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Carfilzomib (CFZ) improves survival in relapsed/refractory multiple myeloma but is associated with cardiovascular adverse events (CVAEs). We prospectively investigated the effect of CFZ on endothelial function and associations with CVAEs. Forty-eight patients treated with Kd (CFZ 20/56 mg/m2 and dexamethasone) underwent serial endothelial function evaluation, using brachial artery flow-mediated dilatation (FMD) and 26S proteasome activity (PrA) measurement in PBMCs; patients were followed until disease progression or cycle 6 for a median of 10 months. FMD and PrA decreased acutely after the first dose (p 40% at the end of first cycle was also independently associated with CVAEs (HR = 3.91, 95% CI 1.29–11.83). Kd treatment impairs endothelial function which is associated with PrA inhibition and recovery. Both pre- and posttreatment FMD predicted CFZ-related CVAEs supporting its role as a possible cardiovascular toxicity biomarker.

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.

Treatment of the plasma cell clone in monoclonal gammopathy of renal significance (MGRS) is necessary in order to reduce toxic immunoglobulin load to the kidneys and salvage renal function. There are limited data on the use of daratumumab in patients with MGRS. We summarize our experience with the use of daratumumab-based therapy in 25 MGRS patients, 12 of whom were previously untreated. The median follow-up of the cohort is 14 months. The best overall haematologic response in evaluable patients was complete response (CR) in five (22%), very good partial response (VGPR) in five (22%) and partial response (PR) in seven (30%) patients for an overall response rate of 74%. Two of five patients in CR and two patients with initially detectable clones, but non-measurable immunoglobulins, had undetectable minimal residual disease (MRD) with next-generation flow cytometry (NGF) after therapy. Haematologic response rate for previously untreated patients was 83% vs. 69% for previously treated and for daratumumab combinations it was 91% vs. 64%, and with CR/VGPR 82% vs. 29%, compared to daratumumab monotherapy. At six months, 12/22 (55%) patients not on dialysis achieved a reduction of proteinuria >30%, of at least 0·5 g/24 h, without an estimated glomerular filtration rate (eGFR) reduction. The toxicity was mild and predictable. In conclusion, daratumumab-based therapy is a new option for patients with MGRS.

A rapid and deep haematologic response is fundamental in order to improve outcomes of patients with AL amyloidosis. We evaluated the impact of timing and depth of haematologic response at early time points (at 1 and 3 months from the start of therapy) in 227 consecutive previously untreated AL patients, who received bortezomib-based primary therapy. After 1 month of therapy, 30.5% had ≥VGPR, 28% PR and 36% no response (NR), with 11% having iFLC

Patients relapsing early after autologous stem cell transplantation (ASCT) are a particular therapeutic challenge.This was a retrospective, single center study that included 297 consecutive patients that received first-line ASCT RESULTS: We identified 43 (14.5%) patients that relapsed within12 months. At diagnosis, these patients had more often elevated lactate dehydrogenase, lower estimated glomerular filtration rate, hypercalcemia, and high-risk cytogenetics; the International Staging System stage distribution was similar. Consolidation and maintenance were associated with lower rates of early relapses. Progression-free survival to second-line therapy was 5 months versus 19 months for those with an early versus late relapse (P .001), the median PFS to second-line therapy was 15.5 months versus5 years (P .001) and the median post-ASCT survival was 18 months versus6 years. The survival after an early relapse has not improved significantly over time. In multivariate analysis, early relapse (hazard ratio, 14; P .001) was the most important prognostic factor for poor survival after ASCT.Patients relapsing12 months after ASCT comprise an ultra-high-risk group, with poor outcomes even with the application of the more recent combinations, that urgently needs more effective therapies.

Panobinostat represents a potent oral nonselective pan-histone deacetylase inhibitor (HDAC) with activity in myeloma patients. It has been approved by the FDA and EMA in combination with bortezomib and dexamethasone for the treatment of multiple myeloma, in patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent. In order to further explore its clinical potential, it is evaluated in different combinations in relapsed/refractory and newly diagnosed multiple myeloma. This review focuses on available data about panobinostat’s pharmacology and its role in clinical practice. This review will reveal panobinostat’s efficacy as antimyeloma treatment, describing drug evolution from preclinical experimental administration to administration in phase III trials, which established its role in current clinical practice. Based on the latest data, we will present its mechanism of action, its efficacy, and most important issues regarding its toxicity profile. We will further try to shed light on its role in current and future therapeutic landscape of myeloma patients. Panobinostat retains its role in therapy of multiple myeloma because of its manageable toxicity profile and its efficacy, mainly in heavily pretreated multiple myeloma patients. These characteristics make it valuable also for novel regimens in combination with second-generation proteasome inhibitors, IMiDs, and monoclonal antibodies. Results of ongoing trials are expected to shed light on drug introduction in different therapeutic combinations or even at an earlier level of disease course.

To gain insights into the characteristics of clinical resistance to lenalidomide, we evaluated the outcomes of 147 consecutive patients with multiple myeloma (MM) homogeneously treated with immunomodulatory imide drugs (IMiDs) pomalidomide and dexamethasone (Pd) for relapsed and/or refractory MM (median, 3 prior lines of treatment). We focused our analysis on the effect of the lenalidomide dose at which resistance was developed, the duration of lenalidomide exposure, and lenalidomide-free interval. On intent to treat, 33% of patients achieved ≥partial remission (PR) with Pd. When Pd was given immediately after lenalidomide, ≥PR was 32% (vs 37% after bortezomib). The response rates were similar for patients that received 5 to 15 mg vs 25 mg of lenalidomide (38.5% vs 30.5%, P = .329). Response rates were higher for patients that had received at least 12 months of lenalidomide (44% vs 27%) and for those with ≥18 months from last lenalidomide dose to pomalidomide dose (65% vs 23%). Median progression-free survival (PFS) and overall survival (OS) were 5 and 12.1 months, respectively, which was similar for patients who received lenalidomide, bortezomib or other regimens just before Pd and similar for patients who were receiving different doses of lenalidomide. IMiD-free interval ≥18 months was associated with longer PFS (10.3 vs 3.9 months, P = .003) and OS (27.1 vs 9.3, P = .008) as well as duration of last lenalidomide therapy ≥12 months (PFS: 7.8 vs 3.2, P = .023; OS: 16.5 vs 7.9, P = .005) even after adjustment for the number of prior therapies, duration of disease, and last lenalidomide dose.

Summary Patients with multiple myeloma (MM) have a suboptimal antibody response following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and lower seroconversion rates following coronavirus disease 2019 (COVID‐19) compared with healthy individuals. In this context, we evaluated the development of neutralising antibodies (NAbs) against SARS‐CoV‐2 in non‐vaccinated patients with MM and COVID‐19 compared with patients after vaccination with two doses of the BNT162b2 vaccine. Serum was collected either four weeks post confirmed diagnosis or four weeks post a second dose of BNT162b2. NAbs were measured with a Food and Drug Administration‐approved enzyme‐linked immunosorbent assay methodology. Thirty‐five patients with COVID‐19 and MM along with 35 matched patients were included. The two groups did not differ in age, sex, body mass index, prior lines of therapy, disease status, lymphocyte count, immunoglobulin levels and comorbidities. Patients with MM and COVID‐19 showed a superior humoral response compared with vaccinated patients with MM. The median (interquartile range) NAb titre was 87·6% (71·6–94%) and 58·7% (21·4–91·8%) for COVID‐19‐positive and vaccinated patients, respectively (P = 0·01).Importantly, there was no difference in NAb production between COVID‐19‐positive and vaccinated patients who did not receive any treatment (median NAb 85·1% vs 91·7%, P = 0·14). In conclusion, our data indicate that vaccinated patients with MM on treatment without prior COVID‐19 should be considered for booster vaccine doses.

Simple Summary Autologous stem cell transplantation (ASCT) remains the standard of care for transplant-eligible newly diagnosed Multiple Myeloma (NDMM) patients. However, despite its overall benefit, patients undergo various clinical outcomes post ASCT. Therefore, the identification of biomarkers that could explain, at least partially, this heterogeneity is of utmost clinical significance. The aim of this study was to assess clonal plasma cell contamination of the stem cell grafts of NDMM and evaluate its potency as a predictive/prognostic marker. Our results showed that worse responses to induction therapy correlate with higher levels of graft contamination. Importantly, our data revealed the significantly higher risk of delaying or not achieving complete remission and minimal residual disease (MRD)-negative responses among patients with graft contamination. Graft contamination is emerging as a promising predictive biomarker of clinical relevance that could be used to stratify patients post ASCT. Abstract High-dose chemotherapy with autologous stem cell support (ASCT) is the standard of care for eligible newly diagnosed Multiple Myeloma (MM) patients. Stem cell graft contamination by aberrant plasma cells (APCs) has been considered a possible predictive marker of subsequent clinical outcome, but the limited reports to date present unclear conclusions. We prospectively estimated the frequency of graft contamination using highly sensitive next-generation flow cytometry and evaluated its clinical impact in 199 myeloma patients who underwent an ASCT. Contamination (con+) was detected in 79/199 patients at a median level 2 × 10−5. Its presence and levels were correlated with response to induction treatment, with 94%, 71% and 43% achieving CR, VGPR and PR, respectively. Importantly, con+ grafts conferred 2-fold and 2.8-fold higher patient-risk of not achieving or delaying reaching CR (4 vs. 11 months) and MRD negativity (5 vs. 18 months) post ASCT, respectively. Our data also provide evidence of a potentially skewed bone marrow (BM) reconstitution due to unpurged grafts, since con+ derived BM had significantly higher prevalence of memory B cells. These data, together with the absence of significant associations with baseline clinical features, highlight graft contamination as a potential biomarker with independent prognostic value for deeper responses, including MRD negativity. Longer follow-up will reveal if this corresponds to PFS or OS advantage.

Simple Summary Multiple myeloma bone disease (MMBD) is one of the most important complications of multiple myeloma with a great impact on quality of life. Recent advances in the field of imaging techniques provided clinicians with a variety of imaging modalities with high sensitivity for the diagnosis of MMBD. However, no circulating biomarkers are available to support the diagnosis of MMBD in cases where the results are inconclusive. The aim of our study was to investigate the clinical utility of 19 miRNAs implicated in osteoporosis in MMBD. Our results suggest that the levels of circulating let-7b-5p, miR-143-3p, miR-17-5p, miR-335-5p, and miR-214-3p (standalone or combined in multi-miRNA models) can effectively predict the presence of MMBD in newly diagnosed MM patients. Abstract Background: Multiple myeloma bone disease (MMBD) constitutes a common and severe complication of multiple myeloma (MM), impacting the quality of life and survival. We evaluated the clinical value of a panel of 19 miRNAs associated with osteoporosis in MMBD. Methods: miRNAs were isolated from the plasma of 62 newly diagnosed MM patients with or without MMBD. First-strand cDNA was synthesized, and relative quantification was performed using qPCR. Lastly, we carried out extensive biostatistical analysis. Results: Circulating levels of let-7b-5p, miR-143-3p, miR-17-5p, miR-214-3p, and miR-335-5p were significantly higher in the blood plasma of MM patients with MMBD compared to those without. Receiver operating characteristic curve and logistic regression analyses showed that these miRNAs could accurately predict MMBD. Furthermore, a standalone multi-miRNA–based logistic regression model exhibited the best predictive potential regarding MMBD. Two of those miRNAs also have a prognostic role in MM since survival analysis indicated that lower circulating levels of both let-7b-5p and miR-335-5p were associated with significantly worse progression-free survival, independently of the established prognostic factors. Conclusions: Our study proposes a miRNA signature to facilitate MMBD diagnosis, especially in ambiguous cases. Moreover, we provide evidence of the prognostic role of let-7b-5p and miR-335-5p as non-invasive prognostic biomarkers in MM.

Noggin is an antagonist of bone morphogenetic proteins (BMPs) and has a strong effect on osteogenesis. Osteoporosis is a common complication of transfusion dependent beta-thalassemia (TDT) and denosumab has been recently emerged as a promising therapeutic option. This was a post hoc investigation of serum noggin levels among TDT patients with osteoporosis who participated in a randomized, placebo-control, phase 2b study.Patients received either 60 mg denosumab (n = 32) or placebo (n = 31) every 6 months for 12 months. Noggin was measured, for the first time in thalassemia patients, at baseline and at 12 months, using a recently developed high sensitivity fluorescent immunoassay.Both groups showed a significant increase in noggin serum levels (denosumab p 0.001; placebo p 0.0001). Interestingly, the increase was higher in the placebo group. Furthermore, we observed a strong correlation between noggin and wrist bone mineral density (r = -0.641, p = 0.002) only in the denosumab group.In conclusion, higher noggin levels reflected more BMP inhibition, since our assay detects free bioactive noggin, which in turn impaired bone formation in placebo group. Therefore, denosumab possibly regulates noggin and favours bone turnover in TDT patients with osteoporosis through a novel mechanism of action.

Carfilzomib with dexamethasone (Kd) is a well-established regimen for the treatment of relapsed/refractory multiple myeloma (RRMM). There is limited information for the effects of Kd on myeloma-related bone disease. This non-interventional study aimed to assess skeletal-related events (SREs) and bone metabolism in patients with RRMM receiving Kd, in the absence of any bone-targeted agent. Twenty-five patients were enrolled with a median of three prior lines of therapy, 72% of them had evidence of osteolytic bone disease at study entry. During Kd treatment, the rate of new SREs was 28%. Kd produced a clinically relevant (≥30%) decrease in C-telopeptide of collagen type-1 (p = 0.048) and of tartrate-resistant acid phosphatase-5b (p = 0.002) at 2 months. This reduction was at least partially due to the reduction in the osteoclast regulator RANKL/osteoprotegerin ratio, at 2 months (p = 0.026). Regarding bone formation, there was a clinically relevant increase in osteocalcin at 6 months (p = 0.03) and in procollagen type I N-propeptide at 8 months post-Kd initiation. Importantly, these bone metabolism changes were independent of myeloma response to treatment. In conclusion, Kd resulted in a low rate of SREs among RRMM patients, along with an early, sustained and clinically relevant decrease in bone resorption, which was accompanied by an increase in bone formation, independently of myeloma response and in the absence of any bone-targeted agent use.

Carfilzomib (CFZ) is a non-reversible proteasome inhibitor approved for the treatment of patients with relapsed and refractory myeloma (RRMM). Its use has been associated with cardiovascular toxicity but although recently a signal of clinically significant renal complications has also been identified, it is less extensively investigated. We analyzed data of 114 consecutive patients with RRMM who received CFZ-based regimens. Renal complications not related to MM progression were observed in 19 (17%) patients; thrombotic microangiopathy (TMA) was seen in 6 (5%) patients, albuminuria >1 gr/day in 7 patients (6%) and at least grade 3 acute kidney injury (AKI) which could not be otherwise explained in 6 patients (5%). A total of 15 patients discontinued CFZ and dosing was reinitiated at a lower level in one patient with AKI. Albuminuria was associated with focal segmental glomerulosclerosis in the renal biopsy (performed in a total of 6 patients). Renal complications during CFZ therapy are common, occur mostly early and are unpredictable. 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.

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.

(1) Background: Soluble urokinase-type plasminogen activator receptor (suPAR) has been implicated in the pathogenesis of kidney disease in different disease settings. The aim of this study was to investigate a possible link between suPAR circulating levels and renal impairment (RI) in newly diagnosed patients with symptomatic multiple myeloma (NDMM) before and after frontline therapy with bortezomib-based regimens. (2) Methods: We studied 47 NDMM patients (57% males, median age 69.5 years) before the administration of anti-myeloma treatment and at best response to bortezomib-based therapy. suPAR was measured in the serum of all patients and of 24 healthy matched controls, using an immuno-enzymatic assay (ViroGates, Denmark). (3) Results: suPAR levels were elevated in NDMM patients at diagnosis compared to healthy individuals (p &lt, 0.001). suPAR levels strongly correlated with disease stage (p-ANOVA &lt, 0.001). suPAR levels both at diagnosis and at best response negatively correlated with estimated glomerular filtration rate (eGFR) values (p &lt, 0.001). Interestingly, no significance changes in suPAR levels were observed at best response compared to baseline values (p = 0.31) among 18 responding patients with baseline eGFR &lt, 50 mL/min/1.73 m2. (4) Conclusions: SuPAR levels reflect renal function in NDMM patients treated with bortezomib-based induction. Responders may have elevated circulating suPAR levels, possibly reflecting persistent kidney damage, despite their renal response.

Monoclonal gammopathies have been associated with a wide spectrum of renal pathologies [1,2]. In symptomatic MM, cast nephropathy is a leading cause of renal dysfunction and acute renal failure [3]...

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.

We retrospectively evaluated 55 consecutive patients who received at least one dose of lenalidomide for relapsed/refractory AL amyloidosis. Their median age was 63 years; 72% had heart and 75% kidney involvement and 13% were on dialysis; while 20%, 46% and 34% had Mayo stage -1, -2 and -3 disease, respectively. Median time from start of primary therapy to lenalidomide was 15 months (range 2–100) and median number of prior therapies was 1 (range 1–4); 73% of the patients had prior bortezomib and 42% were bortezomib-refractory. On intent to treat, haematologic response rate was 51% (5.5% CRs, 20% VGPRs) and was 56% versus 40% for patients with and without prior bortezomib and 47% versus 62.5% for bortezomib refractory versus non-refractory patients (p = .351). Organ response was achieved by 16% of evaluable patients (22% renal, 7% liver and 3% cardiac); however, 10 (21%) patients progressed to dialysis. Median survival post lenalidomide was 25 months. Bortezomib-refractory patients had worse outcome (median survival of 10.5 versus 25 months for bortezomib-sensitive patients versus not reached for bortezomib-naive patients, p = .011). Median lenalidomide dose was 10 mg and no patient received the 25 mg dose; however, in 60% a dose reduction was required. Median duration of lenalidomide therapy was 7.2 months and 46% discontinued lenalidomide before completion of planned therapy, mainly due to toxicity (26%) or disease progression/no response (13%). We conclude that although lenalidomide is a major salvage option for patients with relapsed/refractory AL amyloidosis, its toxicity in patients with AL amyloidosis is significant and doses should be adjusted for optimal tolerability.

Bone disease (BD) is one of the most common features of multiple myeloma. Seventy to eighty percent of patients at diagnosis present with lytic lesions which may lead to skeletal-related events. Areas covered: The aim of this review is to present the possible adverse profile of bisphosphonates (BPs) on renal function, the underlying mechanisms by which BPs may affect renal function and the novel therapeutic approaches on myeloma bone disease management. Expert commentary: BPs remain the cornerstone in the management of myeloma-related BD. Zoledronic acid and Pamidronate are currently the gold standard, however cannot be used in patients with severe renal dysfunction. Renal impairment is another hallmark of myeloma with approximately 60% of the patients presenting with or developing renal dysfunction during the disease course. Although BPs rarely cause renal impairment, they should be administered with caution in patients with impaired renal function. The exact mechanism by which BPs cause renal impairment is yet to be elucidated. Another promising agent is denosumab, a RANKL inhibitor, which can be administrated regardless of renal function and does not need the relevant dose-adjustments.

Liquid biopsyis being integrated into cancer diagnostics with profound therapeutic implications. However, its role in Waldenström’s Macroglobulinemia (WM) and IgM monoclonal gammopathies is still unclear. In this study, we evaluated the role of peripheral blood (PB) cell-free DNA (cfDNA) in characterizing the mutational status of MYD88 and CXCR4 of patients with IgM monoclonal gammopathies. Paired bone marrow (BM) tumor DNA (tDNA) and PB cfDNA samples from 98 patients (9 MGUS, 45 with WM in remission, 44 with smoldering WM, newly diagnosed or relapsed WM) and 10 controls with non-IgM monoclonal gammopathies were analyzed. Regarding MYD88L265P mutation, 76 patients had paired tDNA and cfDNA informative samples. Among patients with WM in remission, 65% harbored the MYD88L265P mutation, whereas the corresponding percentage among smoldering/newly diagnosed or relapsed WM was 92%. The overall concordance rate was 94% (72/76). For CXCR4 mutations, 65 patients had paired informative tDNA and cfDNA samples. The overall concordance rate was 90% (59/65). All controls had wild-type MYD88 and CXCR4. In conclusion, PB cfDNA is a useful, minimally invasive, cost-effective, and time-effective tool for the identification of the presence of MYD88 and CXCR4 mutations in patients with IgM monoclonal gammopathies avoiding unnecessary BM assessment.

Multiple myeloma (MM) is characterized by bone destruction due to increased bone resorption and decreased bone formation. Semaphorin 4D (CD100, Sema4D) is expressed by osteoclasts, binds to its receptor Plexin-B1, and acts as a mediator of osteoclast–osteoblast interaction that ultimately inhibits osteoblastic bone formation. Preclinical data suggest that Sema4D/Plexin-B1 pathway is implicated in MM-induced bone disease. However, there is no information on the role of Sema4D in MM patients. Thus, we evaluated Sema4D and Plexin-B1 in six myeloma cells lines in vitro; in the bone marrow plasma (BMP) and serum of 72 newly diagnosed symptomatic MM (NDMM) patients and in 25 healthy controls. Only one myeloma cell line produced high Sema4D. BMP and circulating Sema4D and Plexin-B1 levels were significantly higher in MM patients compared to controls (p p p p p = 0.07), while patients with diffuse MRI pattern had higher BMP Sema4D levels (p = 0.02). Our data suggest that Sema4D is elevated in MM patients and correlate with adverse myeloma features and increased bone resorption, providing a possible target for novel therapeutic approaches in MM.

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.

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.

Carfilzomib has improved survival in patients with relapsed/refractory multiple myeloma (RRMM), but it may exert cardiovascular adverse events (CVAEs). The aim of this study was to assess whether treatment with daratumumab may ameliorate carfilzomib-related toxicity. We prospectively evaluated 25 patients with RRMM who received either daratumumab in combination with carfilzomib and dexamethasone (DaraKd) (n = 14) or Kd (n = 11). Cardiac ultrasound was performed before treatment initiation and C6D16 or at the time of treatment interruption. Patients were followed for a median of 10 months for CVAEs. The mean (± SD) age was 67.8 ± 7.6 years and 60% were men. The two treatment groups did not significantly differ in baseline demographic characteristics (p &gt, 0.1 for all). In the DaraKd group, we did not observe any significant change in markers of ventricular systolic function. However, these markers deteriorated in the Kd group, left ventricular (LV) ejection fraction, LV global longitudinal strain, tricuspid annular plane systolic excursion and RV free wall longitudinal strain significantly decreased from baseline to second visit (p &lt, 0.05). A significant group interaction (p &lt, 0.05) was observed for the abovementioned changes. CVAEs occurred more frequently in the Kd than the DaraKd group (45% vs. 28.6%). DaraKd was associated with preserved post-treatment cardiac systolic function and lower CVAE rate compared with Kd. The clinical significance and the underlying mechanisms merit further investigation.

Background Anti-CD38 antibodies can alter myeloma pathobiology, and can potentially overcome refractoriness to IMIDs. 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 anti-CD38-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.

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.

Advances in the management of multiple myeloma (MM) have led to a significant prolongation of both progression-free (PFS) and overall survival (OS). Herein, we evaluated the characteristics of patients who achieved a PFS of at least 7 years following frontline therapy, as compared with all other patients who were treated in a single center during the same time period. Thirty-six (8.8%) patients achieved a PFS of at least 7 years (long PFS group) after frontline treatment. Long PFS patients were younger (p

Bortezomib and dexamethasone with cyclophosphamide (CyBorD) or melphalan (BMDex) are commonly used primary treatments for light-chain (AL) amyloidosis, but limited data exist on bortezomib with immunomodulatory drug combinations. We report our experience with primary therapy with a bortezomib, lenalidomide, and dexamethasone (VRD) “light” regimen in 34 consecutive patients with AL amyloidosis. The majority (79%) had cardiac involvement, 15% and 23% were Mayo stage 3A and 3B, respectively, and 54% had renal involvement. After the first VRD cycle, 71% of patients achieved a hematologic response (44% at least very good partial response [VGPR]). On intent to treat, 11 (32%) achieved a complete response (of whom 5 of 11 were minimal residual disease [MRD] negative at 10(−5)), 17 (50%) a VGPR, and 2 (7%) a partial response. The 12-month survival was 73%. Starting lenalidomide dose was 5 mg in 86% of patients. Hematologic toxicity was mild; nonhematologic toxicities included rash (grade 3/4 [16%]), infections (grade ≥3 [12%]), constipation (grade ≥3 [9%]), and peripheral neuropathy (grade 2 [20%]); 37.5% of patients required lenalidomide dose reduction, 27% discontinued lenalidomide, 38% required bortezomib dose reduction, and 12% discontinued bortezomib. We compared VRD to CyBorD in 68 patients matched for Mayo stage and baseline difference between involved minus uninvolved serum free light chain levels, and observed a trend for deeper response at 3 and 6 months with VRD. In conclusion, VRD can be an active regimen for newly diagnosed patients with AL amyloidosis able to induce very deep hematologic responses at the expense of increased toxicity.

Secretion of monoclonal immunoglobulins (MIg) detected in the serum and/or urine is one of the typical features of multiple myeloma (MM). However, some patients secrete MIg in quantities below “measurable” (termed oligosecretory MM) and others have no detectable MIgs by standard serum and urine immunofixation (termed non-secretory MM). In a cohort of 852 consecutive patients with active myeloma, we identified 100 (11.7%) patients with oligo/non-secretory MM, including 20 (2.3%) with non-secretory MM. Compared to patients with secretory MM, these were younger, less anemic, and had less often renal dysfunction and less extensive bone marrow infiltration. Presence and extent of bone disease were similar, however, hypercalcemia was less common and more often is ISS (International Staging System)-1 and, in those with available FISH (Fluoresense In Situ Hybridization) , high-risk cytogenetics were less common. FLCs (Free Light Chains) were available in 17 patients with non-secretory MM: only 3 had normal FLC ratio; the others had abnormal ratio and 9/14 had involved FLC ≥ 100 mg/L. The 4-year OS for patients with oligo/non-secretory disease was 64% vs 58% for secretory MM. In multivariate analysis, oligo/non-secretory disease was not an independent prognostic factor per se. Thus, 12% of MM patients present with oligo/non-secretory disease at diagnosis and have different biologic characteristics but similar outcome to other MM patients.

In the era of an aging population, an increasing number of patients are diagnosed with multiple myeloma at an age of ≥80. The frailty of this population as a result of coexisting comorbidities and age-related organ impairment is a significant management challenge. The aim of our study was to analyze the disease characteristics, frailty scores and toxicity profile in relation to patient outcomes. Among 827 consecutive, newly diagnosed, symptomatic patients treated since 01 January 2000, we analyzed the characteristics and outcomes of the 110 who were ≥80. Median survival was 21 months, and early mortality within 2 months from diagnosis was 20%. Several factors were associated with inferior survival, whereas in the multivariate analysis, estimated glomerular filtration rate (eGFR) 30 ml/min/1.73m

To compare the outcomes of patients with relapsed or refractory multiple myeloma (RRMM) who were treated with lenalidomide combined with high versus low dose of dexamethasone. One hundred forty consecutive relapsed or refractory multiple myeloma (RRMM) patients who received lenalidomide with dexamethasone, in two consecutive time periods, were divided into two groups: group RD (70 consecutive patients in the first period) who received lenalidomide with intermediate doses of dexamethasone and group Rd (70 consecutive patients in the more recent period) who received lenalidomide with low-dose dexamethasone. 62% and 73% of patients who received RD and Rd (p = 0.148) achieved at least a partial response, accordingly. The median OS was 20 and 41 months for the RD and the Rd group, accordingly. In the multivariate analysis, Rd was associated with improved PFS. More patients treated with RD developed grade 3&4 neutropenia and fatigue. It seems that Rd is at least as effective as RD.

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 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.

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.

Context: Autologous stem cell transplantation (ASCT) is the standard frontline therapy for newly diagnosed multiple myeloma (MM) eligible patients. “Contamination” of leukapheresis products with aberrant plasma cells (PCs) has been considered as a possible predictive factor for response and outcome. Objective: To evaluate the frequency and clinical value of clonal PCs remaining in leukapheresis products using next generation flow cytometry (NGFC), which is able to detect aberrant clonal PCs at levels reaching 10−6. Design: Prospective study. Setting: A referral center in Athens, Greece. Patients: MM patients after four cycles of induction therapy (VCD or VRD) followed by ASCT in the Department of Clinical Therapeutics, University of Athens, Greece. Interventions: Ninety-eight patients with newly diagnosed multiple myeloma were assessed for the presence of clonal PCs with the 8-color NGFC protocol suggested by EuroFlow. Eight to ten million cells were examined; the median sensitivity of the test was 2–4 × 10−6 per sample. All patients received high-dose melphalan and ASCT. Using the same NGFC protocol, 53 patients who achieved complete response (CR) post-ASCT, based on the IMWG criteria, were also examined for the presence of minimal residual disease (MRD). Main outcome measures: Aberrant PCs in leukapheresis products. Results: This analysis revealed 58 (59%) “uncontaminated” (con-) and 40 (41%) “contaminated” (con+) leukapheresis products. The majority of con+ cases had very low numbers of aberrant plasma cells detected; 18 (45%) at the level of 10−615 (38%) at the level of 10−4 and 7 (18%) at levels ≥10−3. On day 100 post-ASCT, MRD evaluation was performed on 33 con- and 20 con+ patients, who had achieved CR. MRD positivity was found in 11 out of 53 cases (20.8%). Only 3 out of 33 (9.1%) con- patients were found MRD+, all of which at very low levels ( Conclusions: Using NGFC, we were able to detect aberrant plasma cells in 40% of apheresis products at the level of 10−6. The presence of aberrant plasma cells in the apheresis products correlates with higher probability for MRD+ after ASCT, whereas their absence predicts MRD negativity.

Context: 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). Objective: To evaluate the SRE rate in MM patients who received frontline and second-line therapy with proteasome inhibitors (PIs) or immunomodulatory drug (IMiD)-based therapies. Design: Prospectively maintained database. Setting: A referral center in Athens, Greece. Patients: MM patients who received frontline therapy in the Department of Clinical Therapeutics, University of Athens, Greece, between 20072017. Interventions: Patients had a whole-body skeletal survey using either conventional radiography (WBXR) or low-dose CT (WBLDCT) at diagnosis and whenever clinically indicated. Main outcome measures: SRE incidence. Results: 620 consecutive patients with symptomatic MM (316M/304F, median age: 65 years) were studied. The median follow-up was 54 months. SREs were observed in 271 (44%) patients at diagnosis: 213 (34%) presented with pathological fractures, while 34 (5.5%) needed bone surgery, 45 (7.2%) radiotherapy, and 31 (5%) patients presented with SCC. SRE incidence was higher in patients with osteolytic lesions (76.4% vs. 12.4%, P Conclusions: SREs remain a significant complication in MM.

Optimizing consolidation treatment in transplant-eligible newly diagnosed multiple myeloma patients in order to improve efficacy and bone-related outcomes is intriguing. We conducted an open-label, prospective study evaluating the efficacy and safety of bortezomib and lenalidomide (VR) consolidation after ASCT, in the absence of dexamethasone and bisphosphonates. Fifty-nine patients, who received bortezomib-based induction, were given 4 cycles of VR starting on day 100 post-ASCT. After ASCT, 58% of patients improved their response status, while following VR consolidation 39% further deepened their response; stringent complete response rates increased to 51% after VR from 24% post-ASCT. VR consolidation resulted in a significant reduction of soluble receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio and sclerostin circulating levels, which was more pronounced among patients achieving very good partial response or better. After a median follow-up of 62 months, no skeletal-related events (SREs) were observed, despite the lack of bisphosphonates administration. The median TTP after ASCT was 37 months, while median overall survival (OS) has not been reached yet; the probability of 4- and 5-year OS was 81% and 64%, respectively. In conclusion, VR consolidation is an effective, dexamethasone- and bisphosphonate-free approach, which offers long OS with improvements on bone metabolism and no SREs.

Pre-existing pulmonary disease may affect treatment choices, toxicity, and survival of patients with multiple myeloma (MM). However, data on the prognostic value of pulmonary function tests (PFTs) in myeloma patients’ outcome, at the time of initial assessment of newly diagnosed patients, are scarce. Here, we prospectively performed PFTs in 121 newly diagnosed MM patients, before initiation of treatment, and we evaluated possible associations of lung function with their outcomes. Fifty-four patients (44.63%) had either obstructive or restrictive pulmonary function defects, even among those not reporting a history of lung disease. The survival was significantly worse in those with obstructive pulmonary defect (median OS 32.8 months) vs. those with restrictive (median OS 52.5 months) or normal lung function (median not reached, 3-year survival 76%) (p = 0.013), independently of other myeloma-related factors. Forced vital capacity (FVC) (lt) (p = 0.012), forced expiratory volume in 1 s (FEV1) (lt) (p = 0.018), peak expiratory flow (PEF) (lt/min) (p = 0.008), carbon monoxide diffusion capacity (DLCO) (p = 0.012), and expiratory/inspiratory pressures (Pe) (kPa) (p = 0.032)/(Pi) (kPa) (p = 0.023) were significantly associated with OS. Myeloma-related factors associated with survival included ISS stage (p = 0.008), hypercalcemia (p = 0.064), and high-risk cytogenetics (p = 0.004). In the multivariate analysis, only the presence of high-risk cytogenetics and presence of either or both PEF and DLCO

The treatment of light chain (AL) amyloidosis aims to completely eliminate the toxic light chain production, as assessed by sensitive serum- or urine-based methods such as immunofixation and free light chain (FLCs) quantification. Complete hematologic responses (hemCR) can be achieved in a significant proportion of patients with AL, either with conventional therapies or with high-dose melphalan, and are associated with better overall survival and improved organ function. However, hematologic relapses still occur and organ function may continue to deteriorate due to small residual clones that may lead to disease recurrence and/or may produce very small amounts of toxic light chains which are undetectable by conventional techniques. Next-generation flow cytometry (NGF) is a very sensitive method for the evaluation of minimal residual disease (MRD) and one of the standard methods for the assessment of MRD in patients with multiple myeloma (MM), reflected in the new response assessment criteria2. Patients with MM who are negative for MRD have significantly improved progression-free and overall survival, even among those who have achieved a CR3,4. Such data are sparse in patients with AL amyloidosis, although the presence of MRD may prove a crucial factor for delayed organ response or deterioration of organ function despite conventional hemCR. The aim of the current study was to evaluate feasibility and applicability of MRD by NGF in patients with AL at hemCR.

Bone disease is one of the most common complications of multiple myeloma. It is the result of increased osteoclast activity which is not compensated by osteoblast activity and leads to osteolytic lesions characterized by bone pain and increased risk for pathological fracture, spinal cord compression and need for radiotherapy or surgery to the bone. Recent studies have revealed novel pathways and molecules that are involved in the biology of myeloma bone disease including the receptor activator of nuclear factor-kappa B ligand/osteoprotegerin pathway, the Wnt signaling inhibitors dickkopf-1 and sclerostin, macrophage inflammatory proteins, activin A, and others. A thorough study of these pathways have provided novel agents that may play a critical role in the management of myeloma related bone disease in the near future, such as denosumab (anti-RANKL), sotatercept (activin A antagonist), romosozumab (anti-sclerostin) or BHQ-880 (anti-dickkopf 1). Currently, bisphosphonates are the cornerstone in the treatment of myeloma related bone disease. Zoledronic acid and pamidronate are used in this setting with very good results in reducing skeletal-related events, but they cannot be used in patients with severe renal impairment. Furthermore, they have some rare but serious adverse events including osteonecrosis of the jaw and acute renal insufficiency. This review paper focuses on the latest advances in the pathophysiology of myeloma bone disease and in the current and future treatment options for its management.

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.