ALBERT

Description: A distinct feature of multiple myeloma (MM) is the tight interaction between malignant plasma cells and their bone microenvironment, creating a niche suitable for MM growth. In particular, MM cells inhibit osteoblast (OB) differentiation and stimulate osteoclast (OC) function, resulting in imbalanced bone remodeling and osteolytic bone disease. Here we studied a novel cytokine, activin A, identified from a broad range of cytokines, in the development of MM bone disease. We next asked whether activin A inhibition could restore bone balance and suppress tumor growth. Activin, a member of the TNF-α superfamily, is a pleiotropic cytokine involved in bone remodeling. Here, we observed, that MM patients with multiple osteolytic lesions had a 4-fold increase in activin A expression levels in bone marrow plasma compared to MM patients with one or less osteolytic lesions and non-MM patients (average 123.6 ± 136 vs 26.4 ± 21.4 vs 30.6 ± 25.1 pg/ml respectively, p

Description: Background: Bortezomib (VELCADE®, Vel) and lenalidomide (Revlimid®, Rev) are both highly effective agents in multiple myeloma (MM). Preclinical studies show Rev sensitizes MM cells to Vel and dexamethasone (Dex), suggesting combination therapy may enhance clinical activity. This phase 1 dose-escalation study aimed to determine MTD and activity of Rev-Vel +/− Dex combination therapy in patients (pts) with relapsed and/or refractory MM. Methods: Eight cohorts (≥3 pts each) were planned, with dosing of Vel 1.0 or 1.3mg/m2 (d 1, 4, 8, 11) and Rev 5, 10, 15, or 20mg (d 1–14), in 21-d cycles. Dex 40mg (on day of and day after each Vel dose) could be added in pts with PD. NCI CTCAE v3.0 was used for toxicity assessment; DLT was defined as any grade (G) ≥3 non-hematologic toxicity, G4 neutropenia for ≥5 d and/or neutropenic fever, or platelets 1 occasion despite transfusion. Response was assessed by modified EBMT criteria. Results: 28 pts were enrolled in cohorts 1–6 (Rev 5–15mg, Vel 1.0–1.3mg/m2) plus 10 additional pts at the MTD (Dose Level 5), including 12 with relapsed and 26 with relapsed and refractory MM (n=38). Among 25 men and 13 women, median age was 60yrs (range: 37–79), and median no. of prior therapies was 5 (range: 1–13), including 23 pts with prior SCT, 23 with prior Vel, 6 with prior Rev, and 36 with prior thalidomide (Thal). One DLT was observed in cohort 4 (Rev 10mg–Vel 1.3mg/m2; transient G3 hyponatremia). DLT was reached in cohort 6 (Rev 15mg–Vel 1.3mg/m2) with 1 episode of G3 HZV reactivation (successfully treated with acyclovir) and 1 G4 neutropenia (reversed with GCSF support and dose reduction). MTD was therefore declared at Rev 15mg–Vel 1.0mg/m2. In total, 5 pts had dose reductions for Vel, 6 pts for Rev, and 5 pts for both Rev and Vel. No significant (G≥3) fatigue or peripheral neuropathy has been seen. No anticoagulant prophylaxis was required and only 1 pt had DVT while on Rev alone. In 36 evaluable pts, the overall response rate (CR+PR+MR) is 58% (90% CI: 46%, 75%), including 6% CR/nCR (Table) after a median of 6 cycles (range: 4–17). Responses were durable (median 6 months, range: 1–26), and 11 pts remain on therapy beyond 1 year. Dex has been added in 14 pts with PD, resulting in PR/MR/SD in 10 (71%), with just 1 pt experiencing Dex-related G2 diarrhea and fatigue, which prompted discontinuation of therapy. Conclusions: Rev-Vel +/− Dex is well tolerated and very active with durable responses seen in pts with heavily pretreated relapsed and/or refractory MM, including pts who have had prior Rev, Vel, Thal and SCT. An MTD of Rev 15mg–Vel 1.0mg/m2 has been defined, with Phase 2 studies now ongoing in both newly diagnosed and relapsed/refractory MM. Best responses by Rev-Vel cohort (EBMT criteria) Cohort Rev-Vel dose Vel 1.0mg/m2 Vel 1.3mg/m2 1–2 Rev 5mg 2PR, 1MR 1CR, 2PR 3–4 Rev 10mg 1nCR, 2PR 2PR, 2MR, 1SD, 1PD 5–6 Rev 15mg 2PR, 4MR, 7SD, 1PD 2 PR, 5SD

Description: E1496 is a phase III trial designed to evaluate the ability of 2 years (yr) of maintenance rituximab (MR) to prolong progression-free survival (PFS) after CVP (cyclophosphamide 1 G/m2 day [d] 1, vincristine 1.4 mg/m2 [max = 2 mg] d 1, prednisone 100 mg/m2 d 1–5) chemotherapy in stage III–IV follicular grade 1 and 2 and small lymphocytic lymphoma. After CVP treatment to maximum response, (6–8 cycles), stable and responding patients (pt) were randomized to MR (375 mg/m2 weekly x 4) every 6 months x 4 or observation (OBS). Stratification factors included histology, response and residual disease after CVP. With 3-yr median follow-up, survivals (from time of randomization, one-sided logrank p values) for all pt (n=304) favored MR for PFS (p = 3 x 10–8; hazard rate {HR} = 0.38 [0.28;0.54, 95% confidence intervals]) and OS (p = 0.09; HR = 0.66 [0.36–1.22]). Because the large majority of pt have FL and because rituximab efficacy is notably greater in FL, we focused in this report on the 237 FL pt. Median age was 58 yr, 65% were stage IV, 64% had marrow disease, 64% had high tumor burden and 37% had high-risk disease by the follicular lymphoma prognostic index. PFS after randomization was significantly longer for MR vs OBS (p = 3 x 10-7; HR = 0.39 [0.27;0.57]). The estimated PFS at 4 yr (~4.5 yr after start of treatment) was 56% for MR vs 33% for OBS. Differences in PFS were significant within the predefined strata and the differences were most significant in favor of MR for pt with high initial tumor burden and minimal residual disease after CVP. Overall survival was superior for MR (p = 0.03; HR = 0.51 [0.25;1.04]. Estimated OS at 4 yr (~4.5 years after start of treatment) was 88% for MR vs 72% for OBS. Of 33 deaths, 21 occurred on the OBS arm. These data demonstrate that maintenance rituximab not only significantly delays disease progression in FL compared with OBS but that a substantial proportion of patients treated with MR remain disease-free at 4 years after the completion of CVP. These are the first data to strongly suggest a survival benefit with a therapy that includes rituximab and CVP and the first to strongly suggest a survival benefit with maintenance rituximab in FL.

Description: This multicenter, open-label, randomized phase 2 study evaluated 2 dose regimens of lenalidomide for relapsed, refractory myeloma. Seventy patients were randomized to receive either 30 mg once-daily or 15 mg twice-daily oral lenalidomide for 21 days of every 28-day cycle. Patients with progressive or stable disease after 2 cycles received dexamethasone. Analysis of the first 70 patients showed increased grade 3/4 myelo-suppression in patients receiving 15 mg twice daily (41% versus 13%, P = .03). An additional 32 patients received 30 mg once daily. Responses were evaluated according to European Group for Blood and Marrow Transplantation (EBMT) criteria. Overall response rate (complete, partial, or minor) to lenalidomide alone was 25% (24% for once-daily and 29% for twice-daily lenalidomide). Median overall survival in 30-mg once-daily and twice-daily groups was 28 and 27 months, respectively. Median progression-free survival was 7.7 months on once-daily versus 3.9 months on twice-daily lenalidomide (P = .2). Dexamethasone was added in 68 patients and 29% responded. Time to first occurrence of clinically significant grade 3/4 myelosuppression was shorter in the twice-daily group (1.8 vs 5.5 months, P = .05). Significant peripheral neuropathy and deep vein thrombosis each occurred in only 3%. Lenalidomide is active and well tolerated in relapsed, refractory myeloma, with the 30-mg once-daily regimen providing the basis for future studies as monotherapy and with dexamethasone.

Description: Background: Outcome of patients with immunocompetent primary central nervous system lymphoma (PCNSL) has improved since the introduction of high-dose (HD) methotrexate (MTX). However, treatment may be perturbed by considerable toxicity. Acute toxicity comprises hematologic, renal, hepatic, pulmonary events and mucositis while neurologic impairment is essentially restricted to long-term survivors. MTX acts via inhibition of 5,10-methylentetrahydrofolate reductase (MTHFR) as well as thymidylate synthase (TYMS) in target cells what eventually results in decreased DNA synthesis. Intracellular uptake of folates is mediated by the reduced folate carrier (RFC). Two common MTHFR single nucleotide polymorphisms (SNPs) affect enzyme activity: 677 C→T and 1298A→C. A 28 base pair (bp) tandemly repeated sequence in the TYMS enhancer region (5′-UTR) containing either 2 or 3 repeats alters enzyme activity as does a 6 bp deletion (del) polymorphism in the 3′-UTR of TYMS. An RFC SNP (80G→A) is known to influence folate and MTX transport. We hypothesized that these polymorphisms may be directly linked to toxicity in PCNSL patients receiving high-dose MTX. Patients and methods: Genomic DNA was prospectively collected from patients (pts) with immunocompetent PCNSL who received HD MTX 4 g/m² every 2 weeks after enrolment onto a German multicenter trial. They had to have histological confirmation of their disease as well as adequate organ and bone marrow function. Genotyping of the two MTHFR and the RFC SNPs was performed by melting point analysis using the Light Cycler® technology. Genotyping of the TYMS 28bp polymorphism was performed by conventional PCR followed by agarose gel electrophoresis. The TYMS 6bp del polymorphism was analyzed by PCR, restriction enzyme digest and agarose gel electrophoresis. Hematologic (Hb, WBC, ANC, platelets) and non-hematologic toxicity (renal, hepatic, pulmonary, mucositis) were assessed prospectively and correlated with polymorphisms with respect to presumable functional relevance. Results: 123 pts with a median age of 62 (range, 27 – 80) years received a total of 506 cycles of high-dose MTX. 39 of 119 evaluable pts (33%) experienced any severe (°3/4) toxicity. Incidence of severe toxicity was significantly different for pts with MTHFR 677 TT (95%) when compared to CC/CT genotype (48%; p=.0024). Not considering hematologic parameters, severe toxicity was even more strongly associated with homozygosity for 677TT (p=.0006). A moderate association with lower ANC was found for MTHFR C677T (p=.049) while °3/4 neutropenia was strongly associated with RFC 80 GG vs. AA/GA (p=.0057). In hand, lower WBC nadirs occurred in pts with RFC 80 GG vs. AA/GA (p=.035). Conclusion: We demonstrate for the first time that pharmacogenetic studies might identify PCNSL pts who are at risk for severe acute hematologic and non-hematologic toxicity when treated with HD MTX. Correlation of (late) neurotoxicity with polymorphisms of folate metabolizing genes, however, will require longer follow-up.

Description: Abstract 2727 Poster Board II-703 INTRODUCTION: This study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with relapsed/refractory Waldenstrom's Macroglobulinemia (WM). METHODS: Patients who had at least one previous therapy were eligible. All patients received bortezomib IV weekly at 1.6 mg/m2 on days 1, 8, 15, q 28 days x 6 cycles, and rituximab 375 mg/m2 weekly on cycles 1 and 4. Primary endpoint was the percent of patients with at least a minor response. RESULTS: Thirty-seven patients were treated. Majority of patients (78%) completed treatment per protocol. At least minimal response (MR) or better was observed in 81% (95% CI: [65,92]) with 2 patients (5%) in complete remission (CR)/near CR, 17 (46%) in partial response (PR), and 11(30%) in MR. The median time to progression was 16.4 months (95% CI, 11.4–21.1). Death occurred in 1 patient due to viral pneumonia. The most common grade 3 and 4 therapy related adverse events included reversible neutropenia in 16%, anemia in 11%, and thrombocytopenia in 14%. Grade-3 peripheral neuropathy occurred in only 2 patients (5%). The median event-free survival (EFS) is 12 months (95% CI, 11–20) with estimated 12 month and 18 month EFS of 49% (95% CI: [31, 67%]) and 38% (95% CI: [20, 56%]). The median overall survival has not been reached. CONCLUSIONS: The combination of weekly bortezomib and rituximab showed significant activity and minimal neurological toxicity in patients with relapsed WM. Disclosures: Ghobrial: Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Anderson:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Richardson:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Treon:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Honoraria, Research Funding, Speakers Bureau. Matous:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees.

Description: Donor lymphocyte infusions (DLIs) induce effective graft-versus-tumor responses in patients with multiple myeloma who relapse after allogeneic hematopoietic stem-cell transplantation. The graft-versus-myeloma response is presumably mediated primarily by donor T cells, but recent studies have also demonstrated the presence of antibodies specific for a variety of myeloma-associated antigens in patients who achieve complete remission after DLI. One of the B-cell antigens identified in these studies was B-cell maturation antigen (BCMA), a transmembrane receptor of the tumor necrosis factor (TNF) superfamily that is selectively expressed by mature B cells. The present studies were undertaken to characterize the functional significance of antibodies to BCMA in vivo. Using transfected cells expressing BCMA, antibodies in patient serum were found to react with the cell-surface domain of BCMA. Post-DLI patient serum was able to induce complement-mediated lysis and antibody-dependent cellular cytotoxicity (ADCC) of transfected cells and primary myeloma cells expressing BCMA. BCMA antibodies were only found in post-DLI responders and not in other allogeneic transplant patients or healthy donors. These results demonstrate that BCMA is a target of donor B-cell immunity in patients with myeloma who respond to DLI. Antibody responses to cell-surface BCMA may contribute directly to tumor rejection in vivo.

Description: Background: As MCL has a continuous relapse pattern with current treatments, we designed a study to determine the safety and efficacy of the anti-CD20 radio-immunoconjugate,90Y-ibritumomab tiuxetan (90Y-RIT), following 4 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) induction. Methods: Patients (pt) with untreated stage II-IV MCL (CD20+, cyclin D1+) ≥18 yr with measurable/evaluable disease and adequate organ function were eligible. At 4–8 weeks after 4 cycles of R-CHOP, responding (CR/PR) and stable pt received 0.4 mCi/kg 90Y-RIT. The primary endpoint was failure-free survival (FFS) and secondary objectives were evaluation of response and toxicity after R-CHOP and after 90Y-RIT. The study design required 52 eligible pt to demonstrate a prolongation of FFS by 50% compared with R-CHOP alone (median FFS 16 mo, Howard et al., JCO20:1288, 2002). Results: The characteristics of 56 eligible pt are: 73% male, median age 61 (33–83) yrs, 91% stage III/IV, 68% 〉1 extranodal site, 78% marrow-positive. IPI was 0–2 in 51%, 3–5 in 49%. Fifty-one (91%) pt received all treatment and best response (n=50) was 42% CR/CRu, 32% PR, 12% stable and 4% unevaluable, with an improvement in response in 16 pt after 90Y-RIT. After 90Y-RIT, 55% had grade 3/4 neutropenia with no febrile neutropenia and 45% had grade 3/4 thrombocytopenia with recovery at 12 weeks in 22/23 pt. Median follow-up (all pt) is 24.4 months. Median FFS for all 56 pt is 27 months with an estimated 71% FFS and 93% overall survival at 18 months. Among pt who completed all treatment and have been followed ≥1.5 yr (n=45), 33 remain failure-free and 12 have progressed (4 dead). Conclusions: 90Y RIT after 4 cycles of R-CHOP in untreated MCL is safe and improves the number and quality of responses. These data suggest prolongation of FFS over that expected with R-CHOP alone. Consolidation of remission in MCL with 90Y-RIT shows potential as a strategy to prolong remission duration and is applicable to most pt with MCL. However, longer follow-up in needed to evaluate the durability of remissions achieved.

Description: Abstract 1218 Poster Board I-240 Background The combination of lenalidomide (Len, Revlimid®), bortezomib (Bz, Velcade®), and dexamethasone (dex; RVD) has shown excellent efficacy in relapsed/refractory multiple myeloma (MM) patients, with overall response rates (ORR; ≥partial response [PR]) of 69%, including 26% complete/near complete responses (CR/nCR), and manageable toxicities (Anderson et al. ASCO 2009). The phase I portion of the study (Richardson et al. IMW 2009) found the maximum tolerated dose (MTD) of this combination in newly diagnosed MM patients to be Len 25 mg/day, Bz 1.3 mg/m2, and dex 20 mg. In all phase I patients, the ORR was 100%, including 31% CR, 9% nCR, and 75% 3very good PR (VGPR). Results reported here are for patients treated in the phase II portion of the study. Methods Patients were treated with Len 25 mg/day (days 1–14), Bz 1.3 mg/m2 (days 1, 4, 8, 11), and dex 20 mg (cycles 1–4) and 10 mg (cycles 5–8) on the day of and day after Bz for up to eight 21-day cycles. Patients received prophylactic anticoagulants. Responses were assessed by modified EBMT and Uniform criteria to include nCR and VGPR. Patients with at least PR could proceed to ASCT after 34 cycles; responding patients who did not go on to ASCT could continue therapy at their physician's discretion. Patients with 3grade 2 peripheral neuropathy (PNY) by CTCAE v3 were excluded. Thirty five patients were enrolled in the phase II portion of this study and were evaluable for both efficacy and safety. Results Median age was 59 years (range 22-86), 54% were men, 34% / 54% / 11% were ISS Stage I / II / III, and 57% / 31% had IgG / IgA MM, respectively. Patients received a median of 8 cycles of Bz and dex and 11 cycles of Len; 11 (31%) patients remain on therapy. Among the 24 patients who have gone off therapy, 5 (21%) completed treatment per protocol, 8 (33%) proceeded to ASCT, 3 (13%) had progressive disease (all during cycle 14 or later), 1 (4%) withdrew due to toxicities, 1 (4%) received non-protocol therapy, and the remaining (n=6; 25%) withdrew consent or stopped treatment due to physician decision. All patients (100%) had a best confirmed pre-ASCT response of 3PR, with 54% CR/nCR and 69% 3VGPR (Table). Response rates in the 31 and 24 patients who completed 4 and 8 cycles, respectively, are shown in the Table. Among the 24 patients without CR at cycle 4, response improved between cycles 4 and 8 in 16 (67%) patients. Fifteen of the 35 (43%) patients were mobilized for ASCT, with a median stem cell yield of 4.4 × 106 (2.3–6.6 × 106) CD34+ cells/kg. After median follow-up of 19.3 months, median time to progression (TTP), progression-free survival (PFS), and overall survival (OS) have not been reached; the estimated 1-year TTP and PFS are 76% and the estimated OS is 100%. Treatment-emergent grade 3 and 4 adverse events that occurred in 〉1 patient included lymphopenia (n=7; 20%), hypokalemia (n=3; 9%), and fatigue and neutropenia (n=2; 6% each). Sensory PNY of any grade occurred in 27 (77%) patients, which was grade 1 (n=18; 67%) and grade 2 (n=8; 30%) in the majority of patients; only one patient had grade 3 sensory PNY. Neuropathic pain and motor PNY were reported in 10 (29%; all grade 1 and 2) and 6 (17%; 1 grade 3) patients, respectively, with no grade 3 PNY seen. Importantly, PNY was reversible with dose reduction, supportive care, and/or completion of therapy. Thrombosis/thromboembolism was reported in just 2 (6%) patients. No treatment-related mortality was seen. Conclusion These phase II results suggest that RVD is a highly effective combination, with a pre-ASCT ORR of 100% and high rates of CR/nCR, and encouraging time-to-event analyses to date. RVD was well tolerated, with limited rates of grade 3 PNY and DVT/PE despite prolonged use of Bz and Len. Data from patients treated at the MTD in phase I and the impact of adverse risk factors (including advanced stage and high-risk cytogenetics) on outcome, as well as following ASCT, will be reported at the meeting. Based upon these promising results, phase II/III studies of RVD and RVD-based combinations are either planned or ongoing. Disclosures Richardson: Keryx: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Lonial:BMS: Consultancy; Gloucester: Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy. Jakubowiak:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jagannath:Merck: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria. Raje:AstraZeneca: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Ghobrial:Millennium Pharmaceuticals, Inc.: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Schlossman:Millennium Pharmaceuticals, Inc.: Speakers Bureau; Celgene: Speakers Bureau. Mazumder:Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Munshi:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Laubach:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vesole:Celgene: Consultancy, Equity Ownership. Rosenblatt:Celgene: Research Funding. Doss:Millennium Pharmaceuticals, Inc.: Speakers Bureau; Celgene: Speakers Bureau. Mitsiades:Millennium Pharmaceuticals, Inc.: Consultancy; Novartis Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; Merck & Co.: Consultancy; Kosan Pharmaceuticals: Consultancy; Pharmion: Consultancy; Amgen Pharmaceuticals: Research Funding; AVEO Pharma: Research Funding; EMD Serono: Research Funding; Sunesis Pharmaceuticals: Research Funding; PharmaMar: Licensing royalties. Hideshima:Biotest AG: Consultancy. Knight:Celgene: Employment, Equity Ownership. Esseltine:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Anderson:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding.

Description: Abstract 3856 Poster Board III-792 Background Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (MM) patients following ≥1 prior therapy. mTOR inhibitor RAD001 has been studied as a single agent in MM, and although well tolerated, did not have single agent activity. Given the increased toxicity noted with pulsed high dose steroids, we sought to study a non-steroid containing oral regimen for the treatment of relapsed MM predicated upon our previous studies which demonstrated synergistic anti-MM activity of mTOR inhibitors when combined with len. Here, we extended our in vitro observations to a phase I clinical trial combining RAD001 with len in patients with relapsed or refractory MM. The primary objective was to assess toxicity of this combination and to determine the maximum tolerated dose (MTD). The secondary objective was to determine the activity of this combination. Methods Patients with relapsed and refractory MM were assigned to len and RAD001 to be taken for 21 days of a 28 day cycle. Dose escalation followed a modified Fibonacci design. Patients were allowed to continue therapy until disease progression or unacceptable toxicity. Patients received concomitant anti-thrombotic (aspirin 81 or 325 mg/day) therapy. Response was assessed according to modified EBMT and Uniform Criteria, and toxicities were assessed using NCI CTCAE v3.0. Results Eighteen MM patients have been enrolled to date. One patient in cohort 1 (Len: 10mg and RAD001: 5 mg x 21 days) developed grade 3 neutropenia requiring expansion of the cohort. Cohort 2 (Len: 15mg and RAD001: 5 mg x 21 days) also required expansion because of grade 4 thrombocytopenia noted in 1 patient. Dose limiting toxicities included grade 4 neutropenia and thrombocytopenia in 2/3 patients in cohort 3 (Len: 20mg and RAD001: 5 mg x 21 days). The MTD for patients with MM was therefore declared at 15 mg of len and 5mg of RAD001 for 21 days with a 7 day rest period. Apart from the hematological toxicities expected with the combination, patients otherwise tolerated the regimen well. Most common (≥10%) grade 1 / 2 events included nausea, fatigue, dyspnea, diarrhea, constipation, neuropathy and muscle cramps, all of which were manageable with supportive care. No thromboembolic events were noted. Grade 3 / 4 adverse events ≥ 5% included thrombocytopenia (11%) and neutropenia (22%). Fifteen patients have finished at least 2 cycles of therapy: 8 of 15 patients have either stable disease (SD: 1), minimal response (MR: 5) or a partial response (PR: 2), including 7 of 9 patients treated at the recommended MTD for an overall response rate (MR or better) of 50% (90% CI: [30.76%]). One patient with SD continued therapy for a total of 10 cycles, without significant toxicities. Conclusions The combination of Len plus RAD001 is a well tolerated regimen with predictable hematological toxicities. Promising responses were noted in this heavily pretreated patient population. This combination provides an oral steroid free combination alternative strategy which warrants future evaluation in phase II studies. Disclosures: Raje: Astrazeneca : Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: RAD001 not labelled for use in myeloma. Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hari:Celgene: Research Funding, Speakers Bureau. Laubach:Novartis:. Ghobrial:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Adams:Novartis: Employment. Makrides:Celgene: Employment.