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: Several studies have indicated that the depth and duration of treatment response in multiple myeloma are both reduced in the relapsed setting. With further lines of therapy, responses continue to weaken in depth and shorten in duration. The National Comprehensive Cancer Network (NCCN) Guidelines suggest that regimens may be repeated in the relapsed setting if there has been a duration of at least 6 months since that regimen was given; however, there is limited information regarding treatment response and duration in the setting of re-treating patients with agents previously utilized. Moreover, preliminary data has suggested that carfilzomib-based regimens in the frontline may be able to attain deeper and longer responses than alternative therapies, which has led to carfilzomib being used more frequently in the frontline. This motivated us to investigate the treatment response, depth, and safety of re-challenging patients with carfilzomib in the relapsed setting. Methods: In this retrospective chart review, we identified all patients who were treated with multiple courses of carfilzomib-based regimens at Memorial Sloan Kettering Cancer Center between January 1, 2014 and November 30, 2018. Our primary objectives were to assess the response, duration of response and treatment, and safety of re-exposure to carfilzomib-based regimens. Responses were assessed as per IMWG 2016 consensus criteria (Lancet Oncol 2016). In this review we describe the clinical course, safety, and efficacy of re-challenging patients with carfilzomib in the relapsed and refractory settings. Results: Fifteen patients were identified as having received multiple, independent lines of carfilzomib-based therapy. The median age of the cohort was 58 years (49-76) with 53% male (8); two patients had R-ISS stage 1, eight stage 2, and five stage 3 disease. Five of these patients received their initial carfilzomib in the frontline as part of KRD; four of whom attained a sCR with the fifth attaining a VGPR. The remaining ten patients received their initial carfilzomib in the second-line (4) or 3rd and subsequent lines (6). Upon re-exposure to carfilzomib, patients were heavily treated with a median of four lines of therapy (2-15). All but three patients had at least one adverse cytogenetic abnormality; eight with 17p-, five with 13q-, three with t4;14, and six with 1q+. Regimens utilized in the relapsed setting included KRD (N=4), KPD (N=3), Cyklone (N=2), KD + HDAC inhibitor (N=3), KD (N=1), KCD (N=1), and KRD + daratumumab (N=1). Four patients received carfilzomib at a dose of 27 mg/m2 while the remaining 10 received 〉 36 mg/m2. Responses were seen in all but four patients (two VGPR, five PR, and four MR), with one patient experiencing progression during carfilzomib with no response; notably, this patient only attained a MR to primary carfilzomib therapy and their second exposure was the 15th line of therapy. The median time to next therapy was 4.8 months (1.9-19.4) with one patient being bridged to autologous hematopoietic cell transplantation (HCT), one to allogeneic HCT, and three are currently receiving ongoing carfilzomib treatment (13.9, 2.8, 2.5 months with VGPR, MR, and PR, respectively). Exacerbation of baseline hypertension was identified in three patients, but these instances were treated successfully with standard medications with no further complications. No additional cardiovascular events were identified in the frontline or re-treatment settings. Conclusions: We report that in a heavily pre-treated, high risk patient cohort, patients previously treated with carfilzomib-based regimens may be safely re-challenged with carfilzomib. Importantly, none of these patients experienced cardiovascular adverse effects other than exacerbation of underlying hypertension, further supporting the ability to safely re-treat a select group of patients with carfilzomib. We conclude that depending on the patient and treatment history, re-challenging with carfilzomib at relapse may be appropriate salvage therapy, particularly as a bridge towards HCT and/or clinical trials. Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Lesokhin:Genentech: Research Funding; Serametrix Inc.: Patents & Royalties; Janssen: Research Funding; GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landau:Prothena: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Caelum: 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; Takeda: 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; Karyopharm: Consultancy, Honoraria. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Giralt:Amgen: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Miltenyi: Research Funding; Jazz Pharmaceuticals: Consultancy; Actinium: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Kite: Consultancy. Landgren:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Merck: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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: Background: Despite a number of recent advances in the treatment of multiple myeloma (MM), the majority of patients are likely to relapse or become resistant to current treatment options. PF-06863135 (PF-3135) is a humanized immunoglobulin G (IgG) CD3 bispecific monoclonal antibody that utilizes anti-B-cell maturation antigen (BCMA) and anti-CD3 targeting arms paired through hinge-mutation technology within an IgG2a backbone. The molecule binds to BCMA-expressing myeloma cell lines and to T cells with affinities of 20 pM and ~40 nM, respectively (Panowski et al. Blood 2016). PF-3135 has a half-life of ~4-6 days in cynomolgus monkeys, which is predicted to be similar in humans (Panowski et al. Blood 2016). This is an ongoing open-label, multidose, multicenter, dose-escalation phase I study to assess the safety, pharmacokinetics (PK), and pharmacodynamics of PF-3135 in adult patients with advanced MM who have relapsed from, or are refractory to, standard therapy (ClinicalTrials.gov, identifier: NCT03269136). Methods: Patients aged ≥18 years with relapsed or refractory MM and measurable disease (as per International Myeloma Working Group updated criteria 2014), who have received prior therapy that included a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody, either in combination or as a single agent, received escalating doses of PF-3135 intravenously. The primary objectives include assessment of safety and tolerability at increasing dose levels of PF-3135 to estimate the maximum tolerated dose and select the recommended phase 2 dose (RP2D). Secondary objectives include evaluation of the overall safety profile, anti-myeloma activity, PK, and immunogenicity of PF-3135. A modified toxicity probability interval method, which targets a dose-limiting toxicity rate of 25% with an acceptable equivalence interval (± 5%), is utilized for dose escalation. Results: Five patients have received PF-3135 in the dose-escalation portion of the study. No dose-limiting toxicities or cytokine-release syndrome events have been reported. One patient experienced a grade 1 fever (not related to PF-3135) that was reported as a serious adverse event (AE) because the patient was hospitalized for observation. The majority of reported treatment-emergent AEs (all-causality) have been grade ≤2. One patient experienced acute grade 3 alanine aminotransferase/aspartate aminotransferase elevation (

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: 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.