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Diagnosing the cause of hypoxemia and dyspnea can be complicated in complex patients with multiple comorbidities. This “Case Study in Physiology” describes an man with obesity admitted to the hospital for relapse of acute lymphoblastic leukemia, who experienced progressive hypoxemia, shortness of breath, and dyspnea on exertion during his hospitalization. After initial empirical treatment with diuresis and antibiotics failed to improve his symptoms and because an arterial blood gas measurement was not readily available, we applied a novel, recently described physiological method to estimate the arterial partial pressure of oxygen from the peripheral saturation measurement and calculate the alveolar-arterial oxygen difference to discern the source of his hypoxemia and dyspnea. Using basic physiological principles, we describe how hypoventilation, anemia, and the use of a β blocker and furosemide, collaborated to create a “perfect storm” in this patient that impaired oxygen delivery and limited utilization. This case illustrates the application of innovative physiology methodology in medicine and provides a strong rationale for continuing to integrate physiology education in medical education. NEW & NOTEWORTHY Discerning the cause of dyspnea and hypoxemia in complex patients can be difficult. We describe the “real world” application of an innovative methodology to untangle the underlying physiology in a patient with multiple comorbidities. This case further demonstrates the importance of applying physiology to interrogate the underlying cause of a patient’s symptoms when treatment based on probability fails.

Hematopoietic stem cell transplant (HSCT) is a potentially curative treatment for hematopoietic malignancies, complicated by decreased performance status and quality of life. Exercise therapy improves outcomes in HSCT, but several barriers have prevented exercise from becoming routine clinical practice. Based on existing data that wearable technologies facilitate exercise participation in other sedentary and chronic illness populations, we propose the novel hypothesis that wearable technologies are a valuable tool in transcending barriers and developing exercise therapy programs for HSCT patients.

Introduction The clinical application of the Revised International Staging System (R-ISS) for multiple myeloma may be limited by heterogeneity in clinical interphase fluorescent in situ hybridization (FISH) practices for detecting chromosomal abnormalities (CAs). Next generation sequencing (NGS)-based FISH (Seq-FISH) has demonstrated improved sensitivity and similar specificity relative to clinical FISH, and provides a standardized, single-pass method for identifying high-risk CAs. To date, calculating R-ISS stage using Seq-FISH (R-ISS-NGS) has not been validated. Patients and Methods We identified 672 patients with sufficient data to calculate R-ISS-NGS from the Multiple Myeloma Research Foundation (MMRF) CoMMpass Study. R-ISS-NGS was calculated from original ISS stage, lactate dehydrogenase, and CAs detected by Seq-FISH. Endpoints included overall survival and progression-free survival. We conducted multivariate analyses controlling for age and gender in order to compare outcomes across stages I to III of both the original ISS and R-ISS-NGS. Results The median follow-up was 24 months. The R-ISS-NGS resulted in significant redistribution of patients into stage II, relative to the original ISS. With respect to stage I, R-ISS-NGS stages II and III of were associated with worse progression-free survival or overall survival, more so than the staging schema of the ISS, thus validating the use of Seq-FISH in staging. Conclusion Using CAs detected by Seq-FISH and data from the CoMMpass study, we validated the R-ISS with a large, generalizable cohort. This study validates the substitution of Seq-FISH for clinical FISH, especially in large registry studies. Additionally, use of the validated R-ISS-NGS will strengthen outcomes research generated from the CoMMpass study.

Objectives Elranatamab (PF-06863135) is a humanized bispecific monoclonal antibody (IgG2a) that targets BCMA, a member of the tumor necrosis factor receptor superfamily expressed in multiple myeloma, and CD3 on T cells. We reported results for intravenous (IV) dosing (Raje et al. Blood. 2019;134(S1):1869) and now update for subcutaneous (SC) dosing from the ongoing Phase 1 study (MagnetisMM-1; NCT03269136). Materials and methods Patients received elranatamab at 80, 130, 215, 360, 600, and 1000 μg/kg SC weekly. A modified toxicity probability interval method was used for escalation, with monitoring for dose-limiting toxicity (DLT) to end of the first cycle. Treatment-emergent adverse events (TEAEs) were graded by Common Terminology Criteria for Adverse Events (v4.03), and cytokine release syndrome (CRS) by American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant. 2019;25:625). Response was assessed by International Myeloma Working Group criteria. Pharmacokinetics, cytokine profiling, and T cell immunophenotyping were performed. Results 30 patients had received elranatamab as of 4-Feb-2021 at 80 (n = 6), 130 (n = 4), 215 (n = 4), 360 (n = 4), 600 (n = 6), or 1000 (n = 6) μg/kg SC weekly. Patients had a median of 8 prior treatments; 87% had triple refractory disease, 97% had prior anti-CD38 therapy, and 23% (7 patients) had prior BCMA-directed antibody drug conjugate (6 of 7 patients) or chimeric antigen receptor T cell therapy (3 of 7 patients). The most common all causality TEAEs included lymphopenia (n = 25, 83%; 20% G3, 63% G4), CRS (n = 22, 73%; 57% G1, 17% G2, none ≥G3), anemia (n = 18, 60%; 50% G3, 0% G4), thrombocytopenia (n = 16, 53%; 17% G3, 20% G4), neutropenia (n = 16, 53%; 23% G3, 30% G4), and injection site reaction (n = 15, 50%; 43% G1, 7% G2, none ≥G3). Both CRS and immune effector cell-associated neurotoxicity syndrome (n = 6, 20%) were limited to ≤G2 with median durations of 3 and 2.5 days, respectively. No DLT was observed. Exposure increased with dose, and Tmax ranged from 3–7 days. Cytokine increases occurred with the first dose, and increased T-cell proliferation was observed in peripheral blood. The overall response rate (ORR) for doses ≥215 μg/kg was 70% (n = 14/20) including partial response (PR; n = 1), very good PR (VGPR; n = 7), complete response (CR; n = 1), and stringent CR (sCR; n = 5). Median time to response was 22 days, and 3 of 4 patients (75%) with prior BCMA-directed therapy achieved response (VGPR, n = 2 and sCR, n = 1). Updated data, including duration of response, will be presented. Discussion Elranatamab demonstrated a manageable safety profile and, across the efficacious dose range (≥215 μg/kg), achieved ORR of 70% with CR/sCR rate of 30%, including responses after prior BCMA-directed therapy. Conclusion These results demonstrate the safety and efficacy of elranatamab in this relapsed/refractory population and support ongoing development of elranatamab for patients with multiple myeloma, both as monotherapy and in combination with standard or novel therapies.

Most cancer patients succumb to disseminated disease because conventional systemic therapies lack spatiotemporal control of their toxic effects in vivo, particularly in a complicated milieu such as bone marrow where progenitor stem cells reside. Here, we demonstrate the treatment of disseminated cancer by photoactivatable drugs using radiopharmaceuticals. An orthogonal-targeting strategy and a contact-facilitated nanomicelle technology enabled highly selective delivery and co-localization of titanocene and radiolabelled fluorodeoxyglucose in disseminated multiple myeloma cells. Selective ablation of the cancer cells was achieved without significant off-target toxicity to the resident stem cells. Genomic, proteomic and multimodal imaging analyses revealed that the downregulation of CD49d, one of the dimeric protein targets of the nanomicelles, caused therapy resistance in small clusters of cancer cells. Similar treatment of a highly metastatic breast cancer model using human serum albumin-titanocene formulation significantly inhibited cancer growth. This strategy expands the use of phototherapy for treating previously inaccessible metastatic disease., Most of the systemic cancer therapies lack spatiotemporal control. Here, the authors show targeted activation of a light-sensitive drug by radiopharmaceuticals in disseminated cancer cells as potential in vivo treatment of metastatic diseases with reduced off-target toxicity.

Background Patients (pts) with relapsed/triple-class refractory (R/R; refractory to a proteasome inhibitor, immunomodulatory drug or anti-CD38 antibody) multiple myeloma (MM) have limited treatment options. A need remains for novel combination therapies with manageable toxicity and non-cross-resistant mechanisms of action. B-cell maturation antigen (BCMA) is expressed in most MM pt tumors. SEA-BCMA is an investigational, humanized, nonfucosylated IgG1 monoclonal anti-BCMA antibody. Proposed mechanisms of action of SEA-BCMA include blocking of BCMA-mediated pro-survival and proliferative signaling, mediating antibody-dependent cellular phagocytosis, and displaying enhanced antibody-dependent cellular cytotoxicity. Preclinical data demonstrate promising antitumor activity and versatile combinability. Here, we present preliminary data from the first-in-human Phase 1 clinical trial. Methods SGNBCMA-001 (NCT03582033) is an ongoing phase 1, open-label, multicenter, dose-escalation and expansion study to evaluate the safety, tolerability and antitumor activity of SEA-BCMA in adults with R/R MM not previously exposed to any other BCMA-directed therapy. Part A tested monotherapy safety and tolerability with dose escalation (100-1600 mg flat dosing once every 2 weeks [Q2W] by intravenous infusion), and dose expansion at the highest tolerated dose. Parts B and C aim to optimize efficacy by testing intensified dosing (Part B; weekly [Q1W] induction dosing of SEA BCMA for 8 weeks is followed by Q2W maintenance dosing) and dexamethasone (DEX) combination therapy (Part C) in pts who have received ≥3 prior lines of therapy for MM and are triple-class refractory. Responses are assessed per the 2016 International Myeloma Working Group criteria. Results As of June 15, 2021, Part A completed enrollment. A total of 55 pts received SEA-BCMA (see Table 1 for pt characteristics). SEA-BCMA was generally well tolerated, and the maximum tolerated dose was not reached in the 5 dose levels tested in Part A (100, 200, 400, 800, or 1600 mg Q2W; n=2, 2, 2, 7, and 7, respectively). At 800 mg, 1 of 7 pts reported a Grade 3 infusion-related reaction (IRR), which met dose-limiting toxicity (DLT) criteria by lasting >24 hours despite supportive care. This constituted the single DLT observed during dose escalation. Subsequently, dose expansion (n=15) proceeded at 1600 mg Q2W. The most common treatment-emergent adverse events (TEAEs) observed with 1600 mg Q2W (n=22) were fatigue (32%), pyrexia (23%), IRR (23%), and hypertension (23%) for non-hematological events, and anemia (14%) for hematologic events. The most common ≥Grade 3 TEAEs with 1600 mg Q2W were anemia and syncope (9% each). Following a safety monitoring review, premedication with acetaminophen + antihistamine was introduced to mitigate IRRs in expansion cohorts. Parts B and C completed parallel safety run-ins (n=6 each) at the 1600 mg dose with no DLTs observed and with similar tolerability. Pharmacokinetic (PK) analyses indicate serum SEA-BCMA exposures increased proportionally with increasing dose with a half-life of approximately 10 days. Preliminary analyses suggest the PK profile of SEA-BCMA in combination therapy with DEX (n=5) is comparable to monotherapy and is unaltered with a change in schedule from Q2W to Q1W. Three of 22 pts who received 1600 mg SEA-BCMA Q2W monotherapy (Part A) achieved a confirmed objective response (OR; OR rate: 14% [95% confidence interval: 2.91, 34.91]; 2 partial responses [PR], 1 very good PR [VGPR]). To date, 3 pts remain on treatment (2 PRs and 1 stable disease). The median duration of treatment was 12 weeks (Figure 1; range 4-88). In Parts B and C, 2 of 8 (2 PR) and 2 of 12 (1 VGPR, 1 PR) pts reported a confirmed OR; 3 of the 4 responding pts remain on treatment in cycle 7, 8, and 9, respectively. Conclusions Preliminary results for SGNBCMA-001 suggest a favorable safety profile and combination potential. SEA-BCMA also showed encouraging duration on treatment and initial antitumor activity in a heavily pre-treated late-line R/R MM pt population. Expansion cohorts testing intensified SEA-BCMA dosing and the addition of DEX are underway to further assess the safety, tolerability, and estimate of SEA-BCMA activity in the context of these treatment approaches. An additional expansion cohort (Part D), testing the combination of SEA-BCMA with pomalidomide and DEX in pts who have received ≥2 prior lines of therapy, is now enrolling. Figure 1 Figure 1. Disclosures Hoffman: BMS, Celgene: Honoraria. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Melear: Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau; Janssen: Speakers Bureau. Liedtke: Pfizer: Honoraria; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Niesvizky: Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; GSK: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding. Tomasson: Pfizer, Inc.: Research Funding; Rafael Pharmaceuticals: Research Funding; syros Pharmaceuticals: Research Funding; Janssen R&D: Research Funding; Seagen, Inc.: Research Funding. Yasenchak: Seagen Inc.: Research Funding. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. Li: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Wang: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Ho: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company.

Background Elranatamab (PF-06863135), a humanized bispecific molecule, targets both BCMA expressed in MM and CD3 on T cells. MagnetisMM-1 (ClinicalTrials.gov ID: NCT03269136) is a Phase 1 study of elranatamab with the aim of characterizing the efficacy, safety, pharmacokinetics, and pharmacodynamics of elranatamab as single agent and in combination with immunomodulatory agents for pts with relapsed or refractory MM. Methods Pts received single agent elranatamab 80, 130, 215, 360, 600, or 1000µg/kg/week subcutaneously. A modified toxicity probability interval method was used for escalation, with monitoring for dose-limiting toxicity (DLT) to the end of the first cycle. Treatment emergent adverse events (TEAEs) were graded by Common Terminology Criteria for Adverse Events v4.03, and cytokine release syndrome (CRS) by American Society for Transplantation and Cellular Therapy criteria (Biol Blood Marrow Transplant. 2019;25:625). Responses and minimal residual disease (MRD) status (by next-generation sequencing at a sensitivity of 1 × 10-5) were assessed by International Myeloma Working Group criteria. Pharmacokinetics, cytokine profiling, and T cell immunophenotyping were performed. Results 30 pts had received elranatamab as of 4-Feb-2021 at 80 (n=6), 130 (n=4), 215 (n=4), 360 (n=4), 600 (n=6), or 1000 (n=6) µg/kg. Pts had a median of 8 prior treatments; 87% had triple refractory disease, 97% prior anti-CD38 therapy, and 23% prior BCMA-directed antibody drug conjugate or chimeric antigen receptor T cell therapy. Common all causality TEAEs included lymphopenia (n=25, 83%; 20% G3, 63% G4), CRS (n=22, 73%; none >G2), anemia (n=18, 60%; 50% G3, 0% G4), neutropenia (n=16, 53%; 23% G3, 30% G4), thrombocytopenia (n=16, 53%; 17% G3, 20% G4), and injection site reaction (n=15, 50%; none >G2). Both CRS and immune effector cell-associated neurotoxicity syndrome (n=6, 20%) were limited to ≤G2; median durations were 3 and 2.5 days, respectively. No DLT was observed. Exposure increased with dose, and Tmax ranged from 3–7 days. Cytokine increases occurred with the first dose, and increased T cell proliferation was observed in peripheral blood. For doses ≥215µg/kg, confirmed overall response rate (ORR) was 70% (n=14/20) including partial response (PR; n=1), very good PR (VGPR; n=7), complete response (CR; n=1), and stringent CR (sCR; n=5). The majority of patients with sCR achieved MRD negativity. Median time to response was 22 days. In this dosing group, 3 of 4 pts (75%) with prior BCMA-directed therapy achieved response. Confirmed ORR at the recommended phase 2 dose (RP2D) of 1000µg/kg was 83% (n=5/6). Conclusions Elranatamab achieved confirmed ORR of 83% at RP2D with a manageable safety profile for pts with relapsed or refractory MM. These results confirm the feasibility and potential of BCMA-directed immunotherapy for malignant plasma cell disorders, and support further development of elranatamab for pts with MM. This study was sponsored by Pfizer.

Context Elranatamab (PF-06863135), a humanized bispecific monoclonal antibody (IgG2a), targets BCMA expressed in MM and CD3 on T-cells. Objective Characterize efficacy, safety, pharmacokinetics, and pharmacodynamics of elranatamab. Design Phase 1 study (MagnetismMM-1; NCT03269136). Data cut-off: 4 February 2021. Patients Relapsed or refractory MM. Intervention 80, 130, 215, 360, 600, or 1000 µg/kg/week subcutaneously. Main Outcome Measures 1) Treatment-emergent adverse events (TEAEs) graded by CTCAE v4.03 and cytokine release syndrome (CRS) by ASTCT criteria. 2) International Myeloma Working Group criteria-assessed response. 3) Pharmacokinetics, cytokine profiling, and T-cell immunophenotyping. Results Thirty patients received elranatamab at 80 (n=6), 130 (n=4), 215 (n=4), 360 (n=4), 600 (n=6), or 1000 (n=6) µg/kg. Patients had a median of 8 prior treatments; 87% had triple refractory disease, 97% prior anti-CD38 therapy, and 23% prior BCMA-directed antibody drug conjugate or chimeric antigen receptor T-cell therapy. Common all causality TEAEs included lymphopenia (n=25, 83%; 20% G3, 63% G4), CRS (n=22, 73%; none >G2), anemia (n=18, 60%; 50% G3, 0% G4), neutropenia (n=16, 53%; 23% G3, 30% G4), thrombocytopenia (n=16, 53%; 17% G3, 20% G4), and injection site reaction (n=15, 50%; none >G2). CRS and immune effector cell-associated neurotoxicity syndrome (n=6, 20%) were limited to ≤G2; median durations were 3 and 2.5 days, respectively. No dose-limiting toxicity was observed. Exposure increased with dose and Tmax ranged from 3–7 days. Cytokine increases occurred with the first dose, and increased T-cell proliferation was observed in peripheral blood. For doses ≥215 µg/kg, the confirmed overall response rate (ORR) was 70% (n=14/20); partial response (PR; n=1), very good PR (VGPR; n=7), complete response (CR; n=1), and stringent CR (n=5). Median time to response was 22 days. In this dosing group, 3 of 4 pts (75%) with prior BCMA-directed therapy achieved response. Confirmed ORR at the recommended phase 2 dose (RP2D) of 1000 µg/kg was 83% (n=5/6). Conclusions Elranatamab achieved confirmed ORR of 83% at RP2D with a manageable safety profile for patients with relapsed or refractory MM. These results support further development of elranatamab for patients with MM. This study was sponsored by Pfizer.

8006 Background: Elranatamab (PF-06863135) is a humanized bispecific monoclonal antibody (IgG2a) that targets BCMA, a member of the tumor necrosis factor receptor superfamily expressed in MM, and CD3 on T cells. We reported results for intravenous (IV) dosing (Raje et al. Blood. 2019;134(S1):1869) and now update for subcutaneous (SC) dosing from the ongoing Phase 1 study (MagnetisMM-1). Methods: Patients (pts) received elranatamab at 80, 130, 215, 360, 600, and 1000μg/kg SC weekly. A modified toxicity probability interval method was used for escalation, with monitoring for dose-limiting toxicity (DLT) to end of the first cycle. Treatment-emergent adverse events (TEAEs) were graded by Common Terminology Criteria for Adverse Events (v4.03), and cytokine release syndrome (CRS) by American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant. 2019;25:625). Response was assessed by International Myeloma Working Group criteria. Pharmacokinetics, cytokine profiling, and T cell immunophenotyping were performed. Results: 30 pts had received elranatamab as of 4-Aug-2020 at 80 (n = 6), 130 (n = 4), 215 (n = 4), 360 (n = 4), 600 (n = 6), or 1000 (n = 6) μg/kg SC weekly. Pts had a median of 8 prior treatments; 87% had triple refractory disease, 97% had prior anti-CD38 therapy, and 23% had prior BCMA-directed antibody drug conjugate or chimeric antigen receptor T cell therapy. The most common all causality TEAEs included lymphopenia (n = 24, 80%; 20% G3, 60% G4), CRS (n = 22, 73%; none > G2), anemia (n = 17, 57%; 43% G3, 3% G4), injection site reaction (n = 16, 53%; none > G2), thrombocytopenia (n = 16, 53%; 23% G3, 17% G4), and neutropenia (n = 12, 40%; 17% G3, 17% G4). Both CRS and immune effector cell-associated neurotoxicity syndrome (n = 6, 20%) were limited to ≤G2 with median durations of 2 and 1.5 days, respectively. No DLT was observed. Exposure increased with dose, and Tmax ranged from 3–7 days. Cytokine increases occurred with the first dose, and increased T-cell proliferation was observed in peripheral blood. The overall response rate (ORR) for doses ≥215μg/kg was 75% (n = 15/20) including partial response (PR; n = 6), very good PR (VGPR; n = 3), complete response (CR; n = 1), and stringent CR (sCR; n = 5). Median time to response was 22 days, and 3 of 4 pts (75%) with prior BCMA-directed therapy achieved response (VGPR, n = 2 and sCR, n = 1). Updated data, including duration of response, will be presented. Conclusions: Elranatamab demonstrated a manageable safety profile, and SC doses ≥215μg/kg achieved ORR of 75% with CR/sCR rate of 30%. These results demonstrate the safety and efficacy of SC elranatamab in this relapsed/refractory population and support ongoing development of elranatamab for pts with MM, both as monotherapy and in combination with standard or novel therapies. Clinical trial information: NCT03269136.

BackgroundThe molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. MethodsWe enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. ResultsOf the 116 patients, 53 (46%) had bone marrow blast clearance (

Obesity is the only known modifiable risk factor for multiple myeloma (MM), an incurable cancer of bone marrow plasma cells. The mechanism linking the two is unknown. Obesity is associated with an increased risk of sleep apnea, which results in chronic intermittent hypoxia (CIH), and drives solid tumor aggressiveness. Given the link between CIH and solid tumor progression, we tested the hypothesis that CIH drives the proliferation of MM cells in culture and their engraftment and progression in vivo. Malignant mouse 5TGM1 cells were cultured in CIH, static hypoxia, or normoxia as a control in custom, gas-permeable plates. Typically MM-resistant C57BL/6J mice were exposed to 10 h/day CIH (AHI = 12/h), static hypoxia, or normoxia for 7 days, followed by injection with 5TGM1 cells and an additional 28 days of exposure. CIH and static hypoxia slowed the growth of 5TGM1 cells in culture. CIH-exposed mice developed significantly more MM than controls (67 vs. 12%, P = 0.005), evidenced by hindlimb paralysis, gammopathy, bone lesions, and bone tumor formation. Static hypoxia was not a significant driver of MM progression and did not reduce survival ( P = 0.117). Interestingly, 5TGM1 cells preferentially engrafted in the bone marrow and promoted terminal disease in CIH mice, despite a lower tumor burden, compared with the positive controls. These first experiments in the context of hematological cancer demonstrate that CIH promotes MM through mechanisms distinct from solid tumors and that sleep apnea may be a targetable risk factor in patients with or at risk for blood cancer.

Background Treatment failures in cancers, including multiple myeloma (MM), are most likely due to the persistence of a minor population of tumor-initiating cells (TICs), which are noncycling or slowly cycling and very drug resistant. Methods Gene expression profiling and real-time quantitative reverse transcription polymerase chain reaction were employed to define genes differentially expressed between the side-population cells, which contain the TICs, and the main population of MM cells derived from 11 MM patient samples. Self-renewal potential was analyzed by clonogenicity and drug resistance of CD24+ MM cells. Flow cytometry (n = 60) and immunofluorescence (n = 66) were applied on MM patient samples to determine CD24 expression. Therapeutic effects of CD24 antibodies were tested in xenograft MM mouse models containing three to six mice per group. Results CD24 was highly expressed in the side-population cells, and CD24+ MM cells exhibited high expression of induced pluripotent or embryonic stem cell genes. CD24+ MM cells showed increased clonogenicity, drug resistance, and tumorigenicity. Only 10 CD24+ MM cells were required to develop plasmacytomas in mice (n = three of five mice after 27 days). The frequency of CD24+ MM cells was highly variable in primary MM samples, but the average of CD24+ MM cells was 8.3% after chemotherapy and in complete-remission MM samples with persistent minimal residual disease compared with 1.0% CD24+ MM cells in newly diagnosed MM samples (n = 26). MM patients with a high initial percentage of CD24+ MM cells had inferior progression-free survival (hazard ratio [HR] = 3.81, 95% confidence interval [CI] = 5.66 to 18.34, P < .001) and overall survival (HR = 3.87, 95% CI = 16.61 to 34.39, P = .002). A CD24 antibody inhibited MM cell growth and prevented tumor progression in vivo. Conclusion Our studies demonstrate that CD24+ MM cells maintain the TIC features of self-renewal and drug resistance and provide a target for myeloma therapy.

Purpose Recent advances have uncovered therapeutic interventions that might reduce the risk of progression of premalignant diagnoses, such as monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). It remains unclear how to best screen populations at risk and how to evaluate the ability of these interventions to reduce disease prevalence and mortality at the population level. To address these questions, we developed a computational modeling framework. Materials and Methods We used individual-based computational modeling of MGUS incidence and progression across a population of diverse individuals to determine best screening strategies in terms of screening start, intervals, and risk-group specificity. Inputs were life tables, MGUS incidence, and baseline MM survival. We measured MM-specific mortality and MM prevalence after MGUS detection from simulations and mathematic modeling predictions. Results Our framework is applicable to a wide spectrum of screening and intervention scenarios, including variation of the baseline MGUS to MM progression rate and evolving MGUS, in which progression increases over time. Given the currently available point estimate of progression risk reduction to 61% risk, starting screening at age 55 years and performing follow-up screening every 6 years reduced total MM prevalence by 19%. The same reduction could be achieved with starting screening at age 65 years and performing follow-up screening every 2 years. A 40% progression risk reduction per patient with MGUS per year would reduce MM-specific mortality by 40%. Specifically, screening onset age and screening frequency can change disease prevalence, and progression risk reduction changes both prevalence and disease-specific mortality. Screening would generally be favorable in high-risk individuals. Conclusion Screening efforts should focus on specifically identified groups with high lifetime risk of MGUS, for which screening benefits can be significant. Screening low-risk individuals with MGUS would require improved preventions.

Population-based studies suggest that black patients with multiple myeloma (MM) have a higher mortality rate than white patients. However, other studies suggest that this disparity is related to socioeconomic status (SES) rather than race. To provide clarity on this topic, we reviewed 562 patients diagnosed with MM at our institution. Patients with high SES had a median overall survival (OS) of 62.8 months (95% confidence interval [CI] 43.1-82.6 months), compared to 53.7 months (45.2-62.3 months) and 48.6 months (40.4-56.8 months) for middle and low SES, respectively (p = 0.015). After controlling for race, age, year of diagnosis, severity of comorbidities, stem cell transplant utilization and insurance provider, patients with low SES had a 54% increase in mortality rate relative to patients with high SES. To support our findings, we performed a similar analysis of 45,505 patients with MM from the Surveillance, Epidemiology and End Results-18 (SEER) database. Low SES is independently associated with poorer OS in MM.

PURPOSE:Recent advances uncovered therapeutic interventions that might reduce the risk of progression of premalignant diagnoses, such as Monoclonal Gammopathy of Undetermined Significance (MGUS) to multiple myeloma (MM). It remains unclear how to best screen populations at risk and how to evaluate the ability of these interventions to reduce disease prevalence and mortality at the population level. To address these questions, we developed a computational modeling framework.METHODS:We used individual-based computational modeling of MGUS incidence and progression across a population of diverse individuals, to determine best screening strategies in terms of screening start, intervals, and risk-group specificity. Inputs were life tables, MGUS incidence and baseline MM survival. We measured MM-specific mortality and MM prevalence following MGUS detection from simulations and mathematical modeling predictions.RESULTS:We showed that our framework is applicable to a wide spectrum of screening and intervention scenarios; including variation of the baseline MGUS to MM progression rate and evolving MGUS, in which progression increases over time. Given the currently available point estimate of progression risk reduction to 61% risk, starting screening at age 55 and follow-up screening every 6yrs reduced total MM prevalence by 19%. The same reduction could be achieved withstarting age 65 and follow-up every 2yrs. A 40% progression risk reduction per MGUS patient per year would reduce MM-specific mortality by 40%. Specifically, screening onset age and screening frequency can change disease prevalence, and progression risk reduction changes both prevalence and disease-specific mortality. Screening would generally be favorable in high-risk individuals.CONCLUSION:Screening efforts should focus on specifically identified groups of high lifetime risk of MGUS, for which screening benefits can be significant. Screening low-risk MGUS individuals would require improved preventions.

Introduction : Melphalan 200mg/m2 has been the standard conditioning regimen for ASCT for multiple myeloma. Novel agents in combination with high dose melphan are being evaluated in clinical trials to improve outcomes. We previously reported results of early ASCT ( < 12 months from diagnosis) using VDT (Bortezomib, Thalidomide, Dexamethasone) plus Melphalan 200mg/m2 conditioning chemotherapy followed by combination maintenance therapy in younger MM patients (Age Methods and patients: A total of 41 eligible patients with newly diagnosed multiple myeloma age ≥ 65 were prospectively enrolled in the IRB approved phase II trial beginning in June 2013. After an induction chemotherapy and stem cell collection, ASCT was performed with a preparative chemotherapy consisting of VDT-Melphalan 200mg/m2. The patients were considered to have high risk cytogenetics if they had 17p deletion, t(14;16), amp 1q, or t(4;14) by FISH on CD-138 sorted plasma cells. After engraftment and recovery, patients were started on maintenance therapy for 2 years. Planned regimen for the first year was a combination of VDT as 28 day cycles and year 2 therapy consisted of bortezomib, cyclophosphamide and dexamethasone( VCD) as 28 day cycles. Alternate regimens were used in case of toxicities. Primary end points include PFS, frequency of severe toxicities, ICU admissions, and percentage of patients able to complete the full course of maintenance. Responses were evaluated according to IMWG consensus criteria and adverse events were recorded according to CTCAE v 4.03. Results: 37 of the 41 patients enrolled received single ASCT between 2013 to 2016 of which 35 patients went to receive triple maintenance therapy and were included in this analysis. Median age was 68 (range: 65 to 75y). 12 (59%) and 15(40%) had standard risk and high risk cytogenetics by FISH, respectively. Median follow up was 27 months (3 months - 5 years). Major non-hematologic toxicities ≥ grade 3 were related to infections (25%), diarrhea (16%) and mucositis (11%). Median time to ANC and platelet engraftment was 11 and 17 days, respectively. There was one death within day 100 related to candida sepsis. Only 2 patients were re-hospitalized within 100 days but none required ICU admission. Median time to start post-transplant therapy was 73 days (range: 47 to 185 days). Best responses noted prior to initiation of maintenance were 17 sCR(47.2%), 3CR(8%), 10 VGPR(27%) and 6 PR(17%). 18 patients completed 2 years of maintenance therapy thus far and responses at the time of this analysis include sCR in 16 and CR in 2 patients. A total of 3 patients died during maintenance phase due to progressive disease. Median PFS and OS were not reached and 3 year PFS and OS were around 82 and 90%, respectively. Conclusions: This is the first trial to prospectively evaluate the safety and efficacy of early ASCT in elderly MM patients using a novel agent conditioning regimen followed by an intensive 2 year maintenance therapy. These results from the median follow up of 27 months indicate that the regimen is safe and tolerated without any increased mortality, and results in higher rates of deep and sustained responses. Major non hematologic toxicities included infections and GI related. No increased hospitalizations or ICU admissions were noted. Further follow up will determine the long term effects of the combination maintenance regimen, disease responses and survival in this group of elderly MM patients. Figure Figure. Disclosures No relevant conflicts of interest to declare.

Introduction The role of early intensive treatment of multiple myeloma, including tandem autologous stem cell transplantation( ASCT) with bortezomib, thalidomide, dexamethasone( VDT) and melphalan 200mg/m2 as a preparative regimen, followed by 2 years of combination agent maintenance therapy, is being studied. We sought to analyze a cohort of patients who received early intensive treatment at the University of Iowa between 2012 and 2016. Patients and Methods All consecutive patients who received early( < 12 months since diagnosis) tandem ASCT and have completed at least 2 years of maintenance therapy between 2012 and 2016 were included for analysis. Planned maintenance therapy consisted of a combination of VDT in 28 day cycles for year 1 and bortezomib, cyclophosphamide and dexamethasone(VCD) in 28 day cycles for year 2. Alternate regimen were used in case of toxicities. The patients were considered to have high risk cytogenetics if they had 17p deletion, t(14;16), amp 1q, or t(4;14) by FISH. Event-free (EFS) and overall survival (OS) probabilities were estimated and plotted using the Kaplan-Meier method. For EFS, time was calculated from date of first transplant to relapse or death due to any cause. Treatment-related mortality was defined as death during transplant phase or maintenance phase due to causes other than disease relapse.The effect of clinical characteristics on outcomes was evaluated using Cox regression models. Estimated effects of predictors are reported as hazard ratios (HR) along with 95% confidence intervals. All statistical testing was two-sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC). Responses were measured using IMWG consensus criteria. Results A total of 135 patients met the criteria for inclusion. Key patient characteristics are shown in table 1. The median age at first transplant was 58 years. HCT-CI was high in 68% of patients. 36% of the patients were ISS stage III, and high risk cytogenetics were present in 56%. Preparative regimen was VTD-Mel 200 in 88.9% of patients. Following the first transplant, 59% of patients had achieved CR, and following the second transplant 94.4% of patients achieved CR. At the time of median follow up, 27.4% of patients had died. The cause of death was infection (25%), organ failure (11%), relapsing myeloma (28%) or other (36%). Univariable analysis identified a statistically significant association only for age with risk of progression or death. Kaplan-Meier curves for progression free survival and overall survival in patients with high risk or low risk cytogenetics are shown in Figures 1 and 2 respectively. The hazard ratio for progression free survival and overall survival in patients with high risk vs low risk cytogenetics was 0.86 (95% confidence interval 0.45 - 1.64, p=0.65), and 0.88 (95% confidence interval 0.45 - 1.73, p=0.71), respectively. The 3 year EFS and OS of patients who received early tandem ASCT followed by 2 years of maintenance were 73% and 72%, respectively. Following the 2nd autologous transplant, 128 of 135( 94%) patients were started on maintenance therapy. VTD ( 74%) and VRD (6%) were the most common regimens used. Fifty six patients completed maintenance therapy for 1 year without regimen change, and 60 required regimen change due to toxicities. VRD (20), VPomD (9) and VRMp (8) were the most commonly used alternative regimens in the case of toxicities. Following year 1 of maintenance, 96 patients (75%) started a second year of maintenance. VCD (30%) or RD (23%) were the most common regimens. 63(43%) patients completed 2 years of combination maintenance therapy. Grade III-V non-hematologic toxicities during the combined maintenance phase were infection (56%) and peripheral neuropathy (23%) and hematologic toxicities were thrombocytopenia (13%), neutropenia (12%) and anemia (8%). Conclusion According to our results, patients with high risk cytogenetics did not have an inferior PFS and OS. These results suggest that in newly diagnosed MM patients, upfront treatment using novel conditioning regimen and tandem ASCT followed by intensive maintenance therapy can result in a very high CR rates, particularly in patients with high risk cytogenetics. Infections and peripheral neuropathies were the most common non-hematologic toxicities during maintenance. Longer follow up will determine further impact of maintenance therapy. Disclosures No relevant conflicts of interest to declare.

Multiple myeloma is an invariably fatal cancer of plasma cells. Despite tremendous advances in treatment, this malignancy remains incurable in most individuals. We postulate that strategies aimed at prevention have the potential to be more effective in preventing myeloma-related death than additional pharmaceutical strategies aimed at treating advanced disease. Here, we present a rationale for the development of prevention therapy and highlight potential target areas of study.

BACKGROUND The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown. METHODS Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations. RESULTS A total of 62 of 281 patients (22.1%) had mutations in DNMT3A that were predicted to affect translation. We identified 18 different missense mutations, the most common of which was predicted to affect amino acid R882 (in 37 patients). We also identified six frameshift, six nonsense, and three splice-site mutations and a 1.5-Mbp deletion encompassing DNMT3A. These mutations were highly enriched in the group of patients with an intermediate-risk cytogenetic profile (56 of 166 patients, or 33.7%) but were absent in all 79 patients with a favorable-risk cytogenetic profile (P

The appropriate induction therapy before and the role of maintenance therapy after auto-SCT for patients with multiple myeloma remain areas of active investigation. We conducted a study in 40 patients with bortezomib given sequentially pre-auto-SCT and as maintenance therapy post auto-SCT. Pre-transplant bortezomib was administered for two cycles followed by high-dose melphalan 200 mg/m(2) with auto-SCT of G-CSF-mobilized PBMCs. Post transplant bortezomib was administered weekly for 5 out of 6 weeks for six cycles. No adverse effects were observed on stem cell mobilization or engraftment. An overall response rate of 83% with a CR+very good partial remission (VGPR) of 50% was observed with this approach. Three-year Kaplan-Meier estimates of disease-free survival and overall survival (OS) were 38.2 and 63.1%, respectively. Bortezomib reduced CD8(+) cytotoxic T cell and CD56(+) natural killer cell PBL subsets and was clinically associated with high rates of viral reactivation to varicella zoster.

We retrospectively reviewed the results of transplanting peripheral blood progenitor cell (PBPC) allografts from HLA-matched sibling donors mobilized using various hematopoietic cytokines. Patients had received allografts mobilized with Granulocyte colony-stimulating factor (G-CSF) (G, N = 65) alone, G plus Granulocyte-macrophage colony stimulating factor (GM-CSF) (G/GM, N = 70), or GM-CSF alone at 10 or 15 microg/kg/day (GM, N = 10 at 10 microg/kg/day and 21 at 15 microg/kg/day). The CD34+ and CD3+ cell content of grafts were significantly lower following GM alone compared to G alone (P0.001 and 0.04, respectively). Nonhematopoietic toxicity observed in donors precluded dose escalation of GM-CSF beyond 10 microg/kg/day. Hematopoietic recovery was similar among all three groups. Grades II-IV acute graft-versus-host disease (GVHD) was observed in only 13% of patients in the GM alone group compared to 49 and 69% in the G alone or G/GM groups, respectively (P0.001). In a multivariate analysis, receipt of PBPC mobilized with GM alone was associated with a lower risk of grades II-IV acute GVHD (hazard ratio 0.21; 95% CI 0.073, 0.58) compared to G alone or G/GM. There were no differences in relapse risk or overall survival among the groups. Donor PBPC grafts mobilized with GM-CSF alone result in prompt hematopoietic engraftment despite lower CD34+ cell doses and may reduce the risk of grades II-IV acute GVHD following HLA-matched PBPC transplantation.

Recent studies suggest that cancer patients may be at increased risk for supraventricular tachyarrhythmias (SVTA). We have observed clinically significant SVTA in patients undergoing hematopoietic stem cell transplantation occurring at a median of 6 days post transplant, manifesting as atrial fibrillation/flutter or regular narrow-complex tachycardia and persisting for a median of 3 days (range, 0-8). All patients received aggressive medical therapy and/or electrical cardioversion to restore sinus rhythm and to re-establish hemodynamic stability. Non-Hodgkin's lymphoma (NHL) was the most common diagnosis (53%), and a case control analysis in those patients demonstrated that SVTA occurred in 12% of patients and was associated with older age and pre-existing cardiac conditions. In conclusion, patients undergoing HSCT are at moderate risk for developing SVTA, particularly older patients with a diagnosis of NHL. These arrhythmias are clinically significant, and are a marker for increased mortality and prolonged hospital stay. Additional studies are needed to identify high-risk patients who may benefit from prophylactic anti-arrhythmic therapy.

Summary. Calcineurin inhibitor-induced central nervous system toxicities are uncommon and often resolve after discontinuation of the offending drug. The long-term outcome of these patients is, however, unknown. Resolution of symptoms occurred in 70% of 30 allografted recipients who developed calcineurin inhibitor-induced neurotoxicity. When patients were rechallenged with the same or a different calcineurin inhibitor, symptoms recurred in 41%, leading to permanent discontinuation of the drug. De novo or progressive acute graft-versus-host disease (GVHD) was observed in 54% of patients at a median of 7 d (range 1–70 d) after initial onset of neurotoxicity. The prognosis was grim, with 24 (80%) of these patients dying a median 33 d after the onset of neurotoxicity (range 2–594 d). GVHD and/or infection occurred in 54% and were the most common primary causes of death. We conclude that calcineurin inhibitor-induced neurotoxicity is frequently reversible but associated with a poor prognosis.

Background: The International Staging System (ISS) for multiple myeloma (MM) is a simple risk stratification algorithm based on serum β2-microglobulin and serum albumin that identifies three patient groups with different prognoses. Recently, a revised ISS (R-ISS) has been created that combines ISS stage with serum lactate dehydrogenase (LDH) and chromosomal abnormalities (CAs) identified by fluorescence in situ hybridization (FISH); it has been shown to better stratify patients based on prognosis (Palumbo, et al, J Clin Oncol, 2015). With the increasing availability of deeper sequencing techniques, we sought to determine if the use of next generation sequencing (NGS) instead of FISH for the identification of CAs would further improve the stratification of higher-risk patients. Methods: Data was extracted from the open-access MMRF Researcher Gateway corresponding with interim analysis 8 from the CoMMpass study. The CoMMpass study is enrolling 1000 newly diagnosed MM patients who will be tracked longitudinally for 5 years. CoMMpass collects relevant clinical data as well as sequential tissue samples. Eligibility requirements for CoMMpass include: symptomatic MM with measureable disease by SPEP (≥1.0g/dL), UPEP (≥200mg/24 hours), or SFLC (≥10mg/dL); receiving an immunomodulator (IMID) and/or a proteasome inhibitor (PI) for initial MM treatment; and no prior malignancies in the past 5 years. All sequencing was performed by the Translational Genomics Research Institute (TGEN). CAs were identified using custom software on long-insert whole genome sequencing data. ISS stage was calculated used β2-microglobulin and serum albumin as previously described (Greipp, et al, J Clin Oncol, 2005). R-ISS stage was then calculated as: stage I (ISS stage I, no high-risk CA, and normal LDH); stage III (ISS stage III with high-risk CAs and/or high LDH levels); stage II others. High risk CA were defined as the presence of Del(17p), t(4;14) or (4;16). High LDH was defined as LDH ≥300units/L. We performed a multivariate Cox regression analysis to compare event-free survival (EFS) defined as the interval from diagnosis to disease progression or death controlling for age (>65 vs ≤65 years) and sex for ISS, R-ISS (using FISH data), and R-ISS using NGS data (R-ISS-NGS). The level of significance was set at 0.05 for all tests. Results: 877 patients had β2-microglobulin and serum albumin available and were eligible for analysis. The median age at diagnosis was 64 years, 61% (533) were male, and 76% (666) were white. 34% (296) were ISS stage I, 36% (312) were stage II, and 31% (269) were stage 3. R-ISS was calculated on the 681 patients with available FISH and LDH data. 28% (192) were R-ISS stage I, 61% (417) were stage II, and 11% (72) were stage III. R-ISS-NGS was calculated on the 673 patients with available NGS and LDH data. 32% (212) were R-ISS-NGS stage I, 62% (414) were stage II, and 7% (47) were stage III. ISS stage was significantly associated with EFS; patients with stage II and stage III disease had an 83% (aHR 1.83 [95% CI 1.25-2.69], p = 0.0183) and 171% (aHR 2.71 [95% CI 1.85-3.95], p < 0.0001) increased risk of disease progression or death, respectively, compared to stage I patients. Using R-ISS, the model was able to better stratify patients by risk; patients with stage II and stage III disease had a 111% (aHR 2.11 [95% CI 1.32-3.37], p = 0.0017) and 360% (aHR 4.60 [95% CI 2.58-8.17], p < 0.0001) increased risk of disease progression or death, respectively, compared to stage I patients. Using, R-ISS-NGS the model was able to better stratify patients by risk particularly among stage III patients; patients with stage II and stage III disease had a 125% (aHR 2.25 [95% CI 1.42-3.55], p = 0.0005) and 470% (aHR 5.70 [95% CI 3.12-10.40], p < 0.0001) increased risk of disease progression or death, respectively, compared to stage I patients. Results are summarized in Table 1. Conclusion: R-ISS-NGS improved on FISH based R-ISS stratification, presumably due to more accurate determination of the high-risk CAs of interest. A more thorough analysis including additional candidate CAs may further increase the sensitivity of this NGS based staging system. Table 1 Table 1. Disclosures Vij: Takeda: Consultancy, Research Funding; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Karyopharma: Consultancy; Amgen: Consultancy, Research Funding; Jazz: Consultancy; Shire: Consultancy.

Background: We previously reported on a phase I dose escalation trial of CDD [carfilzomib (CFZ), pegylated liposomal doxorubicin (PLD), and dexamethasone (DEX)] (Keller, et, al, ASH 2014 Abstract 4731). The combination was well tolerated and an MTD was not reached despite administering the currently approved single-agent doses. In the maximum dose level tested, the overall response rate (ORR) was 72% (5/7) in a heavily pre-treated population. Based on the promising results of the phase I study we conducted a phase II expansion to further evaluate the efficacy of the regimen. Patient/Methods: Patients with RRMM after ≥ 1 lines of therapy, with measureable disease, and good performance status, organ function and hematological reserve were eligible. Prior CFZ or PLD/doxorubicin exposure was permitted. CFZ was given on days 1, 2, 8, 9, 15 and 16 in 28 day cycles at a dose of 56mg/m 2 , PLD on day 8 at a dose of 30mg/m 2 ,DEX on days 1, 2, 8, 9, 15 and 16 at a dose of 20mg. Following 6 cycles of combination therapy, PLD was discontinued and patients were treated with maintenance CFZ and DEX (once weekly). Response was assessed per IMWG criteria. Overall response rate (ORR) was defined as partial response (PR) or better, event-free survival as the interval from start of therapy to discontinuation. Results: Twenty-three patients were enrolled from April 2014-Mar 2016 . Median age was 63 years (range 27-70) and 52% were male. Ten patients were ISS stage 1, 6 were stage 2, and 7 were stage 3. By mSMART criteria, 1 patient was high risk and 5 were intermediate risk. Ten patients were IgG Kappa subtype; 4 had IgG Lambda subtype, 2 had IgA Kappa subtype, 2 had IgA Lambda subtype, 3 kappa light chain, and 2 lambda light chain. The median number of prior therapies was 2 (range 1-13); median time from diagnosis to start of protocol was 40 months (range 8-200). All had prior exposure to lenalidomide; 91% to bortezomib; 9% to PLD or doxorubicin; 9% to CFZ; 96% had undergone autologous transplantation. The overall response rate was 83% with 48% achieving a complete or very good partial response. The median number of cycles was 11; the median estimated event-free survival was 7.4 months at a median follow-up of 10.6 months. Five patients discontinued due to disease progression, 7 due to toxicity, 1 to proceed to a second transplant, and 10 remain on treatment at time of submission. Individual patient responses are summarized in Table 1. Grade 3/4 non-hematologic toxicity was uncommon but included: infections (11), hypertension (4), RPLS (1), and MI (1). Grade 3/4 hematologic toxicity included: thrombocytopenia (11), anemia (8), neutropenia (7), TTP (1), and hemolysis (1). Conclusion: CDD is well tolerated and efficacious in relapsed or refractory MM. The estimated ORR of the combination is 83% (95% CI 67%-98%) a notable increase compared to standard dose CFZ and DEX. Disclosures Abboud: Gerson and Lehman Group: Consultancy; Baxalta: Honoraria; Takeda: Honoraria; Novartis: Research Funding; Seattle Genetics: Research Funding; Alexion: Honoraria; Cardinal: Honoraria; Teva: Research Funding, Speakers Bureau; Pharmacyclics: Honoraria; Pfizer: Research Funding; Merck: Research Funding. DiPersio: Incyte Corporation: Research Funding. Vij: Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Shire: Consultancy; Jazz: Consultancy; Karyopharma: Consultancy; Novartis: Consultancy.

Zoledronic acid and pamidronate are the two bisphosphonates approved in the United States to reduce multiple myeloma skeletal complications. Little prior evidence exists comparing survival outcomes between the two. We evaluated the incidence of skeletal-related events and overall survival in patients with myeloma treated with zoledronic acid versus pamidronate using a cohort of 1018 United States veterans. At a median follow-up of 26.9 months, patients receiving zoledronic acid had a 22% reduction in risk of death compared to pamidronate (hazard ratio 0.78; 95% confidence interval, 0.67-0.92). The benefit persisted after controlling for potential confounders. Adjusted Cox modeling with inverse probability weighting and propensity score matching supported these findings. Zoledronic acid was also associated with a 25% decrease in skeletal-related events. Zoledronic acid is associated with increased overall survival and decreased skeletal-related events compared to pamidronate in patients with multiple myeloma and should become the preferred bisphosphonate.

The MYC oncoprotein drives multiple myeloma (MM) pathogenesis, but the utility of small molecule inhibitors of MYC-MAX dimerization is limited by poor efficacy. We first sought to test the efficacy...

Despite tremendous advances in treatments for myeloma in the past decade, the disease remains incurable in the majority of patients. Here, we review recent data demonstrating an association between obesity and increased risk of myeloma development. This may be due to the pro-inflammatory cytokine profile caused by obesity. Currently, there are no screening or prevention strategies for myeloma, but we propose that obesity-associated inflammatory pathways, or obesity itself, may be amenable to intervention, thereby preventing the transition from pre-malignancy to myeloma. In addition, we suggest that the morbidity, mortality and the significant costs associated with myeloma treatment could be reduced by addressing modifiable risk factors, and that research efforts should explore this novel hypothesis.

Background: Persons of African ancestry (AA) have a 2-3-fold higher risk of multiple myeloma (MM) than persons of European ancestry (EA). Like other B-cell malignancies, genome-wide association scans (GWAS) have identified MM risk variants in the HLA region in persons of EA. We conducted a case-control analysis with data from the National Marrow Donor Program (NMDP)1comprising MM patients typed for bone marrow transplant to donor controls matched by race-ethnicity, and found associations between specific HLA alleles/haplotypes and MM risk that varied by race and ethnicity. To confirm our results and identify additional novel signals, we have now investigated associations between HLA alleles and haplotypes and MM risk in the African American Multiple Myeloma Study (AAMMS) Cohort. Methods: The source of subjects was the AAMMS, in which AA MM patients were identified from 10 cancer centers and 4 Surveillance, Epidemiology and End-Results (SEER) Program cancer registries in order to identify genetic risk factors for MM among AAs. A GWAS was conducted using the Illumina Human Core BeadChip array on DNA samples from 1,305 AA MM patients in the AAMMS comparing results to those from 7,078 AA controls with GWAS data generated from the Illumina 1MDuo2. The major histocompatibility complex (MHC) region single nucleotide polymorphisms (SNPs) were imputed to classical HLA variants using HIBAG. Unconditional logistic regression was used to estimate HLA associations, adjusting for sex, age and the first 2 principal components. P-values were adjusted for false discovery rate (FDR) for each locus group. Results: We did not identify any single HLA alleles associated with MM risk among AAs. However, several B*07:02-containing haplotypes were associated with MM risk (odds ratios [OR] ranging from 2.38 to 2.64 and FDR P-values ranging from 1.43 x 10-6 to 3.57 x 10-8). We found associations between MM risk and genotypes containing DRB3*02:02, including DRB3*02:02~DRB1*11:01+ DRB3*02:02~DRB1*11:01 (OR=1.93, PFDR= 9.36 x 10-5) similar to those observed in the NMDP study1. Novel findings included associations between MM risk and HLA Class I haplotypes B*53:01+ B*57:01 (OR=1.94, PFDR= 0.003) and C04:01~B*53:01+C*06:02~B*57:01 (OR=1.96, PFDR= 0.0050). Results from an ongoing meta-analysis between the two data sets (one based on an imputed GWAS and one based on NMDP HLA typing) will be presented. Conclusions: This study is the second to examine HLA alleles and risk of MM among AA's and is by far the largest. We confirmed a previously observed association between an HLA Class II DRB3 variant and MM risk and confirmed an association with B*07 haplotypes previously observed among EAs1. We also identified novel associations between other HLA Class I haplotypes and MM risk in AA's. Because HLA is highly polymorphic, many HLA alleles are rare variants for which genetic associations are difficult to detect without very large sample sizes. Further investigation with large sample sizes will be necessary to refine these associations in order to better identify the underlying causal alleles and determine the functional significance of these HLA associations. 1Beksac M, Gragert L, Fingerson S, et al.: HLA polymorphism and risk of multiple myeloma.Leukemia. 2016 Jul 27. doi: 10.1038/leu.2016.199. 2Rand KA, Song C, Hwang AE, et al. Genetic susceptibility markers of multiple myeloma in African-Americans. Abstract # 2030, 56th Annual American Society of Hematology Meeting, San Francisco, California, 2014. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Nooka:Spectrum, Novartis, Onyx pharmaceuticals: Consultancy. Zonder:Pharmacyclics: Other: DSMC membership; Prothena: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Lonial:BMS: Consultancy; Novartis: Consultancy; Millenium: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Merck: Consultancy; Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Janssen: Consultancy; Onyx: Consultancy.

Background: Over the past 2 decades, treatment advances have greatly improved the outcomes of patients with multiple myeloma (MM) and a glut of new knowledge about the biology, genetic profile, and prognostic factors of the disease have become available. However, much of this research has excluded patients with low performance status and those with impaired renal function or marrow reserve, therefore, relatively little is known about these patients who are largely ineligible for clinical trials. We performed a secondary data analysis of the Multiple Myeloma Research Foundation (MMRF) CoMMpass study to compare the disease manifestation, treatment, and prognosis of these patients with the overall MM population. Methods: Data was extracted from the open-access MMRF Researcher Gateway corresponding with interim analysis 8 from the CoMMpass study. The CoMMpass study is enrolling 1000 newly diagnosed MM patients who will be tracked longitudinally for 5 years. CoMMpass collects relevant clinical data as well as sequential tissue samples. Eligibility requirements for CoMMpass include: symptomatic MM with measureable disease by SPEP (≥1.0g/dL), UPEP (≥200mg/24 hours), or SFLC (≥10mg/dL); receiving an immunomodulator (IMID) and/or a proteasome inhibitor (PI) for initial MM treatment; and no prior malignancies in the past 5 years. We defined ineligibility for clinical trials as one or more of the following at time of MM diagnosis: ECOG performance status 3 or 4; creatinine ≥ 2.0mg/dL or receiving dialysis; absolute neutrophil count (ANC) Results: 799 patients were available for analysis. The median age was 64 years, 61% (486) were male, and 76% (611) were white. 23% (180) met the study definition of ineligibility for clinical trials. 5% (41/778) had low performance status, 16% (128/799) impaired renal function, 3% (22/799) impaired marrow reserve. Patients ineligible for clinical trials were similar to the rest of the population demographically, but were more likely have higher risk disease by ISS (70% stage 3 compared to 20%, p 0.05). Bivariate analyses are summarized in Table 1. After controlling for ISS stage, deletion of 17p, first-line treatment, and SCT utilization, patients ineligible for clinical trials had a 56% (aHR 1.56 [95% CI 1.09- 2.23], p = 0.0141) increase in risk of disease progression or death. Conclusion: Newly diagnosed MM patients with low performance status, impaired renal function, or marrow reserve have long been considered a high-risk group and, thus, most clinical trials have excluded them. IMIDs are contraindicated for these patients due to its myelotoxicity which further limits treatment options. After adjusting for differences in treatment, these patients still have poorer outcomes. Additional research is needed to better understand the needs of these patients and improve their outcomes. Table 1 Table 1. Disclosures Vij: Karyopharma: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Jazz: Consultancy; Shire: Consultancy.

Costa et al. recently reported that racial disparities prevented nearly 40% of non-Hispanic blacks with multiple myeloma (MM) from undergoing stem cell transplantation (SCT), but the authors were unable to provide an explanation for the disparities because of limitations of their datasets. They hypothesized that socioeconomic status (SES) and/or insurance providers might account for the disparity. To examine the issue raised by Costa et al., we performed a secondary analysis using hierarchical multivariate logistic regression with data previously collected to determine if age at diagnosis, sex, SES, primary insurance provider at diagnosis, and comorbidity score help explain the racial disparities in SCT utilization. A model of race, age, sex, SES, insurance provider, and comorbidity score was the most accurate model in predicting stem cell utilization status (χ2[12] = 193.859; P < .001; area under the curve = .837; P < .001). After controlling for the covariates, black patients were less likely to undergo SCT than white patients (adjusted odds ratio, .49; 95% confidence interval, .27 to .89; P = .013). In conclusion, we also observed racial disparities between black and white patients with MM in SCT utilization and these are not fully accounted for by the covariates age, sex, SES, insurance provider, and comorbidity score.

PURPOSE We investigated the association between body mass index (BMI) at the time of multiple myeloma (MM) diagnosis and overall survival in a cohort of patients within the Veterans Health Administration system. We also evaluated the association between weight loss in the year prior to diagnosis and survival. PATIENTS AND METHODS Prospective analysis was performed on a retrospectively assembled cohort of 2,968 U.S. veterans diagnosed and treated for MM between September 1, 1999, and September 30, 2009, with follow-up information through October 22, 2011. Cox modeling controlling for patient- and disease-related prognostic variables was used to analyze the data. RESULTS Underweight patients (BMI

Patients with multiple myeloma who are refractory or intolerant to both bortezomib and lenalidomide have a poor prognosis. Next-generation therapies carfilzomib and pomalidomide have shown promising activity in this dual refractory population. Here we describe the clinical characteristics and ascertain the effects of carfilzomib and pomalidomide on survival in this patient cohort. We retrospectively reviewed the records of 65 patients with dual refractory/intolerant myeloma diagnosed between January 2007 and May 2012 at a single institution. The median overall survival (OS) from the time patients became dual refractory/intolerant was 10.2 months. Patients who received carfilzomib or pomalidomide after they became dual refractory/intolerant had a better OS compared to those who did not (12.6 vs. 6.8 months, p = 0.03 by Wilcoxon test). Prospective randomized control trials are needed for confirmation.

A funding organization was incorrectly omitted from the Funding Statement. The third sentence of the Funding Statement should read: "MHT is also supported by a Senior Research Award from the Multiple Myeloma Research Foundation (MMRF) and the Barnes Jewish Hospital Foundation."

Background: Multiple myeloma (MM) is a disease of older adults, with a median age of diagnosis in the late 60s. While treatment advances have prolonged overall survival (OS) in MM, improvements have been modest among older MM patients. Symptom burden and quality of life are concerns for older patients, as they are more susceptible to treatment intolerance and dose reduction or treatment cessation. Older patients are often under-represented in clinical trials, and less information is available regarding their presenting clinical characteristics and treatment course. The Multiple Myeloma Research Foundation (MMRF) CoMMpass study, is a multicenter study in newly diagnosed multiple myeloma. It collects clinical-molecular data and patient reported health-related quality of life measures (EORTC QLQ-C30 and EORTC QLQ-MY20). In this study, we analyzed data from the CoMMpass study and compared presenting clinical characteristics, symptom burden and genetic features of newly diagnosed MM patients ≥ 75 years of age and those < 75 years of age. An additional analysis of t(4;14) was performed among those aged 75 years to confirm prior observations that the incidence of t(4;14) decreases with age (Avet-Loiseau et al. 2013). Methods: Clinical data from the interim analysis 6 of the CoMMpass study was extracted via the MMRF Researcher Gateway. CoMMpass eligibility requirements include: symptomatic MM with measureable disease by SPEP (≥1.0g/dL), UPEP (≥200mg/24 hours), or SFLC (≥10mg/dL); receiving an immunomodulator and/or a proteasome inhibitor for initial MM treatment; and no prior malignancies in the past 5 years.Enrollment began in July 2011. Clinical data is recorded at enrolling centers by data analysts. Analysis was with STATA 12.0. Categorical variables were compared withχ2; continuous variables were compared with student's t-tests and Wilcoxon rank-sum tests. Results: 625 patients were eligible for analysis. 92 patients were ≥ 75 years of age, and 533 were < 75 years of age. Median ages were 80 years (range 75-93) and 63 years (range 27-74). Distribution of sex and race were evenly divided. Older patients had higher rates of International staging system (ISS), stage III disease at presentation. Baseline measurements of creatinine, platelet counts and hemoglobin were worse for older patients. On symptom and quality of life assessment, older patients were more likely to have difficulties with physical functioning, and were less likely to have difficulties with emotional functioning or finances. Subset analysis of those aged < 65 years, 65-75 years and > 75 years showed a trend towards decreasing rates of t(4;14).Results are summarized in Table 1. Conclusion: Older patients in this study had higher ISS stage at diagnosis and worse ECOG performance status scores. Baseline labs showed inferior renal function and lower platelet and hemoglobin levels. Emotional and financial status was rated higher than younger patients, while physical functioning was worse. A trend towards decreased incidence of t(4;14) was appreciated by age. Table 1. Clinical Characteristics ≥ 75 years (n=92) < 75 years (n=533) P Demographics Median age in years 80 63 Sex % NS Male 63 60 Female 37 40 Race % NS White 81 79 Black 19 18 Other 0 3 Heavy Chain % NS IgG 83 77 IgA 17 23 Light Chain % NS Kappa 65 62 Lambda 33 37 Biclonal 2 1 Disease Burden ISS Stage % 75 years 65-75 years Disclosures Vij: Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy.

Background: Black patients with multiple myeloma (MM) have poorer outcomes than their white counterparts. This has largely been attributed to reduced access to health care; however, little data exists comparing the disease and overall health status at MM presentation between the two races. More severe disease burden, symptom burden, or comorbidities could also explain the differences in outcome. Objective: To compare disease burden, symptom burden, and comorbidities between black and white patients with MM. Methods: Two datasets were analyzed: 1) the Multiple Myeloma Research Foundation (MMRF) CoMMpass study interim analysis 6, and 2) the Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey (SEER-MHOS) 2015 dataset (SEER years 1973-2011; MHOS years 1998-2013). The CoMMpass dataset included 625 patients who completed the EORTC QLQ-C30 and QLQ-MY20 at MM diagnosis. The SEER-MHOS dataset included 377 patients who completed the HOS survey the year of or year prior to MM diagnosis. All patients identified as a race other than white or black/African American were excluded. Data was analyzed using SPSS 21. Categorical variables were compared using χ 2, continuous with the Mann-Whitney U test. Results: CoMMpass: 585 patients were eligible for analysis. 477 (82%) were white, 108 ( 19%) were black. Whites and blacks were similar in median age, but a significantly higher percentage of white patients were female (p=0.027). Overall, black patients were more likely to be stage III (p=0.041), have higher LDH (p=0.006) and creatinine (p=0.001), and lower hemoglobin (p

To determine how AML subclonal architecture changes during decitabine treatment, and whether specific mutations might correlate with sensitivity vs. resistance to decitabine, we performed exome sequencing at multiple time points during single agent decitabine therapy. We enrolled 69 patients with either AML (age ≥ 60, or with relapsed/refractory disease, N = 45) or MDS (N = 24) on a phase I clinical trial. All subjects were treated with decitabine 20 mg/m2 on days 1-10 of 28 day cycles. With a median follow-up of 13.7 months, the intention to treat clinical response (complete remission with or without complete count recovery: CR/CRi) is 40%, with survival correlating with response (median survival - CR/CRi: 583 days; partial response/stable disease (PR/SD): 260 days; progressive disease (PD) or failure to complete cycle 1: 36 days, p < 0.0001). We performed exome sequencing on unfractionated bone marrow cells at diagnosis (day 0), cycle 1 day 10, cycle 1 day 28, cycle 2 day 28, and, when possible, during remission and at clinical relapse/progression. We have completed sequencing analysis for the first 34 cases (outcomes: 5 CR, 15 CRi, 3 PR, 8 SD, and 3 PD). Several important themes have emerged, as follows: 1) We correlated mutation status at diagnosis with clinical response. All six patients with TP53 mutations obtained clinical CR or CRi, and exome analysis demonstrated near complete elimination of the TP53- associated founding clones by the end of cycle 2 (p < 0.03). Long-term outcomes were similar in these patients compared with other patients who achieved CR/CRi: four patients relapsed after 8, 9, 10, or 17 cycles; 1 patient is doing well post-transplant; and one patient died of an infectious complication after cycle 2. No other mutations were significantly associated with clinical response or with consistent mutation clearance. 2) We observed a reduction in blast counts, which preceded mutation elimination in fourteen cases with CR, CRi or PR. This suggests that decitabine may induce morphological blast differentiation in vivo prior to mutation elimination. 3) In eight of nine cases with a clinical response followed by relapse, clinical progression was associated with expansion of a pre-existing subclone. We have not yet observed any recurrent mutations that reliably predict whether a subclone will contribute to relapse. Intriguingly, in two of these cases, the relapse-associated subclone was detectable at diagnosis and was eliminated more slowly than the founding clone mutations, suggesting that this subclone harbored intrinsic decitabine-resistance. 4) Complete remission can occur with concomitant non-malignant, clonal hematopoiesis. In three cases with a CR, a new clonal population was selected for during the remission. In two of these cases, there were no shared mutations between the founding clone and the emergent, non-malignant, clonal hematopoiesis, suggesting that these clones were unrelated. 5) Mutational architecture is generally stable, but differential chemo-sensitivity can be detected even between subclones in the same patient. In ten cases with PR or SD, we observed minimal shifts within the mutational burden over the course of eight weeks, suggesting that "clonal drift" is a relatively slow process. However, in four cases with SD, what appeared clinically to be simple persistent disease was in fact a dynamic elimination of one subclone, and its replacement by a different subclone. Similarly, in three cases with CRi, we observed rapid clearance of a subclone with slower clearance of the founding clone, again suggesting differential chemo-sensitivity among subclones. 6) Finally, we correlated pharmacologic markers with clinical outcomes. We observed no correlation between steady-state plasma decitabine levels and clinical responses. Using Illumina 450k methylation arrays, we observed a correlation between response and the extent of decitabine-induced hypomethylation in total bone marrow cells that persisted on cycle 1 day 28 (p < 0.01), but not on cycle 1 day 10 (p < 0.1). In summary, these data reveal that response to decitabine is associated with morphologic blast clearance before mutations are eliminated, that relapse is associated with subclonal outgrowth that may be identified early in the treatment course, and that TP53 mutations may be predictive of rapid clinical responses, although, like most responses to decitabine, these are not necessarily durable. Disclosures Off Label Use: Decitabine treatment of AML.. Uy:Novartis: Research Funding. Oh:CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Abboud:Novartis: Research Funding; Gerson Lehman Group: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Merck: Research Funding; Teva Pharmaceuticals: Research Funding. Cashen:Celgene: Speakers Bureau. Schroeder:Celgene: Other: Azacitidine provided for this trial by Celgene; Incyte: Consultancy. Jacoby:Sunesis: Research Funding; Novo Nordisk: Consultancy.

Background: Performance Status (PS) is often used to assess the functional status of cancer patients. One of the most commonly used scales is the Eastern Cooperative Oncology Group (ECOG) PS. Using the ECOG PS scale, the oncologist assigns a score ranging from 0 (Fully active, able to carry on all pre-disease performance without restriction) to 4 (completely disabled; cannot carry on any selfcare; totally confined to bed or chair). In multiple myeloma (MM), a PS > 2 has been associated with a 35% increased risk of death following autologous stem cell transplant (ASCT) (Turesson et al, Br J Haematol, 1999), and therefore a PS ≤ 2 is generally required for ASCT and for eligibility in clinical trials. PS is often seen as a surrogate for health-related quality of life (HRQOL), which are patient reported measure(s) of well-being; however, they are separate constructs. While poorer PS has been associated with a decrease in HRQOL, it is unclear how much of the variance in HRQOL is explained by PS. Objectives: 1) To determine the association between PS and HRQOL; 2) to determine how much variance in HRQOL is explained by PS. Methods: Data was extracted from the open-access Multiple Myeloma Research Foundation (MMRF) Researcher Gateway corresponding with interim analysis 6 from the CoMMpass study. The CoMMpass study dataset included 562 patients who completed the EORTC QLQ-C30 and EORTC QLQ-MY20 at MM diagnosis. The range of scores for these HRQOL measures is 0-100, with higher scores indicating higher values. Data was analyzed using SPSS 21. The association between PS and HRQOL was assessed by one-way ANOVA tests; the amount of variance in HRQOL explained by PS was assessed by linear regression modeling. Results: PS was associated with all 9 HRQOL scales analyzed (p

Background: The clinical presentation of multiple myeloma (MM) varies greatly but often includes bone pain, anemia, renal dysfunction, hypercalcaemia, and/or constitutional symptoms. There are no signs or symptoms that are disease specific. The earliest staging system for MM, the Durie-Salmon (DS), associated disease and symptom burden with prognosis; however, it has been largely replaced by the International Staging System (ISS), which is easier to compute and better identifies patients with the poorest prognosis. It is unclear if ISS stage, like DS, is associated with disease or symptom burden. Objective: To compare disease and symptom burden of patients with newly diagnosed MM by ISS Stage. Methods: Data was extracted from the open-access Multiple Myeloma Research Foundation (MMRF) Researcher Gateway corresponding with interim analysis 6 from the CoMMpass study. The CoMMpass study is enrolling 1000 newly diagnosed MM patients who will be tracked longitudinally for 5 years. CoMMpass collects relevant clinical data and patient reported quality of life (EORTC QLQ-C30 and QLQ-MY20), as well as sequential tissue samples. Eligibility requirements for CoMMpass include: symptomatic MM with measureable disease by SPEP (≥1.0g/dL), UPEP (≥200mg/24 hours), or SFLC (≥10mg/dL); receiving an immunomodulator and/or a proteasome inhibitor for initial MM treatment; and no prior malignancies in the past 5 years. All clinical data was reported by trained data analysts at the enrolling center with the exception of flow cytometry which was performed centrally; raw lab values for beta-2 microglobulin and albumin were entered and stage was subsequently calculated by the analysts for this study according to the ISS (Greipp et al, JCO 2005). Twenty-six patients with unknown ISS were excluded from the analysis. Data was analyzed using SPSS 21. Categorical variables were compared using χ2, continuous with one-way ANOVA tests. Results: 599 patients were eligible for analysis. Sex, race, and heavy and light chain isotypes were all evenly distributed among the ISS stages; however, median age for ISS stage III was 67, 65 for stage II and 62 for stage I (p Conclusions: Stage III had a higher disease and symptom burden than stage I and II patients. Stage I and II patients were similar in most measures suggesting that ISS may not discriminate between these groups well, this is supported by other studies that have failed to find outcomes differences between stage I and II patients. Table 1. Stage I n= 204 Stage II n = 210 Stage IIIn = 185 p Demographics Age in years 62 65 67 Disclosures Vij: Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy.

Context Whole-genome sequencing is becoming increasingly available for research purposes, but it has not yet been routinely used for clinical diagnosis. Objective To determine whether whole-genome sequencing can identify cryptic, actionable mutations in a clinically relevant time frame. Design, Setting, and Patient We were referred a difficult diagnostic case of acute promyelocytic leukemia with no pathogenic X-RARA fusion identified by routine metaphase cytogenetics or interphase fluorescence in situ hybridization (FISH). The case patient was enrolled in an institutional review board–approved protocol, with consent specifically tailored to the implications of whole-genome sequencing. The protocol uses a “movable firewall” that maintains patient anonymity within the entire research team but allows the research team to communicate medically relevant information to the treating physician. Main Outcome Measures Clinical relevance of whole-genome sequencing and time to communicate validated results to the treating physician. Results Massively parallel paired-end sequencing allowed identification of a cytogenetically cryptic event: a 77-kilobase segment from chromosome 15 was inserted en bloc into the second intron of the RARA gene on chromosome 17, resulting in a classic bcr3 PML-RARA fusion gene. Reverse transcription polymerase chain reaction sequencing subsequently validated the expression of the fusion transcript. Novel FISH probes identified 2 additional cases of t(15;17)–negative acute promyelocytic leukemia that had cytogenetically invisible insertions. Whole-genome sequencing and validation were completed in 7 weeks and changed the treatment plan for the patient. Conclusion Whole-genome sequencing can identify cytogenetically invisible oncogenes in a clinically relevant time frame.

Background The antimyeloma agent bortezomib functions as an inhibitor of nuclear factor (NF)–κB. Although NF-κB inhibition is predicted to affect osteoclast function, preclinical and clinical studies have primarily reported an effect on osteoblasts. Patients and Methods We examined parameters of bone turnover prospectively in patients with multiple myeloma treated with bortezomib before and after autologous transplantation. Thirty-nine patients received 2 cycles of bortezomib on days 1, 4, 8, and 11 of a 21-day cycle. After high-dose melphalan with autologous stem cell transplantation, bortezomib 1.3 mg/m 2 on days 1, 8, 15, and 22 of a 5-week cycle was administered as maintenance therapy. Results During posttransplantation bortezomib, decreases in the urinary excretion of collagen N-telopeptide indicated that bortezomib suppresses osteoclast function. Conclusion The effects on osteoclasts occurred in the absence of bisphosphonate treatment and independently of changes in monoclonal protein levels. Further studies exploring the role of bortezomib as a bone protective agent could be warranted.

Hydroxychloroquine (HCQ) is an immunosuppressive lysosomotropic amine that has activity against graft-versus-host disease (GVHD). In a single-institution phase III trial, 95 recipients of allogeneic peripheral blood stem cell (PBSC) transplantation were randomized to receive, in a double-blind fashion, and in addition to prophylactic cyclosporine A (CSA), HCQ, or placebo starting 21 days pretransplant and continued until day +365. HCQ was very well tolerated and not associated with side effects. Overall, the incidence of acute GVHD (aGVHD) was 59% in both arms, and severe aGVHD occurred in 11% (HCQ) and 14% (placebo) (P = .76). Sixty percent and 78% of patients developed chronic GVHD (cGVHD) in the HCQ and the placebo arms, respectively (P = .15). With a median follow-up of 18 months, relapse-free and overall survivals (OS) were comparable in both groups. In summary, in this randomized trial, the addition of HCQ to single-agent CSA had no effects on aGVHD or cGVHD or survival.

The MYC oncoprotein drives multiple myeloma (MM) pathogenesis, but the utility of small molecule inhibitors of MYC-MAX dimerization is limited by poor efficacy. We determined the efficacy of lipase labile MYC-MAX inhibitor prodrug (MI1-PD) loaded nanoparticles targeted via integrin {alpha 4 beta1 α4β1) or Very Late Antigen-1 (VLA-4)} in myeloma mice. We hypothesized that NPs containing specific targeting to myeloma cells, would enhance the therapeutic efficacy of MI1-PD containing NPs. The antiproliferative activity of intergin VLA-4-Targeted MI-1PD NPs (iTM-NPs) was determined in mouse cell line (5TGM1) in vitro and its effect on the survival in C57Bl/KaLwRij-5TGM1 murine model of myeloma in vivo. iTM-NPs (approximately 20 nm in diameter, 5% w/w MI1-PD loading) under in vitro conditions exhibited inhibition of cell growth compared to the controls. Also, C57Bl/KaLwRij-5TGM1 mice that received intravenous injection of iTM-NPs demonstrated greater survival rate over the controls. These results demonstrate the feasibility of using VLA-4 targeted nanotherapy approach to improve the availability of anti-Myc small molecule inhibitors for multiple myeloma and other cancers. Citation Format: Deepti Sood Gupta, Dipanjan Pan, Grace Hu, Anagana Senpan, Xiaoxiao Yang, Edward V. Prochownik, Gregory M. Lanza, Michael H. Tomasson. VLA-4 targeted nanoparticles carrying a novel anti-Myc prodrug prolongs survival in a mouse model of multiple myeloma. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B46.

Genome-wide association studies (GWAS) of multiple myeloma (MM) in Northern Europeans have identified seven novel risk loci (2p23.3, 3p22.1, 3q26.2, 6p21.33, 7p15.3, 17p11.2, 22q13.1). We performed a multiethnic meta-analysis of these regions in 1,274 MM patients and 1,486 controls of European ancestry (EA) and 1,049 MM patients and 7,080 controls of African ancestry (AA), leveraging the differential linkage-disequilibrium of these populations in order to better localize the putative functional variants. We observed directionally consistent effects for all seven index SNPs in both populations, with four significantly associated (p Table 1.Most significant associations for each region in the multiethnic meta-analysis.Individuals of European AncestryIndividuals of African AncestryMulitethnic Metar2 with IndexcCHRSNPRAaFreqbORP-valueFreqbORP-valueORP-valueP-het2rs732075G0.591.222.0×10−30.621.122.0×10−21.162.6×10−40.280.09/0.283rs73069394A0.191.243.0×10−30.621.181.5×10−21.201.3×10−50.550.77/0.963rs12637184G0.761.136.0×10−20.921.192.7×10−11.151.0×10−20.640.94/1.007rs4487645C0.671.237.0×10−40.891.485.5×10−51.308.7×10−80.07-d17rs34562254A0.121.452.4×10−50.131.212.2×10−31.312.5×10−60.120.33/0.9022rs139400T0.491.224.0×10−40.531.172.1×10−31.191.2×10−60.630.63/0.96aRisk allelebFrequency of the risk allele in European and African ancestry studiescr2 metrics based on 1000 Genomes Project AFR/EUR populationsdIndex SNP Citation Format: Kristin A. Rand, Chi Song, Eric Dean, Daniel Serie, Karen Curtin, Dennis Hazelett, Amie E. Hwang, Xin Sheng, Alex Stram, David J. Van Den Berg, Carol Ann Huff, Leon Bernal-Mizrachi, Michael H. Tomasson, Sikander Ailawadhi, Anneclaire De Roos, Seema Singhal, Karen Pawlish, Edward Peters, Catherine Bock, David V. Conti, Graham Colditz, Todd Zimmerman, Scott Huntsman, John Graff, African Ancestry Prostate Cancer GWAS Consortium,African Ancestry Breast Cancer GWAS Consortium, Stephen J. Chanock, Michael Lieber, Jayesh Mehta, Eric A. Klein, Nalini Janakiraman, Richard K. Severson, Angela R. Brooks-Wilson, Vincent Rajkumar, Elizabeth E. Brown, Laurence Kolonel, Susan Slager, Brian E. Henderson, Graham G. Giles, John J. Spinelli, Brian Chiu, Kenneth C. Anderson, Jeffrey Zonder, Robert Z. Orlowski, Sagar Lonial, Nicola Camp, Celine Vachon, Elad Ziv, Dan O. Stram, Christopher A. Haiman, Wendy Cozen. Multiple myeloma susceptibility loci examined in African and European ancestry populations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4629. doi:10.1158/1538-7445.AM2015-4629