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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. Imaging techniques for the diagnosis of multiple myeloma bone disease include whole-body X-rays, whole-body low-dose CT (WBLDCT), magnetic resonance imaging (MRI), and PET-CT. Bisphosphonates (BPs) are the cornerstone in the treatment of myeloma-related bone disease. 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. The thorough study of these pathways has 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). In this chapter, we will focus in the imaging techniques used for the diagnosis of multiple myeloma bone disease, as well as the current and future options for its management.

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.

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

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

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

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

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

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

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

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

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

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

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

Supplemental Digital Content is available in the text, Minimal residual disease (MRD) was monitored in 52 patients with sustained CR (≥2 years) after frontline therapy using next-generation flow (NGF) cytometry. 25% of patients initially MRD- reversed to MRD+. 56% of patients in sustained CR were MRD+; 45% at the level of 10−5; 17% at 10−6. All patients who relapsed during follow-up were MRD+ at the latest MRD assessment, including those with ultra-low tumor burden. MRD persistence was associated with specific phenotypic profiles: higher erythroblasts’ and tumor-associated monocytes/macrophages’ predominance in the bone marrow niche. NGF emerges as a suitable method for periodic, reproducible, highly-sensitive MRD-detection at the level of 10−6.

Multiple myeloma remains an incurable disease despite the introduction of the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor bortezomib that have improved the outcome of patients with both newly diagnosed and relapsed/refractory disease. However, patients who relapse after treatment with these agents or are refractory to them represent an unmet need and highlight the necessity for the development of novel anti-myeloma agents. Pomalidomide is an IMiD, structurally related to thalidomide, with enhanced antiangiogenic, antineoplastic, and anti-inflammatory properties and exhibiting potent anti-myeloma activity in vitro and in vivo. Pomalidomide has shown remarkable activity in patients who were refractory to both bortezomib and lenalidomide in Phase II and III studies. This paper reviews the chemistry and mechanisms of action of pomalidomide as well as all the available data from clinical trials on pomalidomide use in patients with refractory/relapsed multiple myeloma.

Clinical trials with carfilzomib have indicated a low but reproducible incidence of cardiovascular and renal toxicities. Among 60 consecutive myeloma patients treated with carfilzomib-based regimens who were thoroughly evaluated for cardiovascular risk factors, 12% (95% confidence interval, 3.8%-20%) experienced a reversible reduction of left ventricular ejection fraction (LVEF) by ≥20%, an objective measure of cardiac dysfunction. The incidence of LVEF reduction was 5% at 3 months, 8% at 6 months, 10% at 12 months, and 12% at 15 months, whereas the respective carfilzomib discontinuation rate unrelated to toxicity was 17%, 35%, 41%, and 49%. The presence of any previously known cardiovascular disease was associated with an increased incidence of cardiac events (23.5% vs 7%; P = .07), but there was no association with the dose of carfilzomib or the duration of infusion. Re-treatment with carfilzomib at lower doses was possible. Carfilzomib was commonly associated with a transient reduction of estimated glomerular filtration rate (eGFR) but also improved renal function in 55% of patients with baseline eGFR

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

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

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

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

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

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

Renal failure (RF) is a common severe complication of symptomatic myeloma and may be severe enough to require extrarenal dialysis in approximately 1-5% of newly diagnosed patients. Severe RF is associated with high risk of early death and increased morbidity. Immediate effective anti-myeloma therapy and vigorous supportive care are the cornerstones of management. The use of high cutoff hemodialysis to rapidly reduce the load of nephrotoxic light chains seems to offer limited additional benefit in patients requiring dialysis when treated with bortezomib-based therapies (Cook M et al EHA 2016, Abs P270). However, outside clinical trials, there are limited data focusing on the management and outcomes of NDMM patients requiring dialysis. Thus, we analyzed the outcomes of consecutive newly diagnosed patients with RF requiring dialysis, who were managed and treated in a single center. Between 1995 and 2016, 50 patients (6.2% of 796 consecutive NDMM) who were treated in the Department of Clinical Therapeutics (Athens, Greece) presented with severe RF requiring dialysis. The analysis included all patients who received at least one dose of any therapy. All patients received similar supportive care and dialysis with regular filters. The median age of patients requiring dialysis was 69 years (37-88), 68% were >65 years of age. At presentation 92% had Hb Treatment was bortezomib-based in 41 (82%) patients: 11 (22%) had bortezomib + dexamethasone (VD), 21 (42%) VD + cyclophosphamide (VCD), 8 (16%) VD + thalidomide (VTD), 1 (2%) VD + doxorubicin (PAD). Nine (18%) patients received non-bortezomib containing regimens: 5 (10%) thalidomide plus high dose dexamethasone and 4 (8%) VAD with high dose dexamethasone. Twenty-five (50%) patients became dialysis independent at a median time of 158 days from start of therapy (range 4-336 days). Age ≤65 years was associated with higher probability (75% vs 38%) and shorter time to dialysis independence (51 vs 336 days; p=0.027); no other baseline factors were associated with dialysis independence in univariate analysis. Among patients treated with bortezomib, three-drug combinations (n=30) vs VD alone (N=11) were associated with higher probability of dialysis independence (57% vs 27%; p=0.06). Among patients who became dialysis independent 12 received VCD, 4 VTD, one PAD, 3 VD, 2 MDT, 2 VAD and one T-VAD. Median follow up for all patients was 33 months and median survival was 29 months. Early mortality (within 2 months from start of therapy) was 16%, mostly due to infectious complications. On intent to treat, 64% achieved ≥PR (CR: 6%, VGPR: 32%, PR: 26%); among patients who survived >2 months, ≥PR was achieved by 76%. At 2-month landmark, patients who achieved ≥PR within the first 2 months had higher dialysis independence rates (68% vs 27%, p=0.004). Becoming dialysis independent was associated with a significant improvement in survival (median OS of 63 vs 22 months of patients who remained on dialysis; p=0.002), even after exclusion of early deaths. Notably, the survival of patients who discontinued dialysis was similar to that of the rest of patients (57 months). High dose melphalan (HDM) followed by autologous stem cell transplantation was performed in five patients while on dialysis. Four of them (80%) become dialysis independent approximately one month after HDM. In conclusion, about 6% of NDMM present with renal failure requiring dialysis but half of them can become dialysis independent after bortezomib-based therapy, without the use of special filters, especially if they achieve a rapid myeloma response. VD-based triplets increase the probability of renal response over VD alone and independence from dialysis is associated with a significant improvement in prognosis. Disclosures Dimopoulos: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Celgene: Honoraria; Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding. Kastritis:Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Pomalidomide with low dose dexamethasone (Pd) is a standard treatment for patients who have failed both lenalidomide (Len) & bortezomib (Bor). Phase III studies showed that Pd is active irrespective of the number of prior therapies and whether Len or Bor were the last therapies prior to Pd. However, it remains unclear what is the activity of Pd when administered immediately after refractoriness to Len or when is administered following secondary resistance. Furthermore, the importance of the time elapsed from the administration of Len to Pd has not been explored. We analyzed the outcomes of 116 consecutive patients with MM after failure of both Len & Bor that were treated in the Department of Clinical Therapeutics, National and Kapodistrian University of Athens, and who all received pomalidomide 4 mg with weekly dexamethasone. Median age was 62 years (range 38-86 years); median number of prior treatments was 4 (range 1-9), 58% had received ASCT, 73% were refractory to the last Bor-based regimen and 90% were refractory to the last Len-based regimen. All patients had MM refractory to the last regimen, but 40% had ≥PR to their most recent regimen prior to development of refractoriness. The last regimen prior to Pd included Bor in 62 (53%), Len in 35 (30%) and conventional chemo in 19 (17%). On intent to treat, 34 (29%) patients achieved ≥PR (CR: 3%, VGPR: 7%, PR: 19%). In those which received Len just prior to Pd, ≥PR rate was 26% vs 33% for Bor and 21% for other regimens (p=0.55). Among patients with Median follow up was 29 months and 95 (83%) patients have progressed or died. Median PFS was 5.2 months (95% CI 3.8-6.5). Patients who received Len as their last treatment before Pd had PFS similar to that of patients who received either Bor or other regimens (p=0.8). Patients who had ≥PR when treated with Len immediately before Pd (secondary resistant to Len), had PFS similar to that of those with In conclusion, Pd is active in MM patients refractory to Len, independently of primary or secondary resistance to Len or if Len was used just prior to Pd. However, patients with ≥18 months of Len-free interval may have longer PFS and OS irrespectively of prior lines of therapy. These data indicate the potential role of "clonal tides" and the emergence of IMiD-sensitive clones after "IMiD-free" periods, but further investigation is needed to identify optimal treatment strategy. Disclosures Dimopoulos: Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Delimpasi:Genesis: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Terpos:Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; BMS: Consultancy, Honoraria; Novartis: Honoraria; Celgene: Honoraria. Kastritis:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Genesis: Consultancy, Honoraria.

Adiponectin is a multimeric protein of the white adipose tissue which has anti-inflammatory, anti-atherogenic, and possibly anti-neoplastic properties. Low levels of adiponectin are associated with endothelial dysfunction in several disorders, while low levels of circulating adiponectin have been recently associated with increased risk for multiple myeloma (MM) in overweight individuals. Furthermore, decreased host-derived adiponectin promotes myeloma tumor growth and osteolysis in myeloma animal models. There is no information in the literature for adiponectin levels in MM patients. The aim of this study was to evaluate circulating adiponectin in MM patients who responded to first line anti-myeloma therapy and explore possible correlations with disease features, including bone disease, endothelial dysfunction which is present in several plasma cell dyscrasias (Waldenstrom's macroglobulinemia and AL amyloidosis), angiogenesis and inflammation. We studied 76 newly-diagnosed MM patients (46M/30F, median age 70.5 years) before the administration of any kind of therapy and after best response to front-line therapy. Forty-five patients received bortezomib-based regimens, while 31 patients were treated with IMiD based regimens (16 with lenalidomide-based therapies). Evidence of bone involvement was documented using plain radiographs. Adiponectin was measured in the serum of all patients and of 24 healthy individuals of similar age, gender and body index along with a series of biochemical markers of: i) endothelial (vWF:antigen and GDF-15) and cardiovascular dysfunction (hs-troponin and NTproBNP); ii) angiogenesis (placental-growth factor, PlGF and its receptor sFlt-1); iii) renal impairment (cystatin-C and NGAL); iv) bone disease (CTX and P1NP); and v) inflammation (hs-CRP and IL-6). Adiponectin levels were elevated in MM patients at diagnosis compared to healthy individuals (mean±SD: 16.2±2.6 mg/L vs. 11.8±0.8 mg/L; p=0.03). The circulating vWF concentrations were markedly elevated in patients compared to controls (mean±SD: 215±16.3 IU/dl vs. 85.3±5.1; p Adiponectin negatively correlated with M-protein (r=-0.408, p=0.01), serum calcium (r=-0.391, p=0.015) and GDF-15 (r=-0.40, p=0.01) and positively with NGAL (p=0.395, p=0.014) and CTX (p=0.385, p=0.018). VWF:antigen strongly correlated with beta2-microglobulin (r=0.524, p=0.001) and all factors of renal impairment: urea (r=0.416, p=0.009), creatinine (r=0.431, p=0.007), cystatin-C (r=0.400, p=0.012), NGAL (r=0.400, p=0.013) and eGFR (based on CKD-EPI; r=-0.416, p=0.009). Both adiponectin and vWF correlated with bone marrow plasma cell infiltration (r=-0.376, p=0.031 and r=0.354, p=0.043, respectively). Notably, all markers of endothelial and cardiovascular dysfunction increased with the increase of ISS stage: p-ANOVA for hs-troponin, NTproBNP and GDF-15 The studied population included 16 (21%) patients who achieved a CR, 19 (25%) with vgPR and 41 with PR. Response to anti-myeloma therapy resulted in a dramatic increase of adiponectin (from 16.2±2.6 mg/l to 24.2±4.2 mg/l, p We conclude that adiponectin and markers of endothelial and cardiovascular dysfunction are elevated in newly-diagnosed patients with MM. Adiponectin and vWF correlates with bone marrow plasma cell infiltration, while all markers of endothelial and cardiovascular dysfunction correlated with ISS stage. Response to therapy increased circulating adiponectin. These results support a role of adiponectin in disease biology as suggested by experiments in murine myeloma models. Disclosures Terpos: Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Novartis: Honoraria. Kastritis:Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Treatment of AL amyloidosis is based on the elimination of the plasma cell clone that produces the amyloidogenic light chains. Typically, these are indolent clones and plasma cell burden is low, thus, even low dose, low toxicity, regimens may be very effective. Bortezomib is effective in targeting plasma cells. Several series have also shown that bortezomib either as single agent or in combinations, such as bortezomib with dexamethasone (VD) or with the addition of cyclophosphamide (VCD) induce high rates of hematologic CRs and organ responses. Patients with AL are frail due to multisystemic involvement and data from the treatment of frail patients with myeloma, usually elderly ones, have shown that addition of a third agent to VD does not improve outcomes and may increase toxicity. However, VCD is considered as a "standard" regimen for primary therapy of patients with AL, in most centers, but, it is not clear whether the addition of a third drug (cyclophosphamide) to bortezomib/dexamethasone (VD) further and significantly improves efficacy, given the substantial activity of bortezomib itself. Thus, we compared the outcomes of patients with AL amyloidosis who received (VD) or with VD plus a third agent (VCD). The analysis included 101 consecutive patients with biopsy confirmed AL amyloidosis, all diagnosed and treated in the Department of Clinical Therapeutics, Athens, Greece. All patients received similar supportive care and were treated in two consecutive periods (up to 2010 received VD and after 2011 received VCD). Median age was 65 years, 70% had cardiac and 71% renal involvement; Mayo stage was -1, -2 & -3 in 20%, 47% & 33% while renal stage was -1, -2 and -3 in 22%, 56% & 22% of the patients respectively. Treatment was VD in 59 (58%) and VCD in 42 (42%) patients. Compared to patients who received VCD, patients who received VD were older (median age 67 vs 60.5 years, p=0.024), were more often Mayo stage 3 (42% vs 29%, p=0.03), had lower eGFR (median 54 vs 86 ml/min/1.73 m2) but had similar distribution in renal stages. Heart, renal and nerve involvement were similar between those who received VD vs VCD (p>0.5 for all). According to our institutional guidelines for patients with AL amyloidosis schedule of bortezomib (twice per week vs weekly) and dexamethasone are adjusted to cardiac risk and presence of neuropathy. Weekly bortezomib was given in 41% of patients who received VD and vs 40% with VCD and the starting dose was 1.3 mg/m2 in 90% and 92.5% respectively. The median dose of dexamethasone for all patients was 160 mg/month, but for patients treated with VD was 240 mg/month and was 144 mg/month for those treated with VCD (p=0.01). Early mortality ( On intent to treat a hematologic response was achieved by 72% (CR:25%, VGPR:17% , PR: 30%) and was 68% for patients treated with VD and 78% for VCD (p=0.26); after adjustment for Mayo stage there was still no difference in response rates. Regarding CR+VGPR, it was 47.5% with VD and 35% with VCD. Notably higher doses of dexamethasone or twice-weekly bortezomib schedule were not associated with significantly higher hematologic response rates or CR+VGPR rates. Organ responses occurred in 35% of patients (cardiac in 26%, renal in 42%). For VD, cardiac response rate was 29% and renal response rate was 43%, while for VCD cardiac response was 21% and renal response was 41% (p>0.5 for all comparisons). Median follow up is 3 years and median overall survival (OS) is 34 months. Median OS of patients treated with VD vs VCD was similar (33 vs 36 months, p=0.45). After adjustment for the dose and schedule of bortezomib and dexamethasone, and Mayo stage, still there was no difference in the OS between patients treated with VD vs VCD and no prognostic effect of higher doses of dexamethasone and twice weekly bortezomib was found. In conclusion, our data indicate that bortezomib even with low doses of dexamethasone is effective for the treatment of AL amyloidosis; higher doses of dexamethasone and addition of a third agent (cyclophosphamide) does not seem to have a profound effect on efficacy and survival. Our data also indicate the limits of bortezomib-based therapies, and new agents either targeting the plasma cell clone (like monoclonal antiCD38) or targeting the amyloid deposits are needed. Disclosures Kastritis: Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Terpos:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria. Dimopoulos:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Carfilzomib (CFZ) combinations have shown activity in phase 2 and 3 studies in multiple myeloma (MM) patients but also a small but consistent signal of cardiac and renal toxicity. The aim of our study was to analyze potential cardiac and renal toxicity of CFZ combinations in consecutive MM patients. The analysis included 60 patients treated with different combination of CFZ in a single center (University of Athens, Greece): 48 (80%) had relapsed or refractory (RRMM) and 12 (20%) had newly diagnosed MM (NDMM). All had baseline evaluation of cardiovascular risk factors and echocardiography with a LVEF ≥40%. Regimens included Kd in 31 (52%), KRd in 17 (28%) and KMP in 12 (20%) patients. CFZ dose was 20/27 in 27 (45%) patients, 20/36 in 12 (20%) and 20/56 in 21 (35%). Median age was 72 (range 39-76) years and 65% were males. Median number of prior therapies was 2 (range 0-7). Median baseline eGFR was 88 ml/min (range 16 to> 120 ml/min), 33% had eGFR Median duration of CFZ therapy was 10 (range 1-43) cycles. During therapy with CFZ, 7 (12%) patients had a reduction in LVEF ≥20% within a median of 6 months (range 1-13 months) from initiation of CFZ. In 6/7 patients, dyspnea of grade (gr) ≥2 was also present and was associated with a significant increase of NTproBNP (median 2412, range 2219-10162 pg/ml) without increase in troponins. With discontinuation because of disease progression or other unrelated reasons as a competing event, the incidence of LVEF reduction ≥20% was 5% at 3 months, 8% at 6 months, 10% at 12 months and 12% at 15 months. The respective CFZ discontinuation rate unrelated to cardiac toxicity was 17%, 35%, 41% and 49%, respectively (Figure). Among cardiovascular risk factors (age, smoking, hypertension, hypelipidemia, diabetes, renal dysfunction) only peripheral artery disease was associated more often with cardiac events (3/7, 43% vs 4/53,8%, p=0.02). The use of ACE-I, ARBs or CCBs was not associated with cardiac events, however, the use of b-blockers was more common in patients who had LVEF reduction (3/10, 30% vs 4/50, 8%, p=0.048); patients on b-blockers also experienced LVEF reduction earlier [2% vs 20% at 3 months, 6% vs 20% at 6 months and 6% vs 30% at 12 months (p=0.02)], while non-toxicity discontinuation at 12 months was 44% vs 57% (p=0.66). There was no association with prior anthracycline exposure or prior HDT and the dose of CFZ was not associated with cardiac event frequency or timing. Baseline parameters of cardiac function assessed by echocardiography did not show correlation with cardiac events. Further evaluation in all patients who had EF reduction established the diagnosis of coronary artery disease (CAD) in 3/7. In all patients LVEF improved after holding CFZ ( We also evaluated the effects of CFZ in renal function, excluding renal dysfunction associated with disease progression. Per CTCAE v4.03, 22 (37%) patients had a creatinine increase ≥gr 1 (18% gr1, 17% gr2 and 2% gr3). According to the same criteria for acute kidney injury (AKI), 17 (28%) patients experienced AKI ≥gr 1 (gr1 in 25% and gr3 in 3%) while 21 (35%) had a reduction of their eGFR by ≥25%, which was transient in 13/21 (62%). These events occurred mostly early, within the 1st cycle in 9/21 (43%). Two patients, both in CR, developed TTP, one after 22 and the other after 8 cycles of CFZ. Higher doses of CFZ were associated with higher frequency of eGFR reduction ≥25% (22% vs 33% vs 52% for 20/27, 20/36 and 20/56 doses respectively, p=0.093). Age >65 years was not associated with higher risk of AKI (25% vs 35% for those 60 ml/min. In conclusion, cardiac toxicity after CFZ occurred in 12% of patients, but was essentially unpredictable and reversible in all patients; standard cardiovascular risk factors were not predictive of cardiac toxicity. However, in about half of the patients was associated with underlying CAD, indicating that further investigation is needed regarding the effects of CFZ to vascular function and endothelium. Decrease in eGFR and low grade AKI is common but transient, and can be associated with higher doses of CFZ. Importantly, 55% of patients with moderate CKD improved their renal function after treatment with CFZ. Figure Figure. Disclosures Dimopoulos: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Novartis: Honoraria. Kastritis:Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

The diagnosis of MM that requires therapy in elderly individuals is increasing. The management of such patients is challenging due to several factors, besides disease characteristics and age that affect outcome. Geriatric assessment (GA) is a multidimensional diagnostic approach that collects data on the medical, psychosocial and functional capabilities and limitations of elderly patients to develop treatment and care decisions and improve the use of health care resources. The IMWG has proposed a simplified GA ("frailty score") based on 3 tools (Katz Activity of Daily Living (ADL), the Lawton Instrumental Activity of Daily Living (IADL) and the Charlson Comorbidity Index (CCI)) as a measure of frailty (Palumbo et al, Blood 2015). "Frailty score" was developed on patients who participated in clinical trials, thus, may have a selection bias. In our current "Real-World" study, we prospectively evaluated consecutive patients >65 years, irrespective of their participation in clinical trials and physical condition, in order to evaluate several different GA tools and comorbidity indices, along with standard disease related prognostic factors. The following tools were used: G8 geriatric assessment screening tool (G8-GAS), VES-13, GDS, Katz ADL, Lawton IADL, MMSE, KPS (%), ECOG PS, number of falls in the past 1 & 6 months, lower-extremity function and disability in elderly tool, nutritional assessment tools (DETERMINE and Mini Nutritional Assessment), social support score, cognition evaluation tools (MMSE), Geriatric Depression Scale and comorbidity indices (CCI, CIRS-G, ACE-27 tool). Since January 2012, 120 consecutive patients >65 years were diagnosed with symptomatic MM in our center (Department of Clinical Therapeutics, University of Athens) and had a GA. The median age of patients with a GA was 76 years (range 66-92); 55% were males; 26% had ISS-1, 24% ISS-2 and 50% ISS-3. In 100 patients cytogenetics were available: 19% had high risk cytogenetics (del17p or t(4;14)). Median eGFR was 60 ml/min/1.73 m2 and 22% had eGFR80 years was 1, 1.5 and 3 and early death rates were 3%, 8% and 20%, respectively. ISS was associated with OS (p=0.004) but the presence of high risk cytogenetics was not (2-year OS 75% vs 68%, p=0.714). There was no significant difference in the OS according to different types of primary therapy (p=0.593). Per IMWG "frailty score", 29% were fit, 17% intermediately fit and 54% frail; the respective 2-year OS was 77%, 81% and 62%. The differences in the allocation of patients in frailty categories compared to the original IMWG cohort (39%, 31% & 30%) is probably due to the fact that our patients were unselected. In univariate analysis several different GA tools showed prognostic significance: number of falls in the past 6 months (0 vs ≥1, p=0.002), lower extremity function (score 2 (p=0.04) and MMSE (score ≥6 vs 2 (p=0.05), Geriatric depression score (p=0.018) and G8-GAS score (p=0.015). IMWG "frailty score" was not associated with early death. In multivariate analysis, which included ISS and age, number of falls in the past 6 months (0 vs ≥1, HR: 4.7, p=0.007) and score In conclusion, in elderly myeloma patients, G8-GAS provides prognostic information related to the risk of early death and overall survival, independently from disease characteristics and the treatment type. IMWG "frailty score" provides a simple tool which may be useful for patients fit to participate in clinical trials but in unselected, "Real-World", patients may have reduced prognostic performance. Disclosures Terpos: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Other: travel expenses; Novartis: Honoraria. Dimopoulos:Celgene: Honoraria; Janssen: Honoraria; Genesis: Honoraria; Novartis: Honoraria; Onyx: Honoraria; Amgen: Honoraria; Janssen-Cilag: Honoraria.

Lytic bone involvement in primary systemic (AL) amyloidosis is uncommon. To-date, there is no systematic study of bone metabolism in patients with AL amyloidosis. For this reason, we evaluated prospectively 102 patients with previously untreated AL amyloidosis who were diagnosed between January 2000 and June 2008 in the Plasma Cell Dyscrasias Unit of the Department of Clinical Therapeutics (Athens, Greece). All patients had histologically confirmed AL amyloidosis, while the definition of organ involvement, hematological and organ response and progression were based on consensus criteria. The levels of the following bone remodeling indices were measured before the administration of any kind of therapy: i) osteoclast regulators: soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), osteoprotegerin (OPG), chemokine C-C motif ligand 3 (CCL-3, previously known as MIP-1alpha) and osteopontin; ii) bone resorption markers: C- and N- telopeptide of type-1 collagen (CTX and NTX, respectively) and tartrate resistant acid phosphatase type-5b; iii) bone formation markers: bone-alkaline phosphatase and osteocalcin. The results were compared with those of 35 age- and gender-matched healthy controls, 40 patients with monoclonal gammopathy of undetermined significance (MGUS) and 35 newly diagnosed, untreated patients with symptomatic multiple myeloma (MM). The median age of AL patient was 65 years (range: 39-80 years); 43% were males; 60% had heart involvement, 73% renal involvement, 11% liver involvement and 40% had peripheral/autonomous nerve system involvement; 67% of patients had two or more organs involved; 16% had a baseline serum creatinine >2 mg/dl. The median serum albumin was 3.2 g/dl, the median serum β2-microglobulin was 1.8 mg/L and the median 24h urine protein was 3350 mg/24h. Median NT-proBNP was 1954 pg/ml; 26%, 41% and 33% of patients were Mayo stage -1, -2 and -3, respectively. None of AL patients had lytic bone lesions in plain radiography or other features suggestive of MM, such as hypercalcemia, significant anemia unrelated to renal impairment or predominant Bence-Jones proteinuria. Bone resorption (assessed by CTX or NTX) in AL-patients was increased (p4 fold higher; p Patients with OPG levels above the upper value of healthy controls had a shorter survival (p=0.026), while AL patients with OPG levels in the top quartile had short survival (12 months vs. 58 months, p=0.024). In the multivariate analysis cardiac biomarkers outperformed OPG; however, in patients with Mayo stage-1 disease, OPG levels remained significant and identified patients with short survival within the “favorable risk” group (12 vs. >60 months, p=0.012; see the Figure). Although renal involvement did not affect bone markers, in AL patients with serum creatinine >1.5 mg/dl, CTX and NTX were higher than in patients with We conclude that elevated bone resorption and high bone turnover is present in AL patients possibly due to direct and indirect activity of amyloid fibrils or light chains in bone cells. Increased OPG in AL is not only a compensation factor to osteoclast activation but it may also reflect tissue damage in the heart. There is published evidence that OPG is produced by cardiac cells and has been associated with poor prognosis in heart disorders, including heart failure and acute coronary disease. In AL amyloidosis, high OPG is able to identify patients at increased risk of death, mainly within the more favorable prognosis group by Mayo staging. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Neutrophil gelatinase-associated lipocalin (NGAL) is a 25 kDa protein, which is produced by the injured tubule epithelium. In contrast to serum creatinine (sCr), NGAL is specifically induced in the damaged nephron and then released into blood and urine; thus it is considered as an early marker of renal tubular injury. Our group has recently shown that urinary and serum NGAL were elevated in the vast majority (90% and 70%, respectively) of newly diagnosed patients with multiple myeloma (MM), while serum cystatin-C (CysC), an accurate marker of GFR, was elevated in 70% of them. However, there is no information for the value of these markers in patients with MGUS, asymptomatic MM (AMM), as well as in symptomatic MM post treatment. Thus, we measured urinary and serum NGAL and serum CysC in 40 patients with MGUS (23M/17F, median age 72 years), 36 with AMM (16M/20F, 60 years) and 120 healthy controls. Furthermore, we measured serum NGAL and CysC in 39 newly diagnosed symptomatic MM patients (24M/15F, 70 years) before and after frontline therapy with novel agents. Serum and urinary NGAL was measured using an ELISA method (BioPorto Diagnostics A/S, Gentofte, Denmark), while CysC was measured using a latex particle-enhanced nephelometric immunoassay (Dade Behring-Siemens Healthcare Diagnostics, Liederbach, Germany). The estimated GFR (eGFR) was calculated using the CKD-EPI equation. Patients were divided into the 5 CKD stages of the KDIGO classification, according to eGFR (stage 1: eGFR >90 ml/min/1.73m2; stage 2: 60-89 ml/min/1.73m2; stage 3: 30-59 ml/min/1.73m2; stage 4: 15-29 ml/min/1.73m2; stage 5: Only two (5%) patients with MGUS and two (5.5%) with AMM had sCr above the upper normal limit, but none had sCr >2 mg/dl. Regarding eGFR, 34 (85%) patients with MGUS and 31 (86%) with AMM had CKD stage 1/2, while 6 (15%) MGUS and 5 (14%) AMM patients had CKD stage 3. Urinary NGAL was elevated in patients with MGUS (median: 14 ng/ml, range 0.5-31 ng/ml) and AMM (22.3 ng/ml, 0.9-78 ng/ml) compared to controls (5.3 ng/ml, 0.7-9.8 ng/ml, p Twelve (31%) patients with symptomatic MM had sCr >2 mg/dl, while 41% had CKD stages 1/2, 28% had CKD stage 3 and 31% CKD stages 4/5. As expected, patients with symptomatic MM had elevated serum NGAL and CysC (p We conclude that the high levels of urinary and serum NGAL in MGUS and AMM indicate the presence of subclinical renal damage in these patients early in the course of their disease, when other markers of renal function, such as sCr or even the more sensitive CysC indicate that renal function is preserved. Thus, NGAL may be useful as an early marker that predicts the development of renal damage and the progression of the disease in these patients. NGAL seems also to increase in patients with renal impairment who receive IMiD-based regimens. Disclosures: No relevant conflicts of interest to declare.

Organ dysfunction in systemic light chain (AL) amyloidosis is caused by the deposition of amyloid fibrils composed of immunoglobulin light chains in tissue microcirculation. vWF is mainly produced, stored and secreted by endothelial cells (ECs) and it is critical for thrombus formation. The secretion of vWF by ECs is triggered by several conditions and it has been proposed that changes in the levels of circulating vWF may reflect a state of “stimulation” of the endothelium. Cardiac involvement is the main determinant of prognosis in AL amyloidosis, but the role of endothelium in this disease has not been extensively studied and no marker of endothelial dysfunction has been evaluated, as yet. Thus, we studied the prognostic role of vWF in patients with AL amyloidosis who were treated with novel agents. The vWF antigen (vWFag) levels were measured using a latex particle-enhanced immunoturbidimetric assay (HemosIL vWF antigen) with an automated coagulometer (ACL Top 3G, Instrumentation Laboratory, Lexington, MA, USA). The inter- and intra-assay CVs were 2% and 3% at a concentration of 123.5 U/dL, respectively, and the lower limit of detection was 2.2 U/dL. The analysis included 81 consecutive patients with newly diagnosed AL amyloidosis who were treated in a single center (Department of Clinical Therapeutics, University of Athens, Greece) from 2005 to 2012. Median age of the patients was 68 years (range 42-82 years) and the median number of involved organs was 2; heart was involved in 62%, kidneys in 74%, peripheral nerve in 24%, liver in 9% and soft tissue in 21% of patients. Median NTproBNP level was 2,318 pg/mL (range 33-75,000 pg/mL); 36% had NTproBNP levels ≥4,000 pg/mL and 28%, 38% and 34% of patients had Mayo stage -1, -2 and -3, respectively. Primary therapy based on bortezomib was given in 52% of patients, on lenalidomide in 44%, while 4% received MDex. Median survival of the cohort was 47 months; 3- and 6-month mortality was 12% and 20%, respectively. The median serum level of vWFag in patients with AL amyloidosis was 181 (range 20-557) U/dL and was significantly higher than that measured in healthy controls (median: 84 U/dL, range 48-124; p We then examined the prognostic significance of vWFag and we found that levels of vWFag within the top quartile (≥230 U/dL) were associated with a very poor outcome (median survival 4 months vs. 47 months, p=0.001). Because the most important predictor of early death in patients with AL amyloidosis is cardiac involvement, we performed a multivariate analysis which included NTproBNP levels: vWFag levels ≥230 U/dL were independently associated with survival (HR: 2.64, 95% CI 1.2-5.8, p=0.01), along with NTproBNP levels ≥4,000 pg/ml (HR: 4.17, 95% CI 1.98- 8.8, p In conclusion, vWFag levels are elevated in patients with AL amyloidosis but are not correlated with other features of the disease, such as pattern of organ involvement and cardiac biomarkers. For the first time, we found that high levels of vWFag are associated with a high risk of early death and shorter survival in patients with AL amyloidosis, independently of cardiac biomarkers. In addition, wWFag levels improve the prognostic ability of cardiac biomarkers in patients with AL amyloidosis. Our data also justify the investigation of the role of endothelial dysfunction in AL amyloidosis. Disclosures: No relevant conflicts of interest to declare.

Severe renal impairment (RI) in MM patients is a medical emergency. Immediate antimyeloma therapy and appropriate supportive measures are needed because these patients are at high risk for early death and other complications associated with their renal dysfunction. Antimyeloma therapy may improve renal function in a significant proportion of patients and the choice of treatment may also be guided by the degree of RI. For the evaluation of the recovery of renal function IMWG has proposed specific criteria (Dimopoulos et al, JCO 2010), which are based on changes of calculated GFR. A new formula for the estimation of GFR has been used by nephrologists as a more accurate method of renal function assessment (CKD-EPI formula). In order to evaluate the currently available IMWG criteria, by using the new CKD-EPI formula, we assessed renal response in patients with newly diagnosed MM who presented with severe RI. We also evaluated simplified criteria for renal response and compared patient outcomes with the IMWG criteria. We analyzed the outcomes of 105 consecutive patients who presented with severe RI (eGFR Most patients (68%) were >65 years of age; 36% were >75 years, while 92% had ISS-3 disease. Primary therapy with bortezomib-based regimens was given in 38% of patients, 43% received IMiD-based therapy (34% thalidomide- and 9% lenalidomide-based) and 19% high dose dexamethasone and conventional chemotherapy (CC) regimens. When GFR was calculated by the MDRD formula then 51% had stage 4 and 49% had stage 5 RI, while by the CKD-EPI formula, 49% had stage 4 and 51% stage 5 RI. Thus, RI stage change between stage 4 & 5 occurred in only 2% of patients with the use of CKD-EPI vs. MDRD equation. According to the IMWG criteria, with GFR calculated by the MDRD formula, 36 (34%) patients achieved CRrenal, 8 (7.5%) PRrenal and 33 (31%) MRrenal. When GFR was calculated by the CKD-EPI formula, then 35 (33%) patients achieved a CRrenal, 8 (7.5%) PRrenal and 34 (32%) MRrenal; only in 3 patients (3%) there was a discrepancy in the quality of renal response between the two equations. Major renal response (CR+PRrenal) was more frequent with bortezomib (57.5% vs. 34% for IMiDs vs. 26% for high dose Dexa+CC, p=0.034). When we applied the proposed simplified renal response criteria, then 47 (45%) patients were considered responders; responses were more frequent in patients treated with bortezomib (62.5% vs. 35% for IMiDs vs. 32% for high dose Dexa+CC, p=0.016). The median survival for all patients who presented with severe RI was 31 months (95% CI 16-46). Early death (65 years (p=0.022). The median survival of patients who presented with stage 4 vs. stage 5 RI was similar (31 vs. 38 months, p=0.230). For patients who survived at least 2 months, the median survival of the patients who achieved ≥PRrenal was 53 months (by MDRD and CKD-EPI) vs. 43 months for patients who had minor renal response vs. 42 months for patients who did not have a renal response, by the IMWG criteria. Among patients who survived at least 2 months, median survival of the responders according to the proposed simplified renal response criteria was 53 vs. 44 of the non responders (p=0.3). There was no difference in the performance of either criteria for overall survival, risk of death at 6 or 12 months, with either of the formulas for eGFR calculation. We conclude that in unselected MM patients with severe RI, the criteria for the improvement of renal function can be simplified without any significant change in their prognostic significance. The GFR calculated by the CKD-EPI can also be used for the assessment of renal response in patients with MM. Disclosures: No relevant conflicts of interest to declare.

The adherence of myeloma cells to the bone marrow stromal cells plays a key role in the biology of the disease as it supports the growth of myeloma cells in the marrow microenvironment. The aim of our study was to evaluate the levels of circulating adhesion molecules in myeloma patients, to explore possible correlations with disease characteristics, including survival, and to examine their alterations post-therapy with novel agents. We measured circulating levels of vascular cell adhesion molecule-1 (VCAM-1; CD106), intercellular adhesion molecule-1 (ICAM-1; CD54), P-, L- and E-selectin using an ELISA methodology (R&D Systems, Minneapolis, MN, USA) in 232 consecutive myeloma patients: 145 with newly diagnosed symptomatic MM (NDMM) who were treated with novel agent based therapies and 87 with relapsed myeloma (RMM) at first relapse. Of the later, 47 received lenalidomide with low-dose dexamethasone (Rd) and 40 patients received bortezomib with dexamethasone (VD). Serum was collected just before initiation of therapy for NDMM patients, or before initiation of the first Rd or VD cycle (on day 1) for RMM patients and after the completion of the 4thcycle of Rd or VD (on day 28 or 21, respectively). Patients with NDMM had increased circulating levels of VCAM-1 and ICAM-1 compared to controls (n=17, p The median follow-up of symptomatic patients with NDMM was 31 months and the median overall survival (OS) was 53 months (CI 95% 46-59 months). The median progression-free survival (PFS) for all patients was 23 months; patients who had VCAM-1 values >median had a median PFS of 19 months vs. 32 months of the others (pmedian was associated with a HR: 2.17, CI 95%: 1.18-4, p=0.012). Increased levels of VCAM-1 (>median) were also associated with inferior survival. In particular, patients with high VCAM-1 had a median OS of 45 months vs. 75 months for those with levels median (HR: 2.46, CI 95%: 1.06-5.68, p=0.034) had an independent prognostic value for inferior survival. MM patients at first relapse had increased levels of ICAM-1 and L-selectin even compared to newly-diagnosed symptomatic MM patients (p=0.001 and p=0.017, respectively) and increased levels of VCAM-1 compared to controls (p Our study provides evidence about the role of microenvironment in the outcome of myeloma patients. In particular, VCAM-1 had an independent prognostic value for both PFS and OS in patients with newly-diagnosed symptomatic disease who were treated with novel agent-based therapies. Interestingly, in patients at first relapse, both Rd and VD produced a dramatic reduction of VCAM-1, irrespective of response to treatment indicating an effect of these drugs on the microenvironment, while Rd altered also the levels of all studied selectins suggesting an effect of Rd on the vascular niche and the endothelium. Disclosures: No relevant conflicts of interest to declare.

The administration of ZA in patients with symptomatic myeloma is associated with reduction of SREs and possible improvement of survival; its use however, is associated with increased risk of osteonecrosis of the jaw (ONJ). Longer exposure and more infusions of ZA have been associated with higher incidence of ONJ. It has been suggested that longer intervals between ZA infusions may reduce the risk of ONJ; however, this has not been proven. Since 2008, we have adopted a strategy in which ZA is discontinued in patients who remain in remission for more than 2 years, while ZA is administered every 8-12 weeks, after the first year, in patients who have achieved vgPR or CR. The aim of our analysis was to assess the incidence of ONJ in a prospectively studied population treated with ZA and to asses potential risk factors related to dosing and schedule of ZA. Since 2003, all patients in the Department of Clinical Therapeutics (Athens, Greece) undergo dental evaluation before ZA initiation and are instructed to avoid procedures that predispose to ONJ. Only patients who received ZA and survived at least 6 months post their first ZA infusion were included in the analysis. Relative dose frequency of ZA (RDF) was calculated as the average number of weeks between infusions of ZA (weeks between first and last infusion divided by the number of infusions). Time of exposure to ZA was calculated from the date of first infusion until the date of last infusion. Death due to myeloma and development of ONJ were treated as competing events. Between January 2000 and January 2013, 266 patients with symptomatic myeloma fulfilled the above criteria and were included in the analysis. Median age was 68 years (range 36-87 years) and 47% were males. Median follow up was 36 months and 35% of the patients have died. The median number of ZA infusions was 16 (range 1-107) and the median time of exposure to ZA was 29 months, corresponding to 9073 person-months of exposure. Median RDF was one infusion per 7.9 weeks (interquartile range (IQR) 5.8-11.4 weeks). ONJ developed in 26 (10%) patients. Median time from first ZA infusion to development of ONJ was 28 months (range 6-122 months). Accounting for death as a competing event, 1-year risk of ONJ was 1.2% (95% CI 0.3-3%), 2-year risk was 5% (95% CI 2.5-8.5%), 3-year risk was 8.5% (95% CI 5-13%), 4-year risk was 11.5% (95% CI 7.3-17%) and 5-year risk was 14% (95% CI 9-19%) (Figure). The respective survival rates were 93%, 84%, 76%, 65% and 56% at 1, 2, 3, 4 & 5 years. The median time of exposure to ZA was 28 months (IQR 22-46 months) for patients who developed ONJ vs. 24 months (IQR 11-42 months) for those who did not (p=0.2). However, the median number of ZA infusions was 23 for those who developed vs. 14 for those who did not develop ONJ (p=0.004). Increasing number of ZA infusions was associated with higher risk of ONJ: 2.3% of patients who received In conclusion, our data, in a large population of consecutive unselected patients with symptomatic myeloma who received ZA, indicate that ONJ remains a frequent complication in patients who receive ZA for prolonged periods and the risk increases with the number of ZA infusions. More frequent infusions of ZA are associated with earlier development of ONJ, but the risk of ONJ is associated mainly with the cumulative dose of ZA. Prospective clinical trials should examine if less frequent administration of ZA can reduce the risk of ONJ without compromising its antiresorptive effect. Disclosures: No relevant conflicts of interest to declare.

The outcome of patients with multiple myeloma (MM) is heterogeneous and the median survival of patients with symptomatic disease ranges from a few months to several years. Although the survival of MM patients has increased over the past 10 years, there is still a proportion of patients who die within a few months from the initiation of therapy, even when they are treated with the most contemporary drug regimens. Our aim was to identify the factors that are associated with early death among patients with symptomatic myeloma and explore whether incorporation of new therapies has also improved short-term outcome. We analyzed 509 consecutive patients that have been treated in a single center (Department of Clinical Therapeutics, Athens, Greece) from January 1994 to December 2012. All patients, irrespective of age or performance status (PS) who received at least one dose of therapy were included in the analysis. Median age of the patients was 69 years (range 31-92 years); 62% were older than 65 and 27% older than 75 years. Osteolytic bone disease (in plain X-rays) was present in 74% of the patients; 25% had ISS-1, 35.5% had ISS-2 and 39.5% ISS-3 disease. Elevated LDH >300 IU/L was present in 8%; 21% had severe renal impairment (eGFR Two-month, 6-month and one-year mortality was 6%, 13% and 18%, respectively. Age >75 years was strongly associated with higher rates of early mortality (2-month, 6-month and 1 year mortality was 8%, 11% and 21% vs. 4%, 5% and 10% for patients 75 years (HR: 3, 95% CI 1.25-7.3, p=0.014), PS >1 (HR: 2.88, 95% CI 1.02-8, p=0.045), while ISS-3 had marginal independent significance (HR: 8, 95% CI 0.99-67, p=0.051). Importantly, the upfront use of bortezomib-based regimens (HR: 0.21 95% CI 0.06-0.73, p75 years, as only a minority of patients >75 years received bortezomib-based therapy. When this interaction was accounted for in the model, then it was significant (p=0.041), indicating that age >75 years was associated with early death also due to the reduced use of bortezomib (but not of IMiDs). In multivariate analysis for predictors of death within the first 12 months from initiation of therapy age >75 years (HR: 4.125, 95% CI 2.2-7.7,p1 (HR: 2.5, 95% CI 1.33-4.7, p=0.005), ISS-3 (HR: 7.5, 95% CI 2.44-23, p The above results indicate that host characteristics (age, PS) are crucial predictors of very early death ( Disclosures: No relevant conflicts of interest to declare.

Multiple Myeloma (MM) patients are vulnerable to infections, which remain a major cause of death, including early death. During infection, human immune cells sense the presence of invading pathogens through the toll-like receptor family (TLR) of receptors. TLRs detect microbes to activate transcriptional programs that orchestrate adaptive responses to specific insults. This means that they induce the endoplasmic reticulum (ER) unfolded protein response (UPR) to accommodate essential protein translation. If the UPR fails to resolve the protein-folding defect, due to severe and prolonged ER stress, apoptosis is activated. However, the timing sequence of the prolonged ER stress has probably implications for ER stress-induced apoptosis that might help cells to adapt under these conditions rather than driving them to apoptosis. Studies have shown that prolonged ER stress occurs in response to microbes and specifically when cells are exposed to lipopolysaccharide (LPS), a TLR4 activator. The prolonged stress, possibly arising from a massive increase in protein synthesis, has shown to suppress CHOP, an apoptosis biomarker, in ER-stressed macrophages, while low levels of CHOP expression promotes B cell survival. Expression and function of TLRs in MM has recently become the focus of several studies and although the regulatory role of TLRs in MM plasma cells has been reported, the underlying molecular mechanisms remain unclear. It has been shown that human myeloma cell lines (HMCL) and primary myeloma cells express high levels of TLRs and specifically of TLR-4 and TLR-9. The aim of our study was to investigate TLR4 signaling in myeloma cells and to explore possible implications with endoplasmic reticulum unfolded protein response as a potential mechanism of drug resistance. We initially investigated whether TLR-4 is expressed in human myeloma cell lines and primary myeloma cells and we found that TLR-4 mRNA is expressed at increased levels (2-10 fold) both in HMCLs and primary cells. To test the hypothesis that TLR-4 signaling may suppress CHOP expression during sustained UPR response, two myeloma cell lines, H929 and U266, were pre-treated with low dose LPS (1 ng/mL) and then subjected to ER stress conditions by treatment with tunicamycin (TM). LPS pre-treatment significantly decreased CHOP mRNA expression after 24 hours. Despite the marked suppression of CHOP, LPS pre-treatment of these myeloma cell lines did not suppress ATF4 mRNA levels which also were not altered by TM treatment. LPS pre-treatment did not also suppress XBP-1 splicing compared to the control ER-stressed cells. To test the specificity of these effects, the same set of experiments where performed on other cancer tissues such as ovarian cancer cell lines. Interestingly, although LPS pre-treatment increased TLR-4 mRNA expression in SKOV3 ovarian cancer cell line, CHOP mRNA levels remained intact prior and after treatment while TM treatment did not make any difference in CHOP mRNA expression. These results suggest the relevance of exploring this pathway in tissues such as plasma cells which are highly dependent on the UPR as a repair mechanism. Pre-treated LPS and TM samples of HMCLs were also subjected to Annexin-PI staining to determine the amount of apoptosis. As expected, pre-treated LPS myeloma cells which were exposed to TM had 30% lower Annexin-FITC stained cells compared to the TM-stressed cells only. These data suggest that blockage of CHOP by TLR4 ligands may promote the growth and survival of MM cells. We then examined the impact of therapy with bortezomib on TLR4 and CHOP mRNA expression in primary tumors cells which were collected before and at day 7 after bortezomib-based therapy from 6 myeloma patients. In 5 out of 6 cases TLR-4 expression was significantly up-regulated and was accompanied with a coupled down-regulation of CHOP mRNA expression. In conclusion, our data suggest that the TLR-4 signaling pathway might provide a translational control pathway which enables cells to carry out essential protein synthesis and avoid CHOP-induced apoptosis. Further exploration of this pathway is needed to establish its role as a potential mechanism of drug resistance. Disclosures: No relevant conflicts of interest to declare.

Waldenstrom's Macroglobulinemia (WM) is an uncommon malignancy which is characterized by the infiltration of the bone marrow by lymphoplasmacytic cells, which produce a monoclonal IgM. The manifestations of the disease are related to the infiltration of the bone marrow and the quantity, physical and immunological properties of the monoclonal IgM. The interactions of lymphoplasmatic cells with other cells in their microenvironment, including mast cells and endothelial cells, support their survival and proliferation and may induce resistance to therapy. Von Willebrand factor (vWF), a glycoprotein produced by the endothelial cells and megakaryocytes, plays a key role in primary hemostasis but is also a marker of endothelial “stimulation”. Recently, it was shown that high levels of vWF, measured in citrated plasma, are associated with adverse prognosis in patients with symptomatic WM and it was suggested that vWF levels may reflect interactions between lymphoplasmacytic cells and other cells of their microenvironment such as mast cells and endothelial cells (Hivert et al; Blood 2012;120:3214-21). Thus, we evaluated the prognostic importance of vWF antigen levels in the serum of patients with symptomatic previously untreated WM, in order to validate vWF as a possible prognostic marker for progression free (PFS) and overall (OS) survival and to validate the measurement of vWF in the serum instead of citrated plasma. The vWF antigen (vWF Ag) levels were measured in serum collected before initiation of therapy by means of a latex particle-enhanced immunoturbidimetric assay (HemosIL vWF antigen) with an automated coagulometer (ACL Top 3G, Instrumentation Laboratory, Lexington, MA, USA). The inter-assay and intra-assay coefficients of variation were 2% and 3% at a concentration of 123.5 U/dL, respectively, and the lower limit of detection was 2.2 U/dL. The analysis included 42 patients with symptomatic WM, treated at the Department of Clinical Therapeutics, University of Athens (Greece), from 1999 to 2012, and 19 healthy controls of matched gender and age. The median age of patients with symptomatic WM was 65 years (range: 37-83 years) and 54% of them were males. Anemia (3 mg/dl in 56%, while 7.5% had serum LDH ≥250 U/L and 58% had serum albumin Median serum level of vWF Ag was 101 U/dL (mean 132.5 U/dL, range 19.9-399 U/dL) and were slightly higher compared to the serum levels of healthy controls (median 85 U/L, mean 85 U/L, range 48-124 U/L). However, 6/42 (14%) had vWF Ag levels There was an inverse correlation of platelet counts with levels of vWF Ag (R=-0.336, p=0.032) and vWF Ag ≥median was more frequent in patients with beta2-microglobulin >3 mg/L (p=0.006) and less frequent in patients with low (11%) vs. patients with intermediate (59%) or high (62%) risk IPSS (p=0.036). There was no correlation of vWF Ag levels with IgM levels or with the extent of bone marrow infiltration or with other manifestations of the disease. Median follow up of symptomatic patients was 4 years. Patients with vWF Ag levels within the upper quartile (i.e. vWF Ag ≥200 U/dL) had a median progression free survival of 12 months vs. 63 months of patients with vWF Ag < 200 U/L (p In conclusion, the serum levels of vWF antigen provide significant prognostic information in patients with symptomatic WM and patients with levels ≥200 IU/dL have a very poor prognosis compared to patients with lower levels. vWF measured in the serum, may become an important prognostic marker in WM and needs further investigation.Figure 1.Figure 1. Disclosures: No relevant conflicts of interest to declare.

The therapeutic efficacy of antimyeloma agents, especially of immunomodulatory drugs (IMiDs), also relies on their ability to influence the tumor-host interaction by modulating immune response, while other agents (chemotherapy, steroids, proteasome inhibitors) may cause significant immunosuppression. Toll like receptors (TLRs) play a central role in the adaptive immune response and TLR-4 signaling involves several intracellular adaptor molecules including MyD88 and Toll/intereukin-1 receptor-associated protein (TIRAP). Germ-line single nucleotide polymorphisms (SNPs) with missense mutations in TLR-4 and TIRAP genes have been associated with susceptibility to infection, autoimmune diseases and inferior outcome in several cancers after chemotherapy or radiotherapy. However, there are no data for multiple myeloma (MM). Thus, we screened 255 patients with MM for the presence of rs4986790 (D299G) and rs4986791 (T399I) SNPs in exons 3 and 4 of TLR4 and rs8177374 (S180L) in exon 5 of TIRAPgene. Median age of the patients was 66 years (range 31-91 years); 52% were males and 29%, 39% and 32% had ISS-1, -2 & -3, respectively. Median follow up was 40 months. Genetic analysis showed that 8.9% and 8.6% of the patients were heterozygous for the rs4986790 and rs4986791, respectively (there were no homozygous patients for either SNP) and co segregated in 81.5% of the heterozygous patients. For the rs8177374 in TIRAP, 25% were heterozygous and only 1% homozygous for the SNP. There was no segregation of the SNPs in TLR and TIRAP. Frontline therapy was based on IMiDs in 52% of the patients (25% received thalidomide- and 27% lenalidomide-based regimens), while 29.5% received bortezomib-based therapy and 19% conventional chemotherapy (CC). Furthermore, at relapse, 57 patients received lenalidomide-based therapy. Response to primary therapy was attained by 86% of the patients; in 72% of patients treated with CC, in 88% of patients treated with IMiDs and in 89% of patients treated with bortezomib. The presence of the studied SNPs was associated with inferior response to primary therapy (for TLR4, in 60% vs. 88% for rs4986790, p=0.001 and in 66% vs. 87% for rs4986791, p=0.009) but there was no effect of TIRAP SNPs. However, the effect on response was treatment specific. Thus, response to primary therapy with IMiDs was affected by TLR4 SNPs (≥PR in 62% of carriers of rs4986790 vs. 90% of others, p=0.016), was less pronounced in patients treated with CC (p=0.055) and did not affect response to bortezomib (p=0.484). For carriers of the rs4986791, the effect on response to IMiDs was also significant (p=0.05) as well as the effect on patients treated with CC (p=0.022), but again not in patients treated with bortezomib (p=0.424).When both SNPs were present the effect was more pronounced both in patients treated with CC (response in 33% vs. 78%, p=0.022) and in patients treated with IMiDs (63% vs. 90%, p=0.016). In contrary, carriers of the SNP in TIRAP had increased response rates to upfront therapy with CC (100% vs. 66%, p=0.039), but there was no significant effect on response to IMiDs or bortezomib, although there was a trend for inferior PFS in patients treated with bortezomib (p=0.037). Importantly, in multivariate analysis which included the type of primary therapy and the presence of SNPs in TIRAP, the presence of both SNPs in TLR4 was independently associated with lower response probability (p=0.01). The effect of the presence of the above SNPs was different at latter stages of the disease. More specifically, presence of SNPS in TLR4 did not affect response to salvage therapy with lenalidomide for relapsed or refractory disease (p=0.15), but SNPs in TIRAP was associated with low response rates (50% vs. 89%, p=0.002), perhaps as a result of the modulated immune responses due to extensive prior therapy with immunomodulatory and/or immunosuppressive drugs. This is the first study of the effect of known SNPs in TKR4/TIRAP signaling pathway in patients with MM. Our data indicate that differences in the immune system, due to genetic variability, may be associated with different responses to various therapies and at later stages of the disease, when the immune status of the host is modulated, due to extensive prior therapy with immunosuppressive/immunomodulating agents. Further investigation is needed for the role of the pathways which may regulate the response of the immune system of the host to malignant cells and to immune modulating drugs. Disclosures: No relevant conflicts of interest to declare.

Skeletal-related events (SREs) which include pathological fractures, spinal cord compression (SCC) and a need for radiotherapy or surgery to bone are frequent complications of multiple myeloma (MM). Although, the frequency and characteristics of SREs in MM patients who received conventional chemotherapy (CC) or thalidomide-based regimens along with bisphosphonates (BPs) have been described, there are no data available in the era of proteasome inhibitors or novel IMiDs. Thus, we retrospectively evaluated the records of 400 consecutive patients with symptomatic MM (207M/193F, median age: 63 years) who were diagnosed, treated and followed in a single center. All patients had a whole body skeletal survey using conventional radiography at diagnosis and then at the time of relapse or whenever clinically indicated, while MRI of the spine and pelvis at diagnosis was available for 223 patients. Furthermore, we tested 125 patients for SNPs in genes that are involved in the biology of bone destruction: LRP5 (rs4988321), GC vitamin D (rs4588), TNFRSF11A (rs3018362), DKK1 (rs1569198), RANKL (rs9594759), OPG (rs6469804) and ERS1 (rs1038304). At diagnosis, the skeletal survey detected osteolytic disease in 284 (71%) patients. In MRI, 34.5% of the patients had focal, 40.5% diffuse, 21% normal, and 4% a variegated pattern of marrow involvement. SREs were observed in 167 (41.7%) patients at diagnosis: 104 (26%) patients presented with pathological fractures (87 with vertebral fractures, 18 with rib fractures and 17 with fractures of the long bones; 22 patients had both vertebral and long bone or rib fractures), while 22 (5.5%) patients required surgery to bone, 21 (5.2%) radiotherapy and 20 (5%) patients presented with SCC. The incidence of SREs was higher in patients with osteolytic lesions (49.5% vs. 24%, p Frontline therapy with IMiD-based regimens was given in 172 (43%) patients, while 80 (20%) patients received bortezomib-based regimens, 111 (27.7%) both IMiD and bortezomib (VTD or VRD) and 37 (9.2%) patients CC. BPs were given in all but 86 patients (21.5%) at diagnosis, mainly due to renal insufficiency; however, almost 60% of them (n=51) received BPs later in the course of their therapy. The vast majority (91%) of patients received zoledronic acid (ZA). Due to renal impairment, ZA was discontinued in 6 patients, while the dose was reduced in 44. During first line treatment, 7 (1.75%) patients developed a SRE: 2 on bortezomib- and 5 on IMiD-based regimens. The rate of SREs was higher in patients who did not receive upfront BPs (4.7% vs. 1%; p=0.021). The median follow-up was 39 months. At the time of first relapse (data available for 176 patients), 3 patients presented with fractures and 35 patients required local radiotherapy to bone (SRE incidence: 21.6%). Patients who had received only bortezomib-based regimens (VD or VCD, n=20) had lower SRE rate (2/20, 10%) vs. all others (36/156, 22%, p=0.173); the 3 patients with fractures had received MPT (n=2) or RD (n=1). In total, during the course of their disease, 52.8% of the patients presented with at least one SRE. Presentation with SREs at diagnosis did not predispose for SREs during the disease course, regardless of anti-myeloma treatment, possibly due to the low number of fractures and the higher number of radiation needed after frontline therapy. In summary, our data from the first systematic report on the incidence and characteristics of SREs in the era of novel agents indicate that SREs remain a significant complication in MM. Importantly, despite high response rates after first line therapy more than 20% of patients required radiotherapy at the time of relapse. The fracture rate was very low during first line therapy and at first relapse probably due to the extensive use of potent BPs and bortezomib, which has bone anabolic effects. The use of modern imaging techniques (i.e. PET/CT or LDWBCT) that can detect bone masses earlier and lead to earlier initiation of treatment may reduce the SRE incidence in the near future. Disclosures: No relevant conflicts of interest to declare.

Abstract 2919 Renal impairment is a common complication of multiple myeloma (MM). The CRAB criteria define the serum creatinine (sCr) level of >2 mg/dl as the cut-off value for starting therapy in MM patients. However, the measurement of sCr for the evaluation of renal impairment has several limitations. Furthermore, the estimation of glomerular filtration rate (GFR) by the MDRD equation has greater value in patients with stabilized sCr, while the majority of MM patients have acute renal damage, which may be irreversible. Thus, identification of individuals at higher risk of early kidney dysfunction is critical to the timely initiation of treatment to prevent permanent renal damage. For this reason, several markers of renal dysfunction have been used in renal disorders. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein overproduced by proximal tubular cells in response to kidney injury, while kidney injury molecule-1 (KIM-1) is a type 1 transmembrane glycoprotein that is overexpressed in dedifferentiated proximal tubule epithelial cells after ischemic or toxic injury. Urinary NGAL and KIM-1 have never been evaluated in MM patients. To assess the value of these molecules in MM, we measured urinary and serum NGAL, urinary KIM-1, urinary and serum cystatin-C (cys-C; a sensitive marker of GFR which is not secreted in the urine) in 48 newly diagnosed symptomatic MM patients (27M/21F, median age 65 years). The estimated GFR (eGFR) was calculated using the CKD-EPI equation (proposed by the CKD Epidemiology Collaboration and is widely accepted in renal impairment). Serum and urinary NGAL was evaluated using an ELISA method (BioPorto Diagnostics A/S, Gentofte, Denmark) with a protocol applied in the Siemens Advia 1800 clinical chemistry system. Serum and urinary cys-C was measured on the BN ProSpec analyser using a latex particle-enhanced nephelometric immunoassay (Dade Behring-Siemens Healthcare Diagnostics, Liederbach, Germany), while urinary KIM-1 was also measured using an ELISA (R&D Systems, Minneapolis, MN, USA). For the urinary measurements, a 24h urine collection was used. Nine (19%) patients had sCr >2mg/dl, while 60% had eGFR ≥60 ml/min (CKD stages 1 & 2), 18.5% had eGFR 30–59 ml/min (CKD stage 3) and 21.5% eGFR All studied markers correlated with eGFR: serum cys-C (r=−0.758, p Our data suggest that almost all newly diagnosed symptomatic MM patients have tubular damage as assessed by elevated urinary NGAL suggesting that renal impairment is present very early in the disease course. Measurement of urinary NGAL and serum cys-C offers valuable information for the kidney function of MM patients and their measurement may help in the identification of patients with high risk for the development of acute renal function. The value of KIM-1 seems to be very low in myeloma reflecting the differences in the pathogenesis of myeloma-related renal dysfunction than toxic acute renal injury of other etiology. Disclosures: No relevant conflicts of interest to declare.