ALBERT

Description: Background : TheHevylite assay (HLC Assay) is a novel assay using antibodies that recognize unique conformational epitopes presented by the association of the heavy and light chain constant regions of intact immunoglobulins (Ig) allowing quantitative measurement of each Ig class concentration and generating ratios for each pair (e.g. IgGK/IgGL). Recent studies indicate that HLC Assay can enhance the ability to detect and quantify monoclonal Ig, potentially providing greater sensitivity for detection of minimal residual disease or early relapse after treatment and providing a prognostic indicator of progression free survival (Ludwig, H. et al. Leukemia (2013) 27, 213-219; Kraj, M. et al. Adv Clin Exp Med 2014, 23, 1, 127-133). While HLC Assay could simplify and enhance the assessment of monoclonal protein response in multiple myeloma (MM), its utility as compared to standard assays (SA) (Serum Protein Electrophoresis (SPEP) and Immunofixation (IF)) is not well established. The goal of this retrospective study was to compare the performance of these tests in patients with MM seen at Memorial Sloan Kettering Cancer Center. Methods : We have previously reported on the patterns of relapse and/or progression (R/POD) in 179 patients with MM transplanted between 2001 and 2009 at MSKCC and determined the precise date of R/POD based on IMWG standard clinical criteria using serum and urine PEP and IF, as well as Free Light Chain Assay (FLCA) (Zamarin, Bone Marrow Transplant, 2013). Serum samples from 63 of these patients, collected at the time of R/POD and/or at time points preceding R/POD were analyzed by HLC Assay and compared to results obtained by SA. Results : Among the 63 patients, 22 had IgA and 41 had IgG isotype. Overall, 207 samples were available for all 63 patients, including 72 IgA and 135 IgG samples. Figure 1 shows the concordance of Hevylite ratio (on the Y-axis) with the results obtained by SA (on the X-axis), for IgA and IgG samples, respectively. These graphs reveal an excellent association between HLC Assay and SA results in the IgA samples: all IgA samples revealing an M spike by SPEP had an abnormal HLC ratio even for low M spike levels (between 0 and 0.5 g/dL). Among IgA samples with a monoclonal band detectable by IF, 43 out of 48 samples also had an abnormal ratio by HLC Assay; and among samples with no detectable band by IF, 18 out of 24 had a normal ratio by HLC Assay (sensitivity 90%, specificity 75%, p〈 0.001) (Table 1, Panel 1). Interestingly, when looking at samples taken prior to relapse in IgA patients having achieved CR, HLC Assay was abnormal in 4 out of 7 patients while SA was still reported as normal. In contrast, the lack of association between the SA and HLC Assay is striking for the IgG samples, with poor sensitivity for the HLC Assay to detect monoclonal gammopathies with M spikes below 1 g/dL on SPEP. Among IgG samples with a monoclonal band detectable by IF, only 48 out of 89 samples also had an abnormal ratio by HLC Assay; while among samples with no detectable band by IF, 40 out of 46 had a normal ratio by HLC Assay (sensitivity 53% and specificity of 86% , p 〈 0.001) (Table 1, Panel 2). Conclusions: Although retrospective, this analysis suggests the following: 1) HLC Assay may be more sensitive than IF or SPEP in patients with IgA disease, as it can detect an abnormal HLC ratio at a time prior to relapse by SA, when IF and SPEP are still normal; 2) HLC Assay appears to be less useful in IgG patients, as its sensitivity in these patients appears much lower than IF; 3) There is a need for further detailed analysis on larger prospective cohorts to test the utility of HLC Assay compared to SA in the management of multiple myeloma patients, especially those with IgA disease. Figure 1 Association between HLC Assay and SA (SPEP/IF) results in patients with IgA disease. Figure 1. Association between HLC Assay and SA (SPEP/IF) results in patients with IgA disease. Figure 2 Association between HLC Assay and SA (SPEP/IF) results in patients with IgG disease. Figure 2. Association between HLC Assay and SA (SPEP/IF) results in patients with IgG disease. Disclosures Hassoun: Celgene: Research Funding; Binding Site: Research Funding; Novartis: Consultancy; Takeda: Consultancy, Research Funding. Kazunori:Binding Site: Research Funding. Landau:Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Korde:Medscape: Honoraria. Landgren:Takeda: Honoraria; Amgen: Honoraria, Research Funding; BMS: Honoraria; Medscape Myeloma Program: Honoraria; Merck: Honoraria; Celgene: Honoraria, Research Funding.

Description: Introduction: Multiple myeloma (MM) is a patchy bone marrow based malignancy of plasma cells, resulting in painful bone lytic lesions that can be visualized by 18F-FDG-PET-CT. We treated 45 NDMM patients with CRd-R therapy that resulted in high rates of minimal residual disease (MRD) negativity (62%)(Korde et al. JAMA Onc 2015). In this study, we assessed longitudinal FDG response through lenalidomide (Len) maintenance period and aimed to correlate with clinical findings and MRD status. Methods: The details of treatment received, study design and patients' characteristics have already been published. As part of the study design, all patients had serial PET imaging at baseline, after achievement of CR and/or at completion of 8 cycles of CRd, and at year-1 and -2 of Len maintenance, or termination of protocol therapy. Whole body (vertex to toes) static FDG imaging was performed at 1-hour post injection, implemented according to institutional practice. Focal lesions on FGD were defined as: increased uptake (above background reference) within the bone, (excluding articular regions due to high prevalence and likelihood of confounding arthritic disease), maximum standardized uptake value (SUV) 〉1.5 for lesion size on CT ranging from 0.5-1.0 cm, or maximum SUV 〉2.5 for lesions 〉1.0 cm. Results: At baseline, 37/45(82.2%) patients had FDG-positive lesions and 8/45(17.8%) were negative. Median follow-up for longitudinal analysis is 30.1 months. Among initial FDG-negative patients, 7/8 (87.5%) patients remained negative throughout follow-up; 1/8 (12.5%) patients developed a sclerotic FDG-positive lesion deemed not to be progression (rib 5 SUV 1.7). Among the 37 patients with baseline FDG-positive lesions, 12/37(32.4%) patients had complete resolution of FDG-PET-CTs (FDG-responders); 25/37(67.5%) remained FDG-long-term positive at time of last protocol scan. Eight of the 25(32%) FDG-long-term positive patients met IMWG criteria for progression, compared to 0/12 FDG-responders (p value=0.04). For patients with available data, MRD negative status after initial CRd (prior to Len maintenance) was not associated with long-term PET-CT response [19/24(79.2%) vs. 8/11(72.7%), FDG-long-term positive vs. FDG-responders, p=NS]. For the remaining FDG-long-term positive patients not meeting progression criteria, all 17 patients had low-positive persistent FDG with decreased or partial SUV response that decreased over time while on Len maintenance. Conclusions: In patients receiving CRd followed by long-term Len maintenance, 68% of baseline FDG-positive patients have persistent longitudinal FDG-positive myeloma lesions. While there is an increased risk of clinical progression among these patients, the majority showed low-positive FDG lesion uptake that decreased over time with long-term Len maintenance. Long-term resolution of FDG-positive lesions is not associated with MRD status after initial CRd therapy. Further follow-up is needed to examine the significance of persistent FDG-positive lesions in relationship to residual disease and mechanisms of resistance. Figure Figure. Disclosures Korde: Medscape: Honoraria. Hassoun:Takeda: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Binding Site: Research Funding. Landgren:Medscape Myeloma Program: Honoraria; BMS: Honoraria; Merck: Honoraria; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Description: Key Points Carfilzomib 56 mg/m2 provided a high overall response rate with a remarkable duration of response in patients with R/RMM. Nonhematologic grade 3/4 AEs likely related to carfilzomib treatment included hypertension and heart failure.

Description: Introduction: BCMA targeted CAR T cell therapy has shown promising results in patients with relapsed/refractory multiple myeloma (MM). Herein, we report on the safety and efficacy of MCARH171, a second generation, human derived BCMA targeted autologous 4-1BB containing CAR T cell therapy, including a truncated epidermal growth factor receptor safety system (Smith EL. Mol Ther 2018). Methods: This is a phase I first in human, dose escalation trial of MCARH171. Patients received conditioning chemotherapy with cyclophosphamide (Cy) 3 gm/m2 as a single dose or fludarabine 30 mg/m2 daily and Cy 300 mg/m2 daily for 3 days followed by MCARH171 infusion in 1-2 divided doses. The trial followed a standard 3+3 design with 4 dose levels where patients received the following mean doses per cohort: (1) 72x106, (2) 137x106, (3) 475x106, (4) 818x106 viable CAR+ T cells. The primary objective was to demonstrate safety, and secondary objectives included efficacy and expansion, and persistence of CAR T cells using PCR from the peripheral blood. The last accrued patient received MCARH171 on Dec 6, 2017 and the data cut-off is July 16, 2018. The study is closed to accrual. Results: 11 patients with relapsed and/or refractory MM were treated. Median number of prior lines of therapy was 6 (range: 4-14), and all patients received prior therapy with a proteasome inhibitor, IMiD, anti-CD38 monoclonal antibody, and high dose melphalan/stem cell transplant. Nine (82%) patients had high-risk cytogenetics and 9 (82%) were refractory to their immediate prior line of treatment. One patient was not evaluable for DLTs given the need for early radiation and steroids for impending spinal cord compression by tumor. There are no DLTs reported. Cytokine release syndrome (CRS) grade 1-2 occurred in 4 patients (40%), grade 3 occurred in 2 (20%), and there was no grade 4-5 CRS. Grade 2 encephalopathy occurred in 1 patient (10%) in the setting of high fevers which resolved in less than 24 hours. There was no grade 3 or higher neurotoxicity observed. Tocilizumab was administered to 3 patients; 2 in cohort 2, and 1 in cohort 3. Laboratory values correlating with CRS reaching grade 3 or requiring Tocilizumab (N=4) compared to those with no or milder CRS (N=6) included peak CRP (mean: 28.5 vs 4.6 mg/dL, p

Description: Background Minimal residual disease (MRD) negativity is a strong predictor for outcome in multiple myeloma. Next generation sequencing (NGS) for immunoglobulin heavy chain and kappa light chain VDJ rearrangements has become increasingly more common for MRD assessment. One of the known challenges with NGS for VDJ rearrangements is the vast diversity of sequences that are present, resulting in a need for a multiplex approach as common primers cannot be used to amplify all rearrangements. Also, somatic hypermutation may affect the annealing of primers and decrease the capture rate. The NGS VDJ assay developed by Adaptive Biotechnologies targets all theoretical combinations of VDJ sequences and has been used in several recent large randomized trials in multiple myeloma. The reported ~80% capture rate of the first version of the Sequenta/Adaptive 1.3 assay limited the ability to track MRD status post therapy. The assay has recently been updated and validated to increase resilience to somatic hypermutation. As there is no published reference data using this assay, we were motivated to assess VDJ capture in the clinical setting. Methods In total, 147 patients with newly diagnosed multiple myeloma (NDMM, n=101) or relapse/refractory multiple myeloma (RRMM, n=46) seen at Memorial Sloan Kettering Cancer Center were identified and included in the study. At bone marrow collection, patient samples were sorted for mononuclear cells and a subset of samples were sorted for CD138+ plasma cells. Stored bone marrow samples from these patients underwent DNA extraction and were sequenced with the Adaptive NGS VDJ assay. The same samples were also sequenced for genomic events using our internal NGS panel myTYPE. myTYPE is a custom capture panel targeting the most frequent multiple myeloma associated-somatic mutations, copy number alterations, and IGH translocations. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) of detection success in relation to clinical parameters such as age, gender, percent bone marrow plasma cells, as well as immunoglobulin heavy and light chain types, and myTYPE positivity. Results There overall capture rate for a unique VDJ sequence was 80%, 75% in NDMM samples and 89% in RRMM samples, respectively. The VDJ capture rate in samples that were myTYPE positive, e.g. samples with at least one genomic aberration detected by myTYPE, was 94%. In univariate analysis, the ORs of detecting a clonal VDJ sequence was 1.8 (95% CI 1.3-2.5) and 1.5 (1.2-1.9) for every 10% increase in plasma cells on bone marrow aspirate and biopsy, respectively. For every 1g/dL increase in M-spike, the OR of VDJ capture was 1.6 (1.2-2.2). Samples with at least one genomic aberration detected by myTYPE had a significantly higher detection rate of VDJ sequence, the OR of VDJ capture in myTYPE positive samples was 8.8 (3.2-31.3). Conversely, age, gender, type of immunoglobulin heavy chain (IgG or IgA), or light chain type (kappa or lambda) had no significant effect on the VDJ detection rate (Table). In multivariate analysis, myTYPE positivity was found to be an independent predictor of VDJ capture, with an OR of 4.9 (1.6-18.4, p=0.009) for myTYPE positive samples. The ORs were 1.4 (1.1-2.2, p=0.052) for an increase in 10% plasma cells on bone marrow aspirate and 1.5 (0.97-2.3, p=0.083) every 1g/dL increase in M-spike. Conclusion The VDJ capture rate using the updated Adaptive NGS VDJ assay was 94% in multiple myeloma samples of high quality as indicated by myTYPE positivity. The capture success rate was higher in samples with a greater disease burden. As expected, the assay was less sensitive in samples with insufficient DNA content. Our results are supportive of the use of this NGS VDJ in multiple myeloma, but also illustrate the importance of optimal sample ascertainment and processing. Disclosures Jacob: Adaptive Biotechnologies: Employment, Equity Ownership. Korde:Amgen: Research Funding. Mailankody:Juno: Research Funding; Physician Education Resource: Honoraria; Janssen: Research Funding; Takeda: Research Funding. Lesokhin:Serametrix, inc.: Patents & Royalties: Royalties; Squibb: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Genentech: Research Funding. Hassoun:Oncopeptides AB: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding.

Description: Key Points Isatuximab (anti-CD38 monoclonal antibody) given with lenalidomide/ dexamethasone is active in heavily pretreated relapsed/refractory myeloma Overall, the safety profile of this combination is similar to the characteristic safety profiles of the individual agents.

Description: Background The alkylating agent melphalan, given at the myeloablative dose of 200mg/m2 preceding autologous hematopoietic stem cell transplantation (AHSCT), is part of the upfront management of patients with multiple myeloma (MM) and has been used in the salvage setting, often as second transplant. Proteasome inhibitors (PI) have been shown in vitro to impair the fanconi/BRCA pathway of DNA repair and increase DNA fragmentation and apoptosis induced by alkylating agents in MM cells. We hypothesized that combining carfilzomib, a second generation PI, with melphalan would result in more effective anti myeloma activity. We herein performed a phase 1 study to identify the maximal tolerated dose (MTD) of carfilzomib when used in combination with myeloablative doses of melphalan as conditioning regimen for patients with relapsed MM and describe toxicity and preliminary activity profile for the combination. Methods Phase 1, multicentric, dose escalation trial with traditional 3+3 design. Eligible subjects had symptomatic MM, relapsed after at least one line of therapy, with evaluable disease and having obtained at least a minimal response (MR) after the most recent salvage regimen. Subjects were also required to have at least 2 x 106 CD34+ cells/kg in storage for transplant and additional 2 x 106 CD34+ cells/kg as “back up”. Treatment consisted of two doses of carfilzomib administered IV over 30 minutes on days -3 and -2. The day -2 dose was administered one hour prior to administration of melphalan200mg/m2. Carfilzomib dose consisted of 20(day-3)/27 (day -2) mg/m2 (cohort 0), 27/27 (cohort 1), 27/36 (cohort 2), 27/45 (cohort 3) and 27/56 mg/m2 (cohort 4). All subjects received pegfilgrastim 6 mg subcutaneously on day +1. Dose limiting toxicities (DLT, non-hematologic grade 4 and selected grade 3 toxicities) were evaluated during the first 30 days after transplantation. Disease response was assessed 100 days after transplantation. Results Enrolment of cohort 4 (last) is ongoing. Twelve subjects were accrued in cohorts 0-3 with no DLT being identified. Median age was 56 (range 45-68). Median number of prior lines of therapy was 3 (range 2-6) and 5 subjects had previously received AHSCT. There was no acute toxicity associated with carfilzomib infusion. Median CD34+ dose infused was 4.15 x 106/kg (range 2.21-9.34). Neutrophil engraftment occurred after a median of 11 days (range 8-15) and platelet engraftment after a median of 17.5 days (range 11-24). There were no non-hematologic grade 4 toxicities. The most frequent grade 3 toxicity was infection in 7/12 subjects consisting of 1 episode of pneumonia, 1 episode of bacteremia, 1 episode of urinary tract infection and 4 episodes of febrile neutropenia. Other grade 3 toxicities were rash (n=2), hypertension (n=1), hypophosphatemia (n=1) and hypocalcemia (n=1). Nine subjects, from cohorts 0, 1 and 2, have reached day +100 response assessment. Prior to transplant the responses to salvage regimen were MR in 1/9, partial response (PR) in 6/9, very good partial response (VGPR) in 1/9 and complete response (CR) in 1/9 subjects. At day +100 cumulative responses were PR in 3/9, VGPR in 3/9 and CR in 3/9 subjects. Pharmacodynamic studies in peripheral blood mononuclear cells revealed that carfilzomib precluded melphalan-induced increase in FANCD2 and FANCI mRNA. Conclusion Conditioning with carfilzomib and melphalan prior to AHSCT is well tolerated in patients with relapsed MM. Final results of this phase 1 study will be presented at the meeting. The MTD cohort (or cohort 4 if no MTD is found) will be subsequently expanded for better determination of this regimen’s activity. Disclosures: Costa: Onyx: Research Funding. Off Label Use: Carfilzomib in conditioning regimen for stem cell transplantation.

Description: BACKGROUND: Cardiovascular (CV) events are a known complication to proteasome inhibitor therapy in myeloma. Underlying mechanisms are unknown. We recently completed an investigator initiated, single institution Phase II study of high dose carfilzomib (56mg/m2) in patients with relapsed/refractory MM (NCT01351623). Among 42 response evaluable patients, 11 patients (25%) developed treatment-emergent heart failure of any grade, and 5 patients (11%) developed severe heart failure requiring mechanical ventilation. We undertook a study to identify potential biomarkers that may point to underlying mechanisms of CV events among multiple myeloma patients treated with carfilzomib therapy. METHODS: We performed a nested case-control study with 7 patients who experienced a CV event on our high dose carfilzomib study and had pre-treatment (baseline) plasma stored and 19 case matched controls treated on the same study who did not have a CV event. We screened for 90 proteins known to be associated with CV disease using O-linked glycosylation. We used the Proseek Multiplex CVD I 96x96 platform which is based on the Proximity Extension Assay (PEA) technique. PEA is a 96-plex immunoassay that allows high throughput detection of protein biomarkers in liquid samples. For each biomarker, a matched pair of antibodies linked to unique oligonucleotides (proximity probes) binds to the respective protein target. Upon binding, the unique proximity probes can hybridize to each other and subsequently be detected and quantified by real-time PCR. Mean biomarker levels were compared using a t-test. False discovery rate (FDR) was used for multiple comparisons adjustment. RESULTS: Using samples collected prior to initiation of carfilzomib therapy, in an agnostic statistical model we identified the following four proteins to have altered levels in myeloma patients who developed CV events (p=0.002-0.004, unadjusted; p=0.089, after FDR correction): matrix metalloproteinase-1 (MMP-1, heparin-binding EGF-like growth factor (HB-EGF), TNF-related apoptosis-inducing ligand (TRAIL), and myoglobin (MB). Myeloma patients who developed CV events had 37% lower MMP-1, 15% lower MB, and 4% lower HB-EGF, while TRAIL was 7% higher in patients who developed CV events. Matrix metalloproteinases are a family of proteolytic enzymes responsible, among other functions, for myocardial extracellular protein degradation. Interestingly, several MMP species, including MMP-1, have been identified within the human myocardium and are thought to be dysregulated in congestive heart failure. HB-EGF is a mitogenic and chemotactic glycoprotein that is essential for maintaining normal cardiac function and is known to play an important role in myocardial remodeling. CONCLUSIONS: We found that there was a trend towards lower MMP-1, HB-EGF, and MB levels and higher TRAIL levels in patients with CV events while receiving proteasome therapy. MMP-1 appears to be the most promising potential biomarker based on our data. Our study supports further investigation of these proteins as potential biomarkers for patients at risk of CV events when treated with carfilzomib. Table 1. CV event No CV event N=7 N=19 CKD Proteins1 Mean (SD) Mean(SD) Unadjusted P-value Adjusted P-value MMP_1 1.7 (0.5) 2.7 (0.9) 0.002 0.089 HB_EGF 6.9 (0.2) 7.2 (0.3) 0.004 0.089 TRAIL 8 (0.3) 7.5 (0.5) 0.004 0.089 MB 5 (0.5) 5.9 (0.8) 0.004 0.089 HSP_27 2.2 (0.3) 2.7 (0.8) 0.032 0.528 PDGF_subunit_B 4 (0.7) 5 (1.5) 0.036 0.528 CD40_L 3.4 (0.6) 4.2 (1.2) 0.042 0.533 EGF 3.7 (0.9) 4.7 (1.4) 0.053 0.592 CX3CL1 5.9 (0.2) 5.6 (0.6) 0.092 0.895 TRAIL_R2 4.2 (0.4) 4.6 (0.6) 0.101 0.895 1. Proteins are listed based on the p-value associated with the difference between patients who did and did not have CV events, with lowest p-value on the top. The top 10 biomarkers are shown. Disclosures Ekman: Olink Bioscience: Employment. Grundberg:Olink Bioscience: Employment. Hassoun:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Research Funding; Novartis: Consultancy. Lesokhin:Aduro: Consultancy; Efranat: Consultancy; Genentech: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Landau:Janssen: Consultancy; Prothena: Consultancy, Honoraria; Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria; Onyx: Honoraria, Research Funding; Takeda: Research Funding. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding. Landgren:Onyx: Honoraria; Celgene: Honoraria; BMJ Publishing: Consultancy; International Myeloma Foundation: Research Funding; Bristol-Myers Squibb: Honoraria; Onyx: Research Funding; Medscape: Consultancy; Medscape: Honoraria; BMJ Publishing: Honoraria; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Onyx: Consultancy.

Description: Introduction: Given that the rate of cardiovascular (CV) morbidity increases with age and the median age of patients with multiple myeloma (MM) is 65, CV complications can occur during MM treatment. The proteasome inhibitors (PIs), bortezomib and carfilzomib, may play a role in the development of treatment-related cardiotoxicity as suggested by phase 2 clinical studies and a phase 3 trial (Stewart AK et al. N Engl J Med 2015;372:142-52). Reported treatment-related cardiotoxicity includes hypertension, congestive heart failure (CHF), myocardial infarction, and cardiac arrest. The objectives of this study are to define the incidence of cardiotoxicity in MM patients treated with bortezomib and carfilzomib and to evaluate whether the dose and pre-existing cardiac history affects that incidence. Study design and methods:Using the pharmacy database, we identified all MM patients treated at Memorial Sloan Kettering Cancer Center between 1/2010 to 10/2014 who were treated with bortezomib or carfilzomib in the second-line and relapsed refractory setting. Of note, all patients in the carfilzomib arm received prior bortezomib; thus, MM patients in the carfilzomib arm were more heavily pretreated and the two arms should be compared with caution. Data collected included: baseline demographics, baseline disease status, treatment given including dose and number of cycles, baseline cardiovascular comorbidities and medications, and pre- and post-treatment ejection fraction. Cardiotoxicity recorded was defined as grade 3 or more (requiring intervention) and included: hypertension, CHF, coronary artery disease, pulmonary hypertension, myocardial infarction, stroke, and/or arrhythmias. Descriptive statistics were used to analyze baseline demographics, including median and range for continuous variables and frequency and percentage for categorical variables. Fisher's exact test was used to assess the association between clinical and treatment characteristics and cardiotoxicity. Results: 157 patients were eligible for analysis with 47 in the bortezomib arm and 110 in the carfilzomib arm. The overall incidence of cardiotoxicity across both arms was 17% with an incidence of 9% (n = 4) and 20% (n = 22) in the bortezomib and carfilzomib arms, respectively. The most common events reported were arrhythmias (n = 3) with bortezomib and CHF (n = 12) with carfilzomib. The incidence of CHF and cardiomyopathy was 4% and 19% in the bortezomib and the more heavily pretreated carfilzomib arms, respectively. Baseline cardiac comorbidities were not found to increase the risk of cardiotoxicity while on treatment with carfilzomib (p = 0.815); due to small numbers, we were unable to assess this aspect in the bortezomib arm. Based on a categorization of carfilzomib dose (≤20 mg/m2, 27 mg/m2, or ≥36 mg/m2) starting on cycle 2, there was a significant association between the dose level received and cardiotoxicity (p=0.003); patients treated at dose level ≥36 mg/m2 were most likely to have a cardiac-related event while on therapy. Patients receiving the higher doses were treated on a clinical trial (Lendvai et al. Blood 2014;124:899-906), and they were among the most heavily pretreated. Management of cardiac events with carfilzomib was largely supportive with all patients requiring pharmacological intervention, 64% (n= 14) requiring hospital admission, and 73% (n = 16) requiring treatment delays. Conclusion: Grade 3 or more cardiotoxicity is a potential complication of treatment with PIs. However, there is no increased risk of CV deaths noted in our study. The results show a higher risk of cardiac toxicity in heavily pretreated MM patients receiving higher doses (≥36 mg/m2) of carfilzomib. The number of prior lines of therapy is a major factor when defining CV events in relation to a given therapy. Importantly, both carfilzomib and bortezomib are highly efficacious anti-myeloma drugs; CV risks should be assessed for individual patients and in relation to benefits. Disclosures Landgren: BMJ Publishing: Honoraria; Medscape: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Onyx: Honoraria; International Myeloma Foundation: Research Funding; Onyx: Research Funding; BMJ Publishing: Consultancy; Medscape: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Onyx: Consultancy.

Description: Introduction: Programmed cell death-1 (PD-1) signaling suppresses the antigen driven activation of T cells upon interaction with its ligands PD-L1 and PD-L2. The PD-1/PD-L1 axis is thought to mediate the resistance of multiple myeloma to conventional therapy (Tamura 2013; Paiva 2015). Nivolumab, a fully human IgG4 monoclonal PD-1 receptor-blocking antibody, has shown clinical activity in a variety of tumor types. Nivolumab has demonstrated a prolonged receptor binding kinetic lasting 〉100 days that may lead to an efficacy or toxicity signal in the post-treatment period. We therefore evaluated the response of patients with relapsed or refractory multiple myeloma to additional myeloma therapy received within 3 months of the end of nivolumab administration. Methods: The preliminary results of an open-label study that treated patients with relapsed or refractory multiple myeloma using a dose escalation design (1 mg/kg and 3 mg/kg) of nivolumab administered every 2 weeks have been reported previously (NCT01592370, Lesokhin et al., ASH 2014). Here we will report responses and safety data using standard criteria to the next line of therapy received immediately after nivolumab. Results: 8 patients with multiple myeloma from the original open label study were treated at Memorial Sloan Kettering Cancer Center. The disease characteristics and efficacy results are shown in the table. 1 of 8 patients (12.5%) experienced progression while on therapy manifested by development of an isolated plasmacytoma. The patient received radiation and then resumed and completed 97 weeks of therapy with nivolumab. He is currently off therapy without any evidence of disease at 48 weeks after cessation of nivolumab. 3 of 8 patients (37.5%) achieved a partial response to the next line of treatment after nivolumab. 2 of 8 patients (25%) who were exposed and refractory to immunomodulatory drugs (IMiDs) received single-agent, low-dose lenalidomide as the next line of therapy and achieved stable disease lasting approximately 100 days after cessation of nivolumab followed by disease progression. 1 of 8 patients (12.5%) experienced progressive disease despite the next line of therapy, and 1 of 8 patients (12.5%) received an experimental treatment as the next line of therapy and was therefore not evaluable. No new drug-related adverse events occurred in the 3 months after completing treatment with nivolumab. Overall, 6 out of 8 patients derived clinical benefit from post-nivolumab therapy, an unusually high response rate for this population. Conclusions: In a small cohort of patients with relapsed and refractory multiple myeloma, evaluation of response kinetics after cessation of nivolumab supports the notion that long PD-1 receptor binding kinetics may increase the efficacy of subsequent therapy without added toxicity. Larger studies are needed to confirm and expand our findings. Table. Patient Characteristics and Efficacy Age Sex ISS Cytogenetics Prior Lines ASCT IMiD E IMiD R Prot E Prot R Best Response to Nivolumab Next Line of Standard Therapy Best Response to Next Line 52 M 1 S 3 Y Y Y Y Y SD Carfilzomib, Cyclophosphamide, Dexamethasone PR 32 M 1 S 3 Y Y Y Y Y SD None* N/A 80 F 1 S 1 N Y N N N SD Lenalidomide PR 52 F 1 I 3 Y Y Y Y N SD Lenalidomide SD 62 M 1 H 1 Y Y N Y N PD Cyclophosphamide, Bortezomib, Dexamethasone PR 58 M 2 S 5 Y Y Y Y Y PD Lenalidomide SD 57 F 1 S 3 Y Y N Y Y PD None^ N/A 59 F 1 S 3 Y Y Y Y Y PD Lenalidomide, Bortezomib, Dexamethasone PD ISS=international staging system; S=standard cytogenetics; I=intermediate cytogenetics; H=high risk cytogenetics; ASCT=autologous stem cell transplant; IMiD E=IMiD exposed; IMiD R=IMiD refractory; Prot E=proteosome exposed; Prot R=proteosome refractory; PD=progressive disease; SD=stable disease; PR=partial response *Patient completed 97 weeks of nivolumab and continues untreated without any evidence of disease at 48 weeks after cessation of therapy ^Patient received treatment on an experimental protocol Disclosures Funt: Kite Pharma: Equity Ownership. Off Label Use: Nivolumab is FDA approved for use in patients with metastatic melanoma but not in patients with multiple myeloma. . Page:Celgene: Consultancy. Landgren:Bristol-Myers Squibb: Honoraria; Celgene: Consultancy; BMJ Publishing: Consultancy; Bristol-Myers Squibb: Consultancy; BMJ Publishing: Honoraria; Medscape: Consultancy; Medscape: Honoraria; Celgene: Honoraria; International Myeloma Foundation: Research Funding; Onyx: Honoraria; Onyx: Research Funding; Onyx: Consultancy. Borrello:Celgene: Research Funding. Lesokhin:Bristol Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Aduro: Consultancy; Genentech: Research Funding; Efranat: Consultancy.