Abstract: Background: The total therapy 3 protocol for multiple myeloma (MM) introduced the use of intensive induction with VDT-PACE, a combination of bortezomib, dexamethasone, thalidomide, cisplatin, adriamycin, cyclophosphamide, and etoposide for newly diagnosed MM patients. This regimen, which demonstrated rapid responses in the first-line setting, has also been used in relapsed disease, to rescue induction failures or for stem cell mobilization. We evaluated the efficacy and toxicity of using VDT-PACE in these clinical settings. Patients and Methods: We identified 84 patients through pharmacy profile review who received at least one cycle of VDT-PACE for the treatment of MM between 1/2007 and 8/2013 at our institution. Patients were grouped into a stem cell collection cohort (C) if stem cell pheresis was performed following VDT-PACE. Remaining patients were analyzed in the relapsed cohort (RR). The primary objective of this study was to determine the overall response rate with combination VDT-PACE. Secondary Objectives include progression-free survival (PFS), overall survival (OS), stem cell collection in patients that underwent chemomobilization, and the extent of toxicity. Results: In the RR group, 45 patients received VDT-PACE after a median of 4 prior therapies (range 1-8) including autologous stem cell transplantation (ASCT) in 79%. The median time between diagnosis and first cycle of VDT-PACE treatment was 35.4 months (range 1.3-163.4). 47% of patients had adverse cytogenetics defined as presence of complex karyotype or FISH with del 17p, t4;14, or t14;16. Patients received a median of 2 cycles of VDT-PACE (range 1-4) with a response rate after all cycles of 51% (2% CR, 22% VGPR, 27% PR). Additional therapy was administered in 82% within 6 months (18% allogeneic SCT, 35% ASCT, 29% chemotherapy regimens). 18% of patients died without additional therapy (13% from disease progression, 5% from toxicity), all within 5 months of their last VDT-PACE cycle. PFS and OS for the RR group was 8.8 months (95% CI 4.6, 13.1) and 10.3 months (95% CI 8.8, 17.4), respectively. Patients that received subsequent lines of therapy following VDT-PACE achieved a median PFS and OS of 9.5 months (95% CI 5.6, 13.3) and 9.5 months (95% CI 7.5, 32.1), respectively, measured from the time of next therapy. In the C group, 39 patients received a median of 2 prior regimens (range 1-4) before starting VDT-PACE and 31% of patients had adverse cytogenetics. Reasons for using VDT-PACE for mobilization included residual or progressive disease (64%), provider discretion (33%), and failure of a prior attempt at collection (3%). The median time between diagnosis and first cycle of VDT-PACE treatment was 7 months (range 2.3-122.7). Patients received a median of 2 cycles (range 1-4) of VDT-PACE. The median number of cells collected was 12.3x106CD34 cells/kg (range 0.21-43.74) and the median number of collection session required was 2 (range 1-6), with 21% of patients requiring plexirafor. Two patients (5%) from this group failed collection. The response rate after all cycles of VDT-PACE was 59% (3% CR, 13% VGPR, 44% PR). 35 out of the 39 patients went to transplant following VDT-PACE (34 ASCT, 1 allogeneic SCT). Of the 4 patients who did not receive transplant, 2 were for toxicity attributed to VDT-PACE, 1 for failure to mobilize, and 1 for personal reasons. The post-transplant response rate was 91% (17% CR, 34% VGPR, 40% PR) with 1 patient (3%) experiencing disease progression immediately after transplant. Median PFS and OS for the C group patients was 34.5 months (95% CI 20.2, n.r.) and 64.8 months (95% CI 26.0, n.r.), respectively. Reported toxicities following treatment included infection (20%), fatigue (19%), nausea (17%), renal complications (6%), thrombosis (4%), and edema (4%), which were seen in 67% and 62% of the RR and C groups, respectively. Hospital readmission for management of side effects occurred in 30% of patients. Conclusions: VDT-PACE is an effective therapy for RR patients and for stem cell mobilization in patients with residual or progressive disease following initial therapy. Importantly, it is also associated with significant morbidity and requires careful monitoring. VDT-PACE does not appear to adversely affect stem cell collection or SCT outcomes. At our institution, this regimen is commonly used for stem cell collection in patients with unfavorable outcomes following initial therapy. Disclosures No relevant conflicts of interest to declare.

Abstract: Patients with multiple myeloma (MM) who achieve minimal residual disease (MRD) negativity after upfront treatment have superior outcomes compared with those who remain MRD+. Recently, associations have been shown between specific commensal microbes and development of plasma cell disorders. Here, we report the association between intestinal microbiota composition and treatment outcome in MM. Microbiota composition of fecal samples collected from 34 MM patients after induction therapy and at the time of flow cytometry–based bone marrow MRD testing was determined by 16S ribosomal RNA sequencing. We observed a higher relative abundance of Eubacterium hallii in the 16 MRD− patients relative to the 18 MRD+ patients. No association was observed between microbial relative abundance and autologous stem cell transplantation history or MM paraprotein isotype. No differences in microbiota α diversity were observed between MRD− and MRD+ patients. The potential association of microbiota composition with treatment response in MM patients is an important parameter for additional correlative and clinical investigation.

Abstract: Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

Abstract: Background: The aggressive approach to first-line treatment of multiple myeloma (MM) incorporating autologous stem cell transplantation (ASCT) remains widely prevalent, although it is not without controversy in the current era of novel effective agents. Some trials and meta-analysis comparing ASCT to non-myeloabaltive standard therapy or delayed ASCT have failed to show an overall survival (OS) difference between the two arms [Fermand et al. Blood 92:3131-3136 (1998); Koreth et al. BBMT 13:183-196 (2007); Kumar, et al. Cancer 118(6):1585-92 (2012)]. On the other hand, analysis of transplant-eligible patients receiving lenalidomide and dexamethasone induction on the E4A03 trial and then either undergoing ASCT or continuing lenalidomide and dexamethasone showed that ASCT conferred improved OS (Blood 2010;116:38a). This controversy lead us to design a phase II clinical trial comparing continuous lenalidomide and dexamethasone (Ld) versus ASCT followed by lenalidomide maintenance, in patients responding to four cycles of Ld. Methods: Patients with newly diagnosed symptomatic MM as defined by IMWG criteria were enrolled. Patients deemed to be in urgent need of aggressive therapy (e. g. symptomatic bone disease, acute renal failure, hyperviscosity syndrome, etc) were not eligible. Patients received induction with lenalidomide (L) 25 mg PO daily on days 1-21, and dexamethasone (d) 40 mg PO daily on days 1,8,15, and 22 of a 28-day cycle with standard prophylaxis. Patients with POD during induction or SD after four cycles of Ld were taken off study. All other patients had stem cells harvested after four cycles of Ld and were randomized to either the continuous (Ld) arm (L at the last tolerated dose during induction, continued indefinitely until progression or toxicity; and d at 20mg weekly for one year) or the ASCT arm (using melphalan conditioning followed by L maintenance started three months post-ASCT at 10mg daily, escalated to 15 mg daily six months post-ASCT and continued indefinitely until progression or toxicity). Results: Fifty seven patients have been registered to the trial. Two patients did not initiate therapy, one because of a concurrent diagnosis of amyloidosis and the other due to aggressive disease mandating alternative therapy according to the treating physician. At this time, four patients are still receiving induction therapy and are not available for response assessments. Among the 51 remaining patients, the response to initial induction therapy includes 12% CR (n=6), 2% uCR (n=1), 4% nCR (n=2), 14% VGPR (n=7), 51% PR (n=26), 6% SD (n= 3), 4% POD (n=2), and 8 % inevaluable (n = 4 who did not receive at least two cycles of Ld). Thirteen patients were removed from the trial prior to randomization due to POD (n=2), SD after four cycles (n=3), toxicity (n=4), physician discretion (n=2), and withdrawal of consent (n=2). Among these 13 patients, one was lost to follow-up, two continued lenalidomide therapy off protocol (one patient refused ASCT, and one patient had inadequate stem cell collection), and 10 proceeded to alternative induction. All 12 patients achieved a response [25 % CR (n=3), 42 % VGPR (n=5), and 33 % PR (n=4)]; 10 patients proceeded to ASCT without event. Thirty-eight patients were randomized, 20 to Ld and 18 to ASCT. Improvement of response by at least one level occurred in 45% and 65% of patients on the Ld and ASCT arms, respectively. The median follow-up for all surviving patients from time of randomization is 38.3 months. The 1- and 3-year PFS in the Ld arm were 100% and 66%, respectively. The 1- and 3-year PFS in the ASCT arm were 89% and 68%, respectively. The 2- and 3-year OS in the Ld arm were 100% and 92%, respectively. The 2- and 3-year OS in the ASCT arm were 100% and 85%, respectively. Considering the entire population of 51 patients, with a median follow-up of 38 months, the median PFS has not been reached. Conclusions: This interim analysis, with relatively short follow-up, suggests that in transplant-eligible patients responsive to Ld during induction, continuous Ld results in similar PFS and OS compared to patients who undergo ASCT followed by L maintenance. Furthermore, this overall approach based on response-adapted treatment results in 100% of patients reaching at least PR at completion of first-line therapy. The trial remains ongoing. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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

Abstract: Background: High-dose chemotherapy followed by ASCT remains the standard of care for patients aged ≤75 years with NDMM. The ability of novel agents, such as lenalidomide and bortezomib, to produce treatment response rates comparable to those seen with ASCT has raised questions about the necessity for upfront ASCT in transplant-eligible NDMM patients. This analysis aimed to compare the efficacy and safety of continuous Ld versus Ld+ASCT in patients with NDMM. Methods: Data were pooled from two randomized clinical trials (NCT01731886 and NCT00807599) that compared Ld alone versus Ld+ASCT in NDMM patients aged ≤75 years. Patients received four 28-day cycles of Ld (lenalidomide 25mg daily on days 1-21; dexamethasone 40mg on days 1, 8, 15, and 22) followed by stem-cell mobilization and collection, and either a) Arm A: continuous Ld (an additional 4 cycles +/- lenalidomide maintenance in NCT01731886, or continuous lenalidomide at the last tolerated dose until disease progression plus dexamethasone 20mg for 1 year following treatment initiation in NCT00807599); or b) Arm B: ASCT conditioned with high-dose melphalan, and followed by lenalidomide maintenance therapy. In both trials, patients were withdrawn if they developed progressive disease (PD) at any time, or had stable disease (SD) after cycle 4 of Ld induction. We evaluated overall response rate (ORR; defined as a partial response or better), progression-free survival (PFS), overall survival (OS), and adverse event (AE) incidence rates, focusing on those randomized patients who responded to 4 cycles of Ld induction. Results: Sixty patients were enrolled into NCT01731886, and 63 into NCT00807599. The analysis included a total of 85 patients who had been randomized and achieved a response to 4 cycles of Ld induction: 41 in Arm A, and 44 in Arm B. Mean ages in Arm A versus Arm B were 61.8 versus 61.7 years; median (range) follow-up times were 3.97 (0.27-6.19) versus 3.71 (0.16-5.66) years. Baseline cytogenetic risk profiles were similar overall, although Arm A contained a higher percentage of intermediate-risk patients (17.1% versus 11.4%). More than half of all patients included in the analysis had International Staging System stage 1 disease: 63.4% of patients in Arm A, and 47.7% of those in Arm B. Median PFS was similar with the two treatment approaches: 4.3 versus 4.4 years (Figure 1; p = 0.9107). OS also did not differ significantly between the two arms (Figure 2). As expected, both treatment regimens were well tolerated. Clinically significant grade 3 and 4 AEs occurring outside of the transplant period included the following: anemia (17.1% Arm A versus 15.9% Arm B); neutropenia (36.6% versus 38.6%); thrombocytopenia (17.1% versus 18.4%); infectious complications (14.6% versus 27.3%); thromboembolic events (7.3% versus 6.8%); and secondary malignancies (7.3% versus 4.5%). Conclusions: The findings of this pooled analysis suggest that, in transplant-eligible patients responsive to Ld induction, continuous Ld results in similar PFS and OS to Ld+ASCT. Larger phase III trials addressing this question are awaited. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Lentzsch: Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Axiom: Honoraria. Landau:Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria; Prothena: Consultancy, Honoraria; Janssen: Consultancy; Onyx: Honoraria, Research Funding; Takeda: Research Funding. Lesokhin:Efranat: Consultancy; Genentech: Research Funding; Aduro: Consultancy; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Kewalramani:Celgene: Consultancy; Abbvie: Consultancy; Getchell v Doon East Community Hospital, Alfred Wakeman et al.: Consultancy. Comenzo:Karyopharm: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Takeda Millennium: Research Funding; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees. Landgren:Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Medscape: Honoraria; Onyx: Honoraria; International Myeloma Foundation: Research Funding; Onyx: Research Funding; BMJ Publishing: Consultancy; BMJ Publishing: Honoraria; Medscape: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Onyx: Consultancy. Hassoun:Novartis: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Research Funding.