associated with the highest probability of organ function and survival improvement in patients with AL amyloidosis. Bortezomib-based therapy is the mainstay of anti-clonal therapy for patients with AL amyloidosis and 70-80% of patients with previously untreated AL may achieve a hematologic response, however, hemVGPR or better is expected in less than 50%. Given that clones in AL are often small and indolent, further improvement of hematologic response may be achieved by consolidation strategies which may include high dose melphalan with autologous stem cell transplantation (HDM-ASCT); however, toxicity is significant and only a minority of patients is eligible for HDM-ASCT. New targets may provide new opportunities to eliminate the residual clonal plasma cells. Anti-CD38 targeting monoclonal antibody daratumumab has shown activity in myeloma and in AL amyloidosis with minimal toxicity. Specifically in AL, recent data indicate that even a short course of daratumumab was able to induce hematologic responses in several patients with relapsed or refractory AL. Thus, daratumumab may be a unique treatment to improve the outcomes of patients with AL amyloidosis. The endpoint was improvement of response 1 month In order to evaluate the feasibility and activity of a short course of daratumumab as a consolidation strategy, we administered 4 weekly infusions of daratumumab in consecutively treated patients at the Department of Clinical Therapeutics, Athens, Greece with AL or LCDD which had achieved either PR or VGPR after completing their primary therapy. Patients that had not achieved a response to primary therapy were excluded and received full dose salvage therapy. All patients received consolidation with 4 weekly infusions of daratumumab 16 mg/kg with dexamethasone 20 mg. Pre-emptive therapy for IRR was given starting two days before the first infusion of daratumumab that included low dose steroids (equivalent of 16 mg of methylprednisolone), H1 & H2 inhibitors and montelukast. So far 17 patients (15 AL and 2 LCDD) have received daratumumab consolidation. Among patients with AL amyloidosis, median age is 67 (range and 73% were males, kidneys and heart were involved in 80% and in 73% respectively, baseline Mayo stage was 20%, 67% and 13% for stage 1,2 & 3 respectively. Baseline immunofixation in serum or urine was positive in all patients (13/15 of AL patients were lambda). Median time from start of first line therapy to daratumumab consolidation was 9 months and all patients had completed the planned therapy of bortezomib-based treatment. At the time of initiation of daratumumab, 16 patients were in VGPR and one in PR and the median level of dFLC was 12 mg/L, all had positive serum or urine immunofixation and in all patients next generation flow (NGF) according to Euroflow protocol was positive for the presence of MRD. Except for one patient, all the others received the planned 4 daratumumab infusion; the single patient that did not receive the planned therapy did so because of a severe infection that occurred 1 day after the first daratumumab infusion and was not considered daratumumab related. IRRs occurred in 3 patients and were mild (grade 1 in 2 and grade 2 in one patient); no IRRs occurred after the first infusion. One month after completion of consolidation with daratumumab, median dFLC dropped to 5 mg/L and 41% of the patients improved their response: 37.5% from VGPR to hemCR and the one patients with PR to VGPR. Notably, small IgGkappa bands were found in 4 patients at one month post daratumumab. Among those that achieved a CR after daratumumab, 50% became MRD negative by NGF; however, further follow up is needed for the evaluation of organ responses after consolidation. We conclude that consolidation with a short course of daratumumab can improve the depth of response in patients with AL or LCDD that have not achieved a hemCR after primary therapy. In addition, some patients may even achieve MRD negative disease status. We will further explore this strategy in a formal clinical trial with a longer duration of daratumumab therapy so that CR and MRD negative rates may improve further. Disclosures Kastritis: Prothena: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Terpos:BMS: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; Novartis: Consultancy. Dimopoulos:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria.

Advances in the management of multiple myeloma (MM) led to a significant prolongation of overall survival (OS), mainly of the younger patients; almost 10% of them experience more than 10-year OS. Although long progression-free survival (PFS) correlates with extended OS, there is very limited information for the characteristics of patients who manage to be progression-free for a long period after first-line therapy. The aim of this analysis was to evaluate the characteristics of patients who achieved at least 7-year of PFS after frontline therapy and compare them with those of all other patients who were treated in a single center during the same time period. Between January 1994 and December 2010, 406 consecutive newly diagnosed MM patients received first line therapy in the Department of Clinical Therapeutics (Athens, Greece). All patients had symptomatic disease, based on the IMWG criteria of that period (at least one CRAB symptom to start anti-myeloma therapy). Thirty-six (8.8%; 23M/13F) patients achieved a PFS of at least 7 years (long PFS group) after frontline treatment. The median PFS of these 36 patients is 10 years, while the other patients had a median PFS of 22 months. Long PFS patients were younger (median age 56 vs 68 years; p All patients received either conventional chemotherapy (CC) or first-generation novel anti-myeloma agent (bortezomib (B), thalidomide (T) or lenalidomide (R)-based regimens as frontline therapy. There was no difference between the two groups regarding CC versus novel agent-based induction treatment. Out of 36 long-term PFS patients, 11 (30%) received CC, 8 (22%) B-based, 8 (22%) RD, 6 (17%) T-based, and 3 (8%) VTD; 10 (28%) patients received first-line therapy participating in a clinical trial. Long PFS patients had received more often autologous stem cell transplantation (ASCT, 61% vs 23%; p=0.001) as part of first line therapy; therefore, more long PFS patients had also received consolidation and/or maintenance (50% vs 15%; p=0.001). Higher proportion of patients achieved at least VGPR (74% vs 41%) or at least CR (32% vs 18%) in the long PFS group. We performed next generation flow cytometry in 23 patients of the long PFS group to evaluate minimal residual disease (MRD) and 14 (61%) of them were MRD (-) at the level of the 10-6. The probability of achieving long PFS (≥7 years) for patients who managed to be progression-free at 2, 3 and 4 years was 11.6%, 13.2% and 15.3%, respectively. In the multivariate analysis, only younger age was associated with probability for long PFS (p In conclusion, our study in an unselected group of patients, the majority of whom did not participate in clinical trials, showed that 9% of patients with newly diagnosed myeloma experience prolonged PFS of more than 7 years (median: 10 years) even in the era of CC or first-generation novel agents. These patients have low risk disease, mainly of ISS-1 or -2, no high-risk cytogenetics, no or mild renal impairment, and achieve deep responses after ASCT. These patients may be considered as "functionally" cured. The incorporation of novel treatment approaches may lead to a significant improvement in the probability of achievement of this "functionally" cured status. Disclosures Terpos: Novartis: Consultancy; BMS: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding. Kastritis:Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria.