ALBERT

Description: Abstract 352 Background: Autologous stem cell transplantation (ASCT) for MM leads to complete responses in ∼20–40% of patients but rare cures. Patients with rapid recovery of T cells post ASCT may have improved outcomes suggesting possible immune mediated tumor control. We have shown that adoptive T-cell transfers after ASCT for MM using vaccine-primed and ex-vivo costimulated autologous T-cells in combination with pre- and post-transplant immunizations using a tumor antigen vaccine (+ GM-CSF and montanide) led to vaccine-directed T-cell responses in about 1/3 of patients and enhanced recovery of polyclonal T and B cell counts and function. We hypothesized that addition of Poly-ICLC (Hiltonol®) – a TLR-3 agonistic vaccine adjuvant could increase tumor antigen vaccine responses through better priming and boosting. Methods: We report interim results of a Phase II clinical trial (NCT01245673) evaluating safety and activity of autologous T cells primed in-vivo with a MAGE-A3 multipeptide vaccine (Orphan Drug Designation: GL-0817) mixed with GM-CSF and Poly-ICLC (Hiltonol®) +/− montanide. Inclusion criteria included measurable disease or high-risk cytogenetics. MAGE-A3 is expressed in ∼50% MM cases and more frequently in relapsed/extramedullary/proliferative disease. The MAGE-A3 vaccine has 2 HLA-A2-restricted class I peptides and 1 promiscuous class II peptide linked to an HIV-1-TAT membrane translocation sequence (Trojan peptide) to enhance peptide presentation. Vaccine-primed T cells were collected by leukapheresis, costimulated and expanded ex-vivo using anti-CD3/anti-CD28 mAb conjugated beads. T-cells were infused at day +2 after ASCT followed by booster immunizations at days 14, 42, 90, 120 and 150 post-transplant. Lenalidomide maintenance was started at day +100. Patients were evaluated for MM responses in accordance with IMWG criteria at days 60, 100, 180 post-transplant and Q3 months thereafter. T-cell and B-cell responses to the vaccine were evaluated by IFN-g or IL-2 cytokine production (all patients), dextramer binding to CD8 cells (HLA-A2 positive patients) and ELISA antibody assays at days 14, 60, 100 and 180 post-transplant. Results: 25 patients were transplanted on study. At a median followup of 6 months (range 2–18 months), 24 patients are surviving while 1 patient relapsed at about day +60 and died. Four additional patients have relapsed at 7,9,18 and 18 months post-transplant, yielding a 1-year Kaplan-Meier EFS of 77%. Of the 16 patients evaluable for response at day 100, 7/16 (44%) had CR/nCR using the study enrollment (post-induction) myeloma markers as a baseline while at day 180, 7/13 (53%) had CR/nCR. T-cell infusions were well-tolerated with no probable/definite grade 3 or higher toxicities. Vaccinations were associated with 〉 50 mm injection site reactions (redness, induration or both) after 1 or more immunizations in the majority of patients. Two patients developed large and prolonged inflammatory reactions which evolved into sterile abscesses. These resolved over 2–3 months with conservative management but as a result montanide was eliminated from the vaccine formulation for patients 11–25. Thereafter vaccine reactogenicity was decreased with no additional sterile abscesses. Of 16 patients tested for immune responses to date, 2 patients were unevaluable due to poor sample viability. Dextramer staining demonstrated MAGE-A3-specific CD8 T-cells in 4/4 (100%) of evaluable HLA-A2+ patients. Cytokine production in response to MAGE-A3 stimulation was seen in 11/14 (79%) patients; responses usually peaked at day 100 or day 180. Robust MAGE-A3 antibody responses were detected in 7/9 patients who received montanide in the vaccine formulation but in 0/7 patients who did not. Conclusions: Combination immunotherapy using a MAGE-A3 multipeptide tumor antigen vaccine plus vaccine-primed and costimulated autologous T-cells after ASCT for MM is well-tolerated and associated with encouraging early clinical responses. The addition of Poly-ICLC (Hiltonol®) to the vaccine formulation was associated with a high frequency of post-ASCT T-cell functional responses. The combination of Poly-ICLC +GM-CSF + Montanide led to robust injection site reactions that were occasionally severe and prolonged. Elimination of the montanide reduced injection site reactogenicity but may also have compromised the B-cell responses to the tumor antigen vaccine. Disclosures: Rapoport: Gliknik, Inc: Research Funding. Stadtmauer:Celgene: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau. Vogl:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Research Funding; Otsuka: Consultancy; Acetylon: Research Funding. Strome:Gliknik, Inc: Equity Ownership, Patents & Royalties, Research Funding. Salazar:Oncovir, Inc: Employment. Levine:TxCell: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of Pennsylvania: financial interest due to intellectual property and patents in the field of cell and gene therapy. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight, financial interest due to intellectual property and patents in the field of cell and gene therapy. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight Patents & Royalties. June:Novartis: Research Funding, entitled to receive royalties from patents licensed to Novartis, entitled to receive royalties from patents licensed to Novartis Patents & Royalties.

Description: Abstract 3877 Poster Board III-813 Background Renal impairment affects 20% of newly diagnosed MM pts and over 50% during the course of their disease. Renal impairment confers shorter survival due to high tumor load and the difficulty in delivering adequate doses of active drugs, such as alkylating agents and immunomodulatory drugs (IMiDs) due to enhanced side effects (Kyle, Mayo Clin 2003). Pts with renal insufficiency have been traditionally excluded from clinical trials. Carfilzomib (CFZ) is a novel peptide epoxyketone proteasome inhibitor designed to have a high level of selectivity for the proteasome. In previous Phase 2 studies, CFZ has demonstrated single agent activity in heavily pretreated MM pts including those with mild renal insufficiency. The primary objective of this study was to evaluate the tolerability and pharmacokinetic properties of CFZ in MM pts with renal insufficiency, including those on dialysis. Methods In this multicenter study, MM pts who had relapsed after at least two prior therapies were enrolled into 4 cohorts based on renal impairment: normal (CrCl 〉 80mL/min), mild (CrCl 50–80 mL/min), moderate (CrCl 30–49 mL/min), and severe (CrCl 〈 30 mL/min) including dialysis pts. The primary and secondary objectives of the study included pharmacokinetics (PK), safety, pharmacodynamics (PDn; proteasome inhibition in blood) and efficacy endpoints: ORR (overall response rate, ≥ PR) CBR (clinical benefit response, ≥ MR), duration of response (DOR) and time to progression (TTP). Pts received CFZ at a dose of 15 mg/m2 IV on day (D) 1, 2, 8, 9, 15 and 16 every 28 d for cycle (C) 1, with dose escalation to 20 mg/m2 in C2 and 27 mg/m2 in C3 and thereafter if tolerated. Pts received 40 mg of dexamethasone (Dex) in cycle 3 if they had less than a partial response (PR). Pts were followed for toxicity and efficacy over the course of the study. EKG changes from baseline including QT/QTc effects were assessed in C1 and C2. PK was measured on C1 D1,15 and C2 D15 and PDn was measured on C1 D1,2,8 and C2 D1. Results Nineteen pts received at least 1 dose of CFZ and were evaluable for safety; 18 pts completed at least 1 C of CFZ and were evaluable for response and PK/PDn. All pts had refractory MM and 42% had progressed during their last therapy. The median number of prior therapies was 5 (range 2–10). All pts had received bortezomib and 26% were refractory; all pts received at lease one IMiD (90% thalidomide and 85% lenalidomide). Seventy percent had prior stem cell transplant. To date, pts have received a median of 3 cycles (range 1–7+) of CFZ; 9 pts have completed ≥ 6 cycles. The most common adverse events were fatigue, anemia, back pain and fever. There was no appreciable difference in the safety profile between the 4 cohorts either in frequency of events or in CTC-AE grade. Two deaths from disease progression with 1 complicated by a parainfluenza upper respiratory tract infection occurred while on study. No treatment emergent QT/QTc prolongations were observed during C1 and C2 in any group. Sixteen pts had grade 1 or 2 peripheral neuropathy at study entry and no cases of newly emergent or exacerbations occurred on study. Two pts discontinued drug due to worsening renal failure, one in the mild and one in the moderate cohort; both were related to disease progression. In all cohorts, CFZ was cleared with a t½ of 30–60 minutes and reached undetectable levels in plasma within 3 hours. There was no accumulation of CFZ after two cycles. Proteasome inhibition measured 1 hr post-dose in whole blood and PBMC ranged from 75–89% at doses of 15–20 mg/m2. PK and PDn were similar between the cohorts of pts with varying degrees of renal impairment. The ORR was 16.6% and CBR was 33.3%. Two BTZ-refractory pts achieved PR. An additional 38.9% had stable disease across all groups despite entering the study with progressive disease. Seven of 18 pts received Dex in ≥ C3 with 2 exhibiting an upgraded response (1 PR and 1 MR). Conclusions CFZ can be administered to MM pts with substantial renal dysfunction and does not require dose adjustment. CFZ toxicities in this study were manageable and importantly, exacerbation of pre-existing PN or myelosuppression was not observed in these renally impaired MM patients. Responses in relapsed and refractory MM pts with renal insufficiency are encouraging. Further evaluation of CFZ in renally impaired patients is ongoing, including in patients receiving hemodialysis. Disclosures: Vij: Proteolix, Inc.: Consultancy, Research Funding. Zonder:Celgene: Speakers Bureau; Pfizer: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen: Consultancy; Millennium: Research Funding. Woo:Proteolix, Inc.: Employment. Wang:Proteolix, Inc.: Employment. Lee:Proteolix, Inc.: Employment. Wong:Proteolix, Inc.: Employment. Niesvizky:Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Seattle Genetics, Inc: Research Funding; Proteolix: Research Funding, data monitoring committee.

Description: The incidence of MM in African-Americans is more than double that in Caucasians. Historically AAs have had a higher mortality rate than Caucasians; but over the past 10 yrs, the age-adjusted mortality rate has been on the decline for AAs while it has been stable for Caucasians as a result of ASCT and novel agents. Previous studies (n=74 AA patients) suggested that response to ASCT is similar, if not better, for AA patients (Verma et al 2008, Saraf et al 2006). We retrospectively analyzed the clinical presentation of a large cohort of AA patients (n=103) who underwent ASCT at our center between 1998 and 2008 and compared their outcome to that of Caucasians patients (n=183) transplanted in the same time period. AA patients were significantly younger than Caucasian patients at diagnosis with median age 53 (range: 32–75) vs 59 (range: 27–80), respectively (p 3.5 mg/L and 〉 5.5 mg/L, respectively. Initial cytogenetic data were not available for the majority of patients. Median time from diagnosis to ASCT was significantly longer for AA than for Caucasian patients at 0.8 yrs (range: 0.23–9.2) vs 0.5 yrs (range: 0.1– 7.0), respectively (p

Description: INTRODUCTION: Lenalidomide (REVLIMID®; CC-5013) is a novel, orally active immunomodulatory drug under investigation for the treatment of multiple myeloma (MM). Phase 1 dose-escalation studies in patients (pts) with relapsed and refractory MM determined that the maximum tolerated dose (MTD) of lenalidomide was 25 mg/day, based upon myelosuppression encountered beyond 28 days, which was manageable with growth factor support and dose reduction. In a multicenter phase 2 study to determine optimal dose and schedule, 102 pts with relapsed or refractory MM were randomized to receive lenalidomide at either 15 mg bid (n=34) or 30 mg qd (n=68), for 21 days every 4 wks. Both treatment arms showed significant activity with manageable toxicity. An increased incidence of cytopenia was noted in the 15-mg bid group and thus the 30 mg qd schedule was taken forward. METHODS: The objective of this multicenter, phase 2, open-label study (CC-5013-MM-014) was to further evaluate the effectiveness and safety of single-agent lenalidomide administered at a dose of 30 mg qd for 21 days every 28 days (28-day cycle) in pts with relapsed and refractory MM. Eligible patients included those who had received prior thalidomide, bortezomib, or SCT. RESULTS: 222 pts were enrolled into the study. All patients had received at least 2 prior anti-myeloma treatments, including bortezomib (41%), thalidomide (80%), and SCT (44%). Table 1 shows Best Response data, excluding patients in whom responses were not evaluable (n=10). Partial response or better occurred in 25% of patients and SD or better in 71%. Time to Progression was a median of 22.4 wks (range 1.8– 66 wks). The median survival has not been reached (the lower bound of the 95% CI exceeds 15 months). The most common treatment-related AEs (those reported in ≥10% of patients overall) included upper respiratory tract infection, neutropenia and thrombocytopenia. AEs that most frequently led to dose reduction or interruption by percentage of cases were neutropenia (40%), thrombocytopenia (23%), fatigue (5%), and anemia (5%). CONCLUSION: Oral lenalidomide in relapsed and refractory MM patients achieved PR+CR in 25%, stable disease or better in 71%, a median TTP of approximately 6 months and a median survival that has not been reached. Toxicity has been manageable with a very low incidence of DVT and minimal treatment-emergent neuropathy. Table 1. Best Response Best Response* n (%) *Excluding patients not evaluable (n=10); CR=complete response and PR=partial response (EBMT criteria) ≥PR (CR + PR) 53 (25) Stable disease 152 (71)

Description: Background Renal impairment (RI) is a major complication of MM. The oral PI ixazomib is currently under phase 3 investigation in MM. PK data from pts with mild or moderate RI (creatinine clearance [CrCl] ≥30 mL/min) suggest no ixazomib dose modification is needed in these pts (Gupta et al BJCP 2015). Hence, this study (NCT01830816) aimed to characterize the PK of ixazomib in pts with severe RI or ESRD requiring hemodialysis to provide posology recommendations in these pt populations. Methods Pts with RRMM or advanced malignant solid tumors were enrolled in the normal (N, CrCl ≥90 mL/min), severe (S, CrCl

Description: Background: P is used in combination with G-CSF to improve the mobilization of peripheral blood hematopoietic stem cells in poor mobilizers. Limited data are available in regard to effects of P on post-transplant outcomes in comparison with non-P chemomobilized patients. Methods: In this retrospective study, we compare the engraftment and the outcomes of 34 patients mobilized with P + G-CSF or just-in-time rescue P in combination with chemotherapy and G-CSF to 143 patients (control group) mobilized with G-CSF with or without chemotherapy in lymphoma and myeloma patients who underwent ASCT between February 2012 and April 2014 at the University of Maryland Greenebaum Cancer Center. Post-transplantation outcomes including infections, hematologic recovery, relapse, progression and survival were recorded. Results: The median number of collected of CD34+ cells/Kg was 5.9 x 10(6) in the P group and 12.3 x 10(6) in the control group (p=0.0002). Median time to neutrophil engraftment (〉0.5 × 10(9) /L) was comparable between the 2 groups: 12 days for the P group and 11 for the control group (p=0.28). There was a trend toward a shorter time to platelet engraftment (〉20 × 10(9) /L) in the control (12 days) compared to the P group (14 days) (p=0.056). Progression-free survival at 1 year after (ASCT) was 88.2% in the P group and 81.8% in the control group. There was no difference in the overall survival of both groups (p=0.62) Conclusions: Short and long-term engraftment and outcomes after ASCT seem to be comparable in lymphoma and myeloma patients receiving plerixafor compared to chemomobilized patients without plerixafor. This observation support the use of plerixafor + G-CSF or just-in-time rescue P in patients who mobilize poorly without P. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Background: The incidence of MM is 2 to 3 fold higher in blacks than in whites; they present at a younger age and have better overall survival. The biological bases for these disparities remain unclear. Outcome of MM is linked to cytogenetic and molecular changes, both primary (hyperdiploidy and heavy chain (IgH) translocations) and secondary (rearrangements of MYC, activating mutations of NRAS, KRAS or BRAF, and deletions of 17p). Methods: Cytogenomic alterations in consecutive MM patients were assessed using integration of metaphase chromosome analysis by GTG-banding and interphase fluorescence in situ hybridization (iFISH) in CD138-positive cells isolated from fresh BM samples using a protocol of magnetic-activated cell sorting. Changes evaluated included monosomy 13/del(13q), monosomy 17/del(17p), gain of 1q21, and rearrangements of the IGH gene including t(4;14), t(11;14) and t(14;16). Results: Samples from 218 consecutive MM patients were analyzed (Table 1). 108 were from black and 110 were from white patients. Median age for blacks was 59 years (range: 36 - 82) and for whites, 63 years (range: 39 - 83) (p=0.008). Fewer black men than whites were observed (46.3% versus 64.6%, p=0.007). Overall, blacks had fewer abnormal karyotypes compared to whites (18.1% versus 31.8%; p=0.02). Black patients had a lower frequency of non-hyperdiploid karyotypes (8.5% versus 20.6%; p=0.01) and had a trend toward lower frequencies of rearrangements of IGH (30.8% versus 43.5%; p=0.055) than white patients. Most notably, they had significantly lower frequencies of monosomy 17/del(17p) (5.6% versus 18.5%; p=0.003) and monosomy 13/del(13q) (28.9% versus 46.3%; p=0.008). After stratification by age (Figure 1), younger patients showed significantly higher frequencies of the monosomy 17/del(17p) abnormality (p=0.001) and the t(4;14) (p=0.04) than older patients, with the difference more significant in white patients. The associations among molecular cytogenetic abnormalities (Figure 2) showed a different association pattern for black and white patients. White patients with t(11;14) were more likely to have monosomy 13/del(13q) (p=0.003) and gain of 1q21 (p=0.02), while this association was not observed in black patients. Conclusion: Black MM patients had significantly different cytogenetic profiles detected by iFISH on CD-138 selected malignant cells, compared to whites. Black MM patients had a more favorable profile, including lower frequencies of non-hyperdiploid karyotype and of IGH rearrangements. This study supports a biological basis for previously described outcome disparities between black and white patients with MM. Further studies will focus on identifying specific molecular targets and their impact on therapy and on overall outcome. Table 1. Demographics and cytogenetic abnormalities of the MM patients Demographics Black White P-value# Total, n 108 110 Gender, n (%) =0.007* Male 50 (46.30%) 71 (64.55%) Female 58 (53.70%) 39 (35.45%) Age (median) 59 63 =0.008* Chromosome (karyotype) =0.022* Normal 86 (81.90%) 73 (68.22%) Abnormal 19 (18.10%) 34 (31.78%) Hyperdiploidy 8 (7.6%) 8 (7.4%) Non-hyperdiploidy 9 (8.5%) 22 (20.6%) =0.013* 11;14 translocation 2 (1.9%) 4 (3.7%) FISH abnormality -13/del(13q) 31 (28.97%) 50 (46.30%) =0.008* Gain of 1q21 35 (32.71%) 47 (43.52%) =0.103 -17/del(17p) 6 (5.61%) 20 (18.52%) =0.003* IGH rearrangements 33 (30.84%) 47 (43.52%) =0.055^ t(4;14) 7 (6.54%) 13 (12.38%) =0.146 t(11;14) 15 (20.55%) 15 (19.48%) =0.870 t(14;16) 2 (3.85%) 6 (10.71%) =0.175 others 16 (14.95%) 15 (13.89%) =0.824 *means statistical significant (p-value 〈 0.05), where ^ means marginal significant (0.05 〈 p-value 〈 0.10). #p-values come from the Cochran-Mantel-Haenszel tests for categorical variables, and t tests for continuous variables. Associations among eight molecular cytogenetic abnormalities. Each solid black line indicates one abnormality is statistically significantly associated with another abnormality. Figure 1. Distributions of cytogenetic abnormalities by age and race Figure 1. Distributions of cytogenetic abnormalities by age and race Figure 2. Relationship of various cytogenetic abnormalities in the MM patients Figure 2. Relationship of various cytogenetic abnormalities in the MM patients Disclosures No relevant conflicts of interest to declare.

Description: Introduction: MRZ is a novel, irreversible, proteasome inhibitor (PI) under clinical development for the treatment of relapsed and refractory multiple myeloma (RRMM). MRZ potently inhibits the 3 proteolytic activities of the 20S proteasome with specificity and activity distinct from that of bortezomib (BZ) and carfilzomib (CFZ). The combination of MRZ and POM has demonstrated promising synergy in in vitro and in vivo models of MM. Methods: As of July 22, 2015, 22 of 36 planned patients (pts) were enrolled with 14 pts in the 3+3 dose-escalation stage and 8 pts into the Recommended Phase 2 Dose (RP2D) stage. All pts received ≥2 prior therapies that must have included both lenalidomide (LEN) and BZ, and have been refractory to their last therapy. Intravenous MRZ (0.3 to 0.5 mg/m2) was administered over 120 minutes on Days (D) 1, 4, 8, and 11; POM (3 or 4 mg) once daily on D1 through 21; and Lo-DEX (5 or 10 mg) once daily on D1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, and 23 of every 28-D cycle. Safety, pharmacokinetics (PK), cytogenetics, proteasome inhibition, and clinical response were assessed. Results: Pts were 68% male, median (range) age 62 yrs (31 - 76), and with a median of 5 (2 - 15) prior lines of therapy. All pts received prior BZ and LEN; 41% and 55% had also received prior CFZ and thalidomide (THAL), respectively. There were no DLTs during dose-escalation and the most common (〉10% incidence) adverse events (AEs) related to any study treatment in the 22 pts included fatigue (41%), neutropenia (41%), anemia (27%), thrombocytopenia (23%), nausea (18%), diarrhea, dyspnea, insomnia, edema peripheral, and white blood cell count decreased (14%). The grade 3 AEs related to any study treatment in more than one pt included neutropenia (27%) and anemia (9%), pneumonia (9%), and thrombocytopenia (9%). The only grade 4 AE related to any study treatment was neutropenia in one pt. Tumor lysis syndrome (grade 2) related to study treatment was observed in 1 pt; 2 pts had grade 1 peripheral neuropathy (1 considered related to POM alone and 1 related to possibly MRZ and POM); 2 pts came off study and subsequently died from progressive disease (61 and 102 days after last dose); and 1 pt died suddenly during Cycle 1 due to cardiopulmonary arrest, considered possibly related to POM. Since no DLTs were observed the maximum tolerated dose was not exceeded, the highest dose cohort studied, MRZ 0.5 mg/m2, POM 4 mg, and Lo-DEX 10 mg, was determined to be the RP2D. All 17 pts with pre and post dose measurements demonstrated a rapid decrease in their myeloma proteins by C2D1. Preliminary IMWG response assessments provided for the 14 pts with response data through C3D1 included 9 (64%) with partial response (PR); 2 (14%) with minimal response (MR); and 3 (21%) with stable disease (SD). The overall response rate (PR) was 64% and the clinical benefit rate (MR + PR) was 79%. Subset analyses of these 14 pts included high risk cytogenetics (17p deletion and/or 4:14 chromosome translocation) and prior CFZ treatment. In the high risk cytogenetics there were 4/5 PRs and 1/5 MR. Of the 7 pts with prior CFZ treatment there were 5 with PR and 2 with SD, and all 4 pts who had CFZ in their last regimen achieved PR. There was ~100% inhibition of the chymotrypsin-like subunit as early as C1D11, with robust inhibition of the trypsin-like and caspase-like subunits evolving over time in whole blood assays. MRZ, POM, and Lo-DEX PK are in process and will be presented. Conclusions: MRZ in combination with POM and Lo-DEX was generally well tolerated and demonstrated promising activity in heavily pre-treated pts with RRMM including those with high risk cytogenetics and who were refractory to prior treatment with CFZ. The trial will enroll up to 22 pts at the RP2D (36 pts total) to provide additional safety and efficacy data. Disclosures Off Label Use: marizomib for relapsed multiple myeloma. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Zonder:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support. Harrison:Celgene: Honoraria, Research Funding. Khot:Amgen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Janssen: Honoraria. Chauhan:Triphase: Consultancy. Anderson:Celgene: Consultancy; Millennium: Consultancy; BMS: Consultancy; Gilead: Consultancy; Oncopep: Equity Ownership; Acetylon: Equity Ownership. Reich:Triphase Accelerator Corporation: Consultancy. Trikha:Triphase Accelerator Corporation: Employment. Richardson:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background: Treatment of multiple myeloma has evolved considerably in the past few years with availability of several news drugs as well as increasing use of multidrug combinations. These changes have no doubt led to the improved survival seen among patients with MM. We have previously shown that outcomes of patients intolerant or refractory to one of the IMiDs and bortezomib had a poor outcome. Since that time, other drugs of the same class as well as new classes of drugs have been introduced for the treatment of MM. We designed this retrospective study to estimate the outcomes in patients with relapsed myeloma, who have become refractory to the current generation IMiDs and proteasome inhibitors. Patients and Methods: Patients with relapsed multiple myeloma who have received at least 3 prior lines of therapy, is refractory to both an IMiD (lenalidomide or pomalidomide) AND a proteasome inhibitor (bortezomib or carfilzomib), and has been exposed to an alkylating agent were identified from multiple centers. The time patients met the above criteria was defined as T0, and details of all treatment regimens before and after T0 were collected using electronic CRFs. The study was approved by the IRB at the respective centers. Results: 543 patients were enrolled in this study; median age was 62 years (31-87) and 61% were males. Patients were enrolled from centers in North America (n=181), Europe (n=318), and Asia Pacific (n=44). Patients were diagnosed between 2006 and 2014, the median duration between diagnosis of myeloma and study entry (T0) was 3.1 years (0.3 to 9). The median (95% CI) estimated follow up from diagnosis and from T0 were 61 (57, 66) months and 13 (11, 15) months respectively. The median number of lines of therapy prior to T0 was 4 (3-13), 48% had a prior transplant. The median OS from T0 for the entire cohort was 13 (11, 15) months. For these 462 patients, the median number of recorded regimens was 2 (1-9). The overall response and the depth of response to each line of treatment following T0 are as shown in the table. The median (95% CI) PFS and OS from T0 was 5 (4, 6), and 15.2 (13, 17), respectively. The overall survival for the 81 patients with no treatment post T0 was only 2.1 months. In a multivariate analysis, duration from diagnosis to T0, ISS stage III and number of lines of therapy were all associated with inferior PFS, as well as OS, and in addition, serum creatinine〉2 mg/dL at T0 also predicted inferior OS. Conclusions: The study provides the expected outcome following development of myeloma that is refractory to a PI and an IMiD. The outcomes of these patients appear to be better than we had seen historically in patients refractory/ intolerant to bortezomib and IMiDs, highlighting the increased treatment options available for these patients. However, there is decreasing response rate to sequential regimens highlighting the development of drug resistance. The data provides a bench mark for comparison of new therapies that are being evaluated in this disease. Table Table. Disclosures Dimopoulos: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kastritis:Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria. Hillengass:Sanofi: Research Funding; Novartis: Research Funding; Amgen: Consultancy, Honoraria; BMS: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Leleu:TEVA: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; LeoPharma: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Pierre Fabre: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Honoraria. Oriol:Janssen: Honoraria, Other: Expert board committee; Amgen: Honoraria, Other: Expert board committee. Cavo:Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vij:Shire: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy; Karyopharma: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding. Lokhorst:Genmab: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. van de Donk:Amgen: Research Funding; Janssen: Research Funding; BMS: Research Funding; Celgene: Research Funding. Mark:Onyx: Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ludwig:Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; BMS: Speakers Bureau; Janssen: Speakers Bureau. Jagannath:Novartis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Merck: Consultancy. Usmani:Array: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Dytfeld:Janssen Poland: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Moreau:Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau. Lee:Amgen: Membership on an entity's Board of Directors or advisory committees. Shustik:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. de la Rubia:Celgene: Consultancy; Bristol Myers: Consultancy; Amgen,: Consultancy; Janssen: Consultancy. Durie:Takeda: Consultancy; Amgen: Consultancy; Janssen: Consultancy.