Citations

8009 Background: Measuring response among patients with multiple myeloma is essential for the care of patients. Deeper responses have been associated with better progression free survival (PFS) and overall survival (OS). Serum (SIFE) and urine immunofixation are the currently used markers for biochemical documentation of CR after which marrow is tested for plasma cell clearance. Next generation flow cytometry and sequencing are used to document the presence of minimal residual disease (MRD). Mass spectrometry of blood by MALDI (Mass-Fix) is a new simple, inexpensive, sensitive, and specific means of detecting monoclonal immunoglobulins. To better test the hypothesis that Mass-Fix is superior to existing methodologies to predict for survival outcomes—especially SIFE-- samples from the STAMINA trial (NCT01109004), a trial comparing 3 transplant approaches among patients who have already received induction, were employed. Methods: Five-hundred and seventy-five patients were included. Samples from enrollment post-induction (post-I) and 1-year post enrollment (1YR) were tested when available. Four response parameters were assessed univariately: Mass-Fix, SIFE, complete response, and MRD by next generation flow cytometry. Mass spectrometry spectra were evaluated in a blinded fashion. Complete response was according to the 2006 International Myeloma Working Group criteria. Multivariate Cox proportional hazard models using stepwise regression were developed to explore the independent effect of the different response parameters on PFS and OS and interactions with other risk factors. Results: Of the 4 response measures, only MRD and Mass-Fix predicted for PFS and OS at multiple testing points on multivariate analyses (Table). Of the 4 post-I measurements, only MRD predicted for PFS; however, Mass-Fix was the only post-I measurement to predict for OS. Of all the 1-year measures, both 1YR Mass-Fix and 1YR MRD positivity predicted for inferior PFS and OS. In models including MRD and Mass-Fix, SIFE and CR were not prognostic for PFS or OS. Conclusions: Mass-Fix is a powerful means to track monoclonal proteins. The full utility of Mass-Fix was not exploited given the absence of a diagnostic sample and the fact that only serum (and not urine) was tested. Despite these limitations, it performed well at pre-induction and at 1 year. Mass-Fix provides a convenient and non-invasive means of predicting for myeloma outcomes. Clinical trial information: NCT01109004. [Table: see text]

Introduction: New targets and treatment modalities are needed for multiple myeloma (MM). Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed on B cells and plasma cells, and is found on myeloma cells with near 100% prevalence. BFCR4350A, a humanized immunoglobulin G-based T-cell-engaging bispecific antibody (bsAb), targets the most membrane-proximal domain of FcRH5 on myeloma cells and CD3 on T cells. Dual binding facilitates efficient immunological synapse formation, resulting in T-cell activation and potent killing of myeloma cells (Li et al. Cancer Cell 2017). GO39775 (NCT03275103) is an ongoing, multicenter Phase I trial evaluating the safety, activity, pharmacodynamics, and pharmacokinetics of BFCR4350A monotherapy in pts with relapsed/refractory (R/R) MM. We present dose-escalation data from the single step-up dosing cohort (Arm A). Methods: All pts have R/R MM for which no established therapy is available, appropriate, or tolerated. Prior exposure to CAR-T cells, T-cell engaging bsAbs, and antibody-drug conjugates (ADCs), including those targeting BCMA, is allowed. In dose-escalation, pts receive BFCR4350A by IV infusion in 21-day cycles (Q3W). In Arm A, a single step-up dose is used in Cycle (C) 1 to mitigate the risk for cytokine release syndrome (CRS), with the step dose (0.05-3.6mg) given on C1 Day (D) 1 and the target dose (0.15-132mg) given on C1D8, and on D1 of each subsequent cycle. Results: At cut-off (April 13, 2020), 51 pts (median age: 62.0 years [range: 33-80]; high-risk [HR] cytogenetics [1q21, t(4;14), t(14;16), or del(17p)]: 28 pts) had been enrolled into Arm A. Median number of prior lines of therapy was 6 (range: 2-15). Prior treatments included: proteasome inhibitors (PIs), 100% (94.1% refractory); immunomodulatory drugs (IMiDs), 100% (98.0% refractory); anti-CD38 mAbs, 78.4% (92.5% refractory); autologous stem cell transplant, 86.3%. Overall, 66.7% of pts were triple-class refractory (≥1 PI, ≥1 IMiD, and ≥1 anti-CD38 mAb), and 94.1% of pts were refractory to their last therapy. At cut-off, 46/51 pts were evaluable for efficacy. Responses were observed at the 3.6/20mg dose level and above, in 15/29 pts (51.7%) (Table). Responses included 3 stringent CRs, 3 CRs, 4 VGPRs, and 5 PRs (Table). At the 3.6/20mg dose level and above, responses were observed in pts with HR cytogenetics (9/17), triple-class refractory disease (10/20), and prior exposure to anti-CD38 mAbs (11/22), CAR-Ts (2/3), or ADCs (2/2). Duration of response data are evolving, with 6/15 pts in response for >6 months at cut-off. Median follow-up for safety was 6.2 months (range: 0.2-26.3 months). Almost all pts (49/51) had ≥1 treatment-related AE. The most common treatment-related AE was CRS (Lee et al. 2014 criteria; 38/51 pts, 74.5%). CRS was Grade (Gr) 1 in 20 pts (39.2%), Gr 2 in 17 pts (33.3%), and Gr 3 in 1 pt (2%) (due to Gr 4 transaminase elevation). CRS was most common in C1 (38 pts) and was uncommon or absent in subsequent cycles (4 pts). Most CRS events (49/58, 84.5%) resolved within 2 days. 18/38 (47.3%) pts with CRS received tocilizumab and/or steroids. Other treatment-related AEs in ≥5 pts were neutropenia and lymphocyte count decreased (6 pts each, 11.8%), aspartate aminotransferase increased and platelet count decreased (5 pts each, 9.8%). Treatment-related Gr 3-4 AEs (20 pts, 39.2%) in ≥3 pts were lymphocyte count decreased (6 pts, 11.8%), neutropenia (5 pts, 9.8%), anemia and platelet count decreased (3 pts each, 5.9%). No treatment-related Gr 5 (fatal) AEs were observed. Treatment-related AEs leading to withdrawal of treatment were uncommon (1 pt, 2.0%). One DLT (Gr 3 pneumonia) was observed in the 3.6/90mg cohort, but the MTD was not reached. BFCR4350A PK was linear across the active dose levels tested and the estimated half-life was supportive of the Q3W dosing regimen. Conclusions: BFCR4350A monotherapy demonstrates promising activity in heavily pre-treated R/R MM, with deep and durable responses observed in pts with HR cytogenetics, triple-class refractory disease, and/or prior exposure to anti-CD38 mAbs, CAR-Ts, or ADCs. Toxicity was manageable, with C1 single step-up dosing effectively mitigating the risk for severe CRS and allowing escalation to clinically active doses. Updated data will be presented. Disclosures Cohen: Novartis: Other: Patents/Intellectual property licensed, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Haemalogix: Consultancy; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Krishnan:Sutro: Membership on an entity's Board of Directors or advisory committees; Z Predicta: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Regeneron: Consultancy; Takeda: Speakers Bureau; Amgen: Speakers Bureau; BMS/Celgene: Consultancy, Other: Stock BMS, Speakers Bureau; Sanofi: Consultancy. Fonseca:Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Merck: Consultancy; Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Forsberg:Celgene: Speakers Bureau; Genentech, Inc., Sanofi, Karyopharm, Abbvie: Research Funding. Spencer:AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria; Celgene, Janssen and Takeda: Speakers Bureau. Berdeja:BMS: Consultancy, Research Funding; Glenmark: Research Funding; Genentech, Inc.: Research Funding; Bioclinica: Consultancy; Teva: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Cellularity: Research Funding; Acetylon: Research Funding; CURIS: Research Funding; Legend: Consultancy; Lilly: Research Funding; Constellation: Research Funding; EMD Sorono: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy; Poseida: Research Funding; Amgen: Consultancy, Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; Bluebird: Research Funding; Karyopharm: Consultancy; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Kesios: Research Funding. Li:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment. Choeurng:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Vaze:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Samineni:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Sumiyoshi:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Cooper:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Fine:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Trudel:Janssen: Honoraria, Research Funding; Sanofi: Honoraria; GSK: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Karyopharm: Honoraria; AstraZeneca: Honoraria; BMS: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Honoraria. OffLabel Disclosure: BFCR4350A is a humanized IgG-based T-cell-engaging bispecific antibody that targets the most membrane-proximal domain of FcRH5 on myeloma cells and CD3 on T cells. Dual binding facilitates efficient immunological synapse formation, resulting in T-cell activation and killing of myeloma cells. BFCR4350A is an investigational agent.

Outcomes in multiple myeloma (MM) have improved dramatically in the last two decades with the advent of novel therapies including immunomodulatory agents (IMiDs), proteasome inhibitors and monoclonal antibodies. In recent years, immunotherapy for the treatment of MM has advanced rapidly, with the approval of new targeted agents and monoclonal antibodies directed against myeloma cell-surface antigens, as well as maturing data from late stage trials of chimeric antigen receptor (CAR) T cells. Therapies that engage the immune system to treat myeloma offer significant clinical benefits with durable responses and manageable toxicity profiles, however, the appropriate use of these immunotherapy agents can present unique challenges for practicing physicians. Therefore, the Society for Immunotherapy of Cancer convened an expert panel, which met to consider the current role of approved and emerging immunotherapy agents in MM and provide guidance to the oncology community by developing consensus recommendations. As immunotherapy evolves as a therapeutic option for the treatment of MM, these guidelines will be updated.

TPS8551 Background: Multiple myeloma (MM) remains an incurable disease, with estimated median survival of 8–9 months in patients with relapsed or refractory (R/R) disease (Kumar et al. 2014; Usmani et al. 2016). There is no uniform standard of care for R/R MM, and combinations used in later lines have diminishing responses, especially after re-exposure to previously received classes of therapy (Gandhi et al. 2019). New targets and treatment modalities are needed. Fragment crystallizable receptor-like 5 (FcRH5) is expressed on myeloma cells across lines of therapy, and is overexpressed by myeloma cells with 1q21 gain; expression in healthy tissue is restricted to the B-cell lineage, and is retained in plasma cells (Li et al. 2017). BFCR4350A is an IgG-based T-cell-dependent bispecific antibody that was specifically engineered to target the most membrane-proximal domain of FcRH5 on myeloma cells and cluster of differentiation 3 (CD3) on T cells, with dual binding resulting in efficient immune synapse formation and T-cell killing of myeloma cells. BFCR4350A demonstrates potent killing of plasma cells and patient-derived myeloma cells (including those with low levels of FcRH5 expression) in vitro, and complete depletion of bone marrow plasma cells in primates, without severe or prolonged cytokine release (Li et al. 2017). GO39775 (NCT03275103) is an open-label, multicenter Phase I dose-escalation and dose-expansion trial evaluating the safety, pharmacokinetics (PK), and activity of BFCR4350A monotherapy in patients with R/R MM. Methods: Patients must be aged ≥18 years and must have R/R MM for which no established therapies are available or appropriate, or be intolerant to those therapies. Patients with prior CAR-T therapy and/or prior BCMA-directed therapy are not excluded. BFCR4350A is administered by intravenous infusion, and q3w dosing with Cycle 1 single-step or multi-step dosing is being investigated in dose-escalation (Arms A and B, respectively). Enrolment into both arms is ongoing, with patients receiving up to 17 cycles of treatment until disease progression or unacceptable toxicity. Primary objectives are to evaluate safety (including the maximum tolerated dose and dose-limiting toxicities) and to identify a recommended Phase II dose. Secondary objectives include assessment of PK, activity, immunogenicity, and pharmacodynamic biomarkers. Clinical trial information: NCT03275103 .

TPS8057 Background: Multiple myeloma (MM) is the second most prevalent blood cancer, representing approximately 1% of all cancers. Although overall survival has improved in recent years due to new approved agents, the vast majority of MM patients (pts) ultimately stop responding to treatment. Moreover, about a quarter of MM pts characterized as “high risk” experience limited benefit from existing treatments. Seminal genomic sequencing research efforts, such as the MMRF CoMMpass study, have highlighted that a large number of MM cases harbor potentially actionable oncogenic molecular alterations and published reports on small numbers of cases suggest that Precision Medicine (PM) interventions clinically targeting such actionable drivers may benefit MM pts. These results suggest that PM approaches in MM are possible and should be further studied clinically. To that end, we have launched MyDRUG, a master protocol aimed at developing new myeloma regimens based on individual pt’s genomics. Methods: This study is a Phase I-II, multicenter master protocol in functional high risk MM patients (i.e patients having progressed from baseline treatment within 18 months without maintenance or 3 years on maintenance) with 1-3 prior lines of therapy. Patients are screened for actionable genomic alterations on the CLIA-grade MI-ONCOSEQ platform. Patients with actionable alterations are assigned to the appropriate targeted agent used in combination with a backbone regimen ixazomib, pomalidomide and dexamethasone (IPd), whereas patients without such alterations go on an immune arm (see Table). Inclusion criteria include measurable disease (as measured by M-protein and FLC) and acceptable hematologic and metabolic functions. A maximum of 12 evaluable pts will be accrued onto the phase I portion of each arm and an additional 21 evaluable phase II pts will be accrued onto each arm for a total of 27 evaluable pts at the MTD combination dose. The primary objective of the study is to evaluate ORR per IMWG consensus criteria. Secondary objectives are to assess adverse events (AEs), progression-free survival, and overall survival (OS). Experimental correlative aims include assessing molecular or clonal response, molecular and immune signatures of resistance/response, MRD. Clinical trial information: NCT03732703. [Table: see text]

Abstract Abstract 2877 FLC assay measures circulating unbound k and l light chains and is of diagnostic and prognostic value in plasma cell disorders. Normalization of FLC ratio is considered a higher level of complete response (CR) in MM but this has not been well validated prospectively. HLC is a novel antibody based assay that targets the unique junctional epitopes between the heavy chain and light chain constant regions of intact immunoglobulin (Ig) molecules. It separately measures in pairs the light chain types of each immunoglobulin class generating ratios of monoclonal Ig/background polyclonal Ig concentrations (i.e IgGκ/IgGλ, IgAκ/IgAλ and IgMκ/IgMλ); potentially simplifying assessment of monoclonal protein response. To assess the prognostic impact of these assays and to correlate them with electrophoretic/immunofixation (SPE/IFE) assessment, we analyzed 497 stored serum samples from patients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 clinical trial, sponsored by the NHLBI and NCI, of tandem autologous (autoHCT) vs. tandem autoHCT- allogeneic (alloHCT). Samples were collected prior to the first autoHCT and analyzed for FLC (Freelite™) and HLC (Hevylite™) at The Binding Site, UK. Corresponding disease status determination was centrally performed by an expert data review committee using uniform response criteria and correlated with FLC and HLC results. HLC remission was defined as normalization of composite heavy and light chain ratios across all 3 measured heavy/light chain pairs or the normalization of clonal isotype with normal ratios of uninvolved pairs. The demographics of 497 patients with HLC/FLC samples at baseline were concordant with the main study and showed similar patient proportions from the 2 study arms. Of the 211 pts with baseline SPE response better than or equal to a very good partial response (>VGPR), 188 also had an HLC remission (Sensitivity=89%). Comparison of the HLC remission with the >VGPR disease state also identified a specificity of 52%, positive predictive value (PPV) of 58% and a negative predictive value (NPV) of 87%. Similarly, all 56 patients in complete remission (CR) by SPE/IFE were in HLC remission. Compared with conventional CR assessment, sensitivity of HLC remission was 100%, specificity 39%, PPV and NPV values of 17% and 100% respectively. FLC remission correlated with >VGPR disease state had a sensitivity of 47%, specificity of 81% and a PPV and NPV of 64% and 67% respectively. Multivariate models for post transplant progression free survival (PFS) indicated that baseline disease response (>VGPR vs. partial remission (PR) or<PR) was associated with longer PFS. Adjusted models including baseline response, myeloma stage and study arm were used to compare the predictive utility of HLC and FLC assays. There was a lower risk of treatment failure (HR 0.74, p=0.02) and superior PFS for patients who achieved an HLC remission. When stratified by baseline disease response states, there was no additional prognostic impact for HLC remissions on PFS. Normalization of FLC ratio among patients with >VGPR disease state did not impact PFS (HR 0.96, p=0.83). Abnormal HLC after induction therapy has a high negative predictive value (100%) for identifying patients not achieving CR by uniform response criteria and is also associated with shorter PFS after transplant. FLC ratio normalization had no impact suggesting that stringent CR criteria may need further validation. Disclosures: Krishnan: Celgene: Speakers Bureau; Millenium: Speakers Bureau. Alvi:the binding site: Employment. Harding:The Binding Site Group Ltd: Employment. Maloney:Cellgene: Consultancy.

Abstract Abstract 1024 Background: The MMRC is a non-profit, disease-focused consortium founded in 2004. Sixteen North American member institutions with expertise in multiple myeloma (MM) work collaboratively with the MMRC Inc. (Norwalk, CT) and numerous pharmaceutical partners to speed development of new treatment options to MM patients. In December 2007, MMRC Inc. implemented business solutions to address barriers to rapid activation of phase I-II trials and established benchmarks for initiating and conducting these studies. In December 2010, we reported significantly faster trial start up and accrual data from previous years1,2. Today, we update and expand on MMRC performance data and analysis of progress. Methods: Twenty-five (25) trials conducted within the Consortium from May 2006 to July 2011 had sufficient start up trial data for review. FPFD was defined as the time from the member institutions' receipt of the final protocol (FP) from the trial sponsor, to the time the first patient was dosed on the trial at any participating MMRC member institution. With respect to enrollment, pre-study enrollment commitment (EC) established between MMRC and the study sponsor was defined as the total number of subjects committed to receive at least one dose of study drug across all participating MMRC centers on a trial; baseline enrollment timeline (BET) was prospectively defined as the target time period to attain EC. Results: Mean time to FPFD in the recent group of trials (RG; n=18; Sept 08-Jul 11) held steady at 131 calendar days from receipt of FP as compared to 181 days for the early group of trials (EG; n=7; Jun06-Sept08) representing a 28% reduction in time to FPFD. More importantly, there was a 20% decrease in time to FPFD by all participating MMRC centers on any MMRC trial from 189 days in the RG compared to 236 days in the EG representing an important achievement especially in the Phase I/II arena. MMRC trial accrual data was available for 17/25 trials (2 EG trials were missing data and 6 RG trials continue enrolling). The pre-study mean MMRC EC was 44 subjects per trial (n=19 trials; 849 patients); the mean actual MMRC enrollment was 49 subjects per trial (n=19; 935 patients through July 11) representing a 10% over enrollment versus committed enrollment. A total of 17/19 evaluable trials (89%) met their EC; 12/19 trials met EC within BET (71%) of which 8/12 trials (67%) reached EC 34% faster than their BET (representing a mean reduction of 4.5 months). The overall pre-study mean BET for 19 trials was 13.6 months. MMRC's actual mean enrollment timeline was 12.8 months for the group of 17 evaluable trials representing improvement over the original BET by a mean of 10%. Discussion: MMRC's acceleration of clinical trials provides physicians and patients with rapid access to novel compounds; industry with data for important drug development decisions; and academic institutions with more trials of high scientific interest. Even so, our data uncovered opportunities for improvement. The submission time from receipt of the final protocol from the trial sponsor to Scientific Review Committee (SRC) took an average 30 calendar days across all trials. A reduction to half this time could make a difference to patients and therefore warrants further exploration. Conclusion: Today, drug development in multiple myeloma is fast-paced and highly competitive. MMRC's frequent review of trial metrics provides valuable insight to continually speed answers to physicians, patients and industry. Disclosures: Richardson: Multiple Myeloma Research Consortium: Annual grant in support Clinical Trial Project Management. Vij:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Lonial:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Siegel:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Jakubowiak:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Reece:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Jagannath:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Hofmeister:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Stewart:Multiple Myeloma Research Consortium: Annual Grant in support of clinical trial Project Management. Wolf:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Krishnan:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Zimmerman:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Kumar:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Roy:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Fay:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Anderson:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management.

Abstract Background: Combination regimens incorporating bortezomib (VELCADE®, Vc), lenalidomide (REVLIMID®, Rev), dexamethasone (Dex) and cyclophosphamide (Cy) (Vc–Dex, Rev–Dex, Vc–Dex–Rev [VDR], and Vc–Dex–Cy [VDC]), have all shown substantial activity in previously untreated multiple myeloma (MM). A combination of all four agents (VDCR) may result in even greater activity. This randomized multi-center 3-arm phase I/II EVOLUTION study is investigating the efficacy and safety of VDR, VDC, and VDCR as initial therapy in previously untreated MM patients (pts). We now report safety and efficacy results from the phase l dose-escalation portion of the study, which sought to determine the maximum tolerated dose (MTD) of the VDCR regimen. These results represent the first clinical data with this novel 4-drug combination that includes bortezomib, lenalidomide, an alkylator, and a corticosteroid. Methods: Pts received Vc 1.3 mg/m2 IV (d 1, 4, 8, 11), Dex 40 mg PO (d 1, 8, 15), Rev 15 mg PO (d 1–14), plus Cy 100, 200, 300, 400, or 500 mg/m2 PO (d 1, 8) for up to eight 21-d cycles, followed by Vc 1.3 mg/m2 (d 1, 8, 15, 22) for four 42-d maintenance cycles. Pts received prophylactic antibiotics, acyclovir, transfusion support and concomitant anticoagulants as required. Eligible pts wishing to receive autologous stem cell transplant (ASCT) could undergo stem cell mobilization any time after cycle 2, and discontinue therapy for ASCT any time after cycle 4. The MTD was defined as the highest dose of Cy in combination with VDR resulting in ≤1 dose-limiting toxicity (DLT) in 6 pts. A DLT was defined as: platelet count <25,000/mm3 lasting >7 days or any platelet count <10,000/mm3; grade 4 neutropenia lasting >7 days; any ≥grade 3 non-hematologic toxicity considered to be related to Cy except for inadequately treated nausea, vomiting, and diarrhea, or any toxicity resulting in a >2 week treatment delay. Results: Twenty-six pts were enrolled; 1 pt was not dosed due to a heart problem and was excluded (dose level 4) and 4 pts were not evaluable for DLT. In the 25 treated pts, median age was 61 years (range 49–79); 52% were male; 48% had ISS Stage lI and 4% Stage III disease, and 44% had KPS ≤80%. At data cut-off, 11 pts remain on treatment and 9 have undergone successful ASCT. To date, median treatment duration is 4 cycles (range 2–11). Two pts experienced DLT: 1 grade 4 febrile neutropenia at dose level 4 (Cy 400 mg/m2), and 1 grade 3 herpes zoster virus reactivation despite antiviral prophylaxis at dose level 5 (Cy 500 mg/m2). The recommended phase II dose of Cy in the VDCR regimen was the highest planned dose of 500 mg/m2. The most common treatment-emergent AEs were constipation (64%), fatigue (60%), and nausea (52%). Hematologic toxicities were acceptable, with grade 3 neutropenia in 16% of patients, grade 4 in 4%, and grade 4 thrombocytopenia in 4%. Peripheral neuropathy (56%), included 8% grade 3 but no grade 4; no deep-vein thrombosis/pulmonary embolism events were reported. Overall rate of serious AEs was 40%; the only SAE reported in >1 pt was febrile neutropenia (2 pts). Best responses to date by International Uniform Response Criteria are shown in the table. Preliminary response rates are: 100% ≥PR, 68% ≥VGPR, 32% CR/nCR, 28% CR/stringent CR and 20% sCR. Ten pts have undergone stem cell mobilization with median CD34+ yield of 4.95×106/kg. Conclusions: VDCR was well tolerated and hematologic toxicities were manageable. The current study shows that the VDCR regimen is feasible and highly active in newly diagnosed myeloma and merits further testing in clinical trials. Enrollment to the 3 arms (VDR, VDC and VDCR) of the phase ll portion of the study and testing for minimal residual disease by flow cytometry are ongoing. Best unconfirmed response to date with VDCR Dose level 1 2 3 4 5 Cyclophosphamide dose, mg/m2 100 200 300 400 500 Enrolled 3 4 4 8 7 Treated 3 4 4 7 7 Still on treatment – 1 1 2 7 Best unconfirmed response to date CR (sCR) 2 (2) 1 (1) 1 (1) 2 1 (1) VGPR (nCR) 1 – 3 (1) 4 2 PR – 3 – 1 4

Abstract Abstract 3803 Background: The MMRC is a non-profit, disease-focused consortium founded in 2004 comprised of 13 North American centers with expertise in multiple myeloma (MM). The MMRC Inc. (Norwalk, CT), MMRC's member institutions, and several pharmaceutical partners work closely to speed early development of new treatment options for MM patients. In December 2007, MMRC headquarters staff implemented multiple project management (PM) business solutions to address trial barriers that delay activation of our phase I-II clinical trials and established trial metric benchmarks considered attainable at our member institutions. In November 2009, we reported initial data1 on trial activation: MMRC trials initiated between Sep08-Jul09 (n=5) demonstrated a 38% decrease in mean time to first patient dosed (FPFD), compared with the Early Group trials (EG) initiated before PM solutions (Jun06-Sept08; n=7 trials). These results also confirmed improvement over published metrics from Dilts et al 2,3. We present additional data on time to FPFD and now enrollment, to assess impact of the MMRC PM resources and processes on trial efficiency. Methods: Twenty-one (21) trials conducted within the MMRC from May 2006 to June 2010 had sufficient trial data for review. Data were collected by MMRC-funded project managers at the clinical centers using a web-based clinical trial management system (CTMS). FPFD was defined as the time from the member institutions' receipt of the final protocol (FP) from the trial sponsor, to the time the first patient was dosed on the trial at any participating MMRC member institution. With respect to enrollment, pre-study enrollment commitment (EC) established between MMRC and the study sponsor was defined as the total number of subjects committed to receive at least one dose of study drug across all participating MMRC centers on a trial; baseline enrollment timeline (BET) was prospectively defined as the target time period to attain EC. Results: Mean time to FPFD was 181 calendar days for the early group trials (EG, n=7) and 122 days for the recent group (RG) trials (n=14, Sep08 – Jun10), representing a 32% reduction of time to FPFD in the RG. Additionally, time from final protocol to first patient dosed at all MMRC centers on a trial decreased 18% from a mean of 7.7 months (EG) to 6.3 months (RG). With respect to MMRC trial enrollment, data was available for 16/21 trials (5 EG and 11 RG). 2 EG trials were missing data and 3 RG trials were still enrolling as of June 2010. The mean MMRC pre-study EC was 39 subjects per trial (n=16 trials; 626 enrollment target); the mean actual MMRC enrollment was 49 subjects per trial (n=16; 783 enrolled through Jun 29, 2010) representing a 25% increase in actual versus committed enrollment. Two trials did not meet MMRC EC: MMRC investigators discontinued their involvement in these trials at approximately 30% target EC due to trial complexity or low patient enrollment. 14/16 evaluable trials (88%) met their EC; 11/16 trials met EC within BET (69%) of which 8/16 trials (50%) reached EC 34% faster than their BET (representing a mean reduction of 4.5 months). The overall pre-study mean BET for 16 trials was 13.1 months. MMRC's actual mean enrollment timeline was 11.3 months for the group of 14 evaluable trials representing improvement over the original BET by a mean of 1.9 months (14%). We believe FP to FPFD is a more meaningful metric beyond that of first patient consented. Moreover, we believe that if all participating trial centers focus their efforts on dosing the first patient and within a targeted timeframe, it may improve our research efforts overall. Conclusion: Development of drugs in the clinical setting has become time and resource intensive. Activating and enrolling trials promptly is a priority for drug development. The MMRC's standardization of processes and support for site-based PM resources results in improved trial metrics. MMRC member centers met or exceeded pre-specified enrollment targets in 88% of the trials analyzed to date. Ongoing monitoring of trial conduct continues to reveal areas where increased focus is needed to realize further trial efficiencies. These trial metrics and measures to improve efficiency may be applied with similar expected benefit in all oncology disciplines. Disclosures: Wear: Multiple Myeloma Research Consortium (MMRC): Employment. Richardson:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Revta:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Vij:Multiple Myeloma Research Consortium (MMRC): Research Funding; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Fiala:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Lonial:Bristo-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Francis:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Siegel:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Speakers Bureau; Millennium: Speakers Bureau. Schramm:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Jakubowiak:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC, Research Funding; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Centocor Ortho-Biotech: Honoraria, Speakers Bureau; Exelixis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Harvey:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Reece:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Facet: Research Funding; Otsuka: Honoraria, Research Funding. Gul:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Jagannath:Celgene: Honoraria; Millenium: Honoraria; Orthobiotec: Honoraria; Onyx Pharma: Honoraria; Merck: Honoraria; Proteolix: Honoraria; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. La:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Hofmeister:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Jansak:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Stewart:Millennium: Consultancy; Celgene: Honoraria; Multiple Myeloma Research Consortium: Member Institution of the MMRC. Hagerty:Mayo Clinic: Employment; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Wolf:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Speakers Bureau; Millennium: Speakers Bureau; Novartis: Speakers Bureau; Orthobiotech: Speakers Bureau. Davis:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Krishnan:Celgene: Speakers Bureau; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Duarte:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Zimmerman:Millennium, Celgene: Speakers Bureau. Cisneros:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding; Bayer: Research Funding; Multiple Myeloma Research Consortium: Member Institution of the MMRC. Birgin:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Ott:Multiple Myeloma Research Consortium (MMRC): Employment. Tasca:Multiple Myeloma Research Consortium (MMRC): Employment. Kelley:Multiple Myeloma Research Consortium (MMRC): Employment. Anderson:Millennium: Consultancy; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; Bristol-Myers Squibb: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Giusti:Multiple Myeloma Research Consortium (MMRC): Employment.

Abstract Abstract 2965 Background: Alkylating agents have been the mainstay of multiple myeloma (MM) therapy for decades and despite introduction of several new therapies, it continues to play a significant role in its management as part of various drug combinations. While melphalan has been the most commonly used alkylator in MM, recent studies have suggested significant activity for bendamustine, a bifunctional alkylator. The combination of lenalidomide and melphalan has been associated with high response rates in relapse and newly diagnosed MM. Based on these promising results we designed a trial to evaluate the maximally tolerated dose of lenalidomide and bendamustine when used in combination as well as the efficacy of the combination in relapsed disease. Patients and Methods: Patients with relapsed MM and measurable disease were enrolled on this phase 1/2 trial provided they had not more than 4 prior lines of therapy for MM, had adequate performance status and organ and hematological function. Patients refractory to lenalidomide were allowed to enroll. The primary objectives were to (i) to determine the MTD of bendamustine and lenalidomide in combination with dexamethasone in subjects with relapsed MM (phase 1) and (ii) to evaluate the confirmed response rate of bendamustine in combination with lenalidomide and dexamethasone in patients with relapsed MM (phase 2). Bendamustine (B) was administered on days 1 and 2 of a 28-day cycle at doses of 50–100 mg/m2. Lenalidomide (R) was given days 1–21 at doses of 15–25 mg daily. Dexamethasone (D) was administered at 40 mg weekly. Dose escalation was done using a 3+3 design and MTD was defined as one dose level below that resulted in >=2 DLTS among 6 patients. The primary end point for this trial was the proportion of patients with confirmed hematologic response (sCR, CR, VGPR, or PR) over the first 6 cycles of treatment. Results: A total of 72 patients were accrued to this study from March 2010 to May 2012: 21 patients in phase 1 and 51 in phase 2. The 6 patients from the MTD dose level of phase 1 were also included in phase 2. The median age of all 72 patients was 62.1 (range, 40–86) and 57% were male. Majority (75%) of patients had previously been exposed to lenalidomide and 69% had prior exposure to bortezomib. Median # of prior therapies was 3 (range, 1–5) and 74% of patients had a prior autologous stem cell transplant. Patients have received a median of 4 cycles (range, 1–25), with 27 patients still continuing on active treatment. Disease progression led to study discontinuation in 22 (49%) and adverse events were the reason for discontinuation in 14 (31%). In phase I, two DLTs (Grade (Gr) 2 neuropathy and Gr 4 neutropenia) were seen at the highest dose level (100 mg/m2 B, 25 mg R), and the MTD was determined as 75 mg/m2 of B given days 1 and 2 and 25 mg of R days 1–21, along with D 40 mg weekly. Overall patients, 12/21 (57%) had a PR or better. In phase 2, 17 (40%) confirmed responses (>=PR) were seen among the 43 patients evaluable for response (received at least 6 cycles of treatment or have gone off study prior to 6 cycles); including 9 (21%) VGPR and 8 (19%) PR. An additional 5 patients had a minor response. Over all dose levels, a gr 3 or higher adverse event at least possibly attributed to the study was seen in 75% of patients. The most common toxicities were all hematological (thrombocytopenia and leukopenia), and most common non-hematological toxicity was infection. Prolonged time to recovery of blood counts was seen in a few patients, but majority of patients were able to tolerate the regimen with adequate dose reductions. Conclusion: The recommended dose of the combination for further studies is bendamustine at 75 mg/m2 days 1 and 2, lenalidomide 25 mg daily on days 1–21 and dexamethasone days 1, 8, 15, 22; with cycles repeated every 28 days. The regimen is well tolerated with hematological toxicity being the most common and manageable with dose reductions. The regimen is effective with high response rates and durable responses seen. Updated results with response rates and time to event analyses will be available for the entire cohort at the time of meeting. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Krishnan:celgene: Consultancy, Speakers Bureau. Zimmerman:Celgene: Honoraria; Millennium: Honoraria; Novartis: Expert Testimony, Expert Testimony Other. Vij:Teva: Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Millennium: Speakers Bureau; Onyx: Honoraria, Research Funding.