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This multicenter phase 1/2 trial investigated the combination of bendamustine, lenalidomide, and dexamethasone in repeating 4-week cycles as treatment for relapsed refractory multiple myeloma (MM). Phase 1 established maximum tolerated dose (MTD). Phase 2 assessed overall response rate at the MTD. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A total of 29 evaluable patients were enrolled. Median age was 63 years (range, 38-80 years). Median number of prior therapies was 3 (range, 1-6). MTD was bendamustine 75 mg/m2(days 1 and 2), lenalidomide 10 mg (days 1-21), and dexamethasone 40 mg (weekly) of a 28-day cycle. Partial response rate was 52%, with very good partial response achieved in 24%, and minimal response in an additional 24% of patients. Median follow-up was 13 months; median OS has not been reached. One-year OS is 93% (95% confidence interval [CI], 59%-99%). Median PFS is 6.1 months (95% CI, 3.7-9.4 months) with one-year PFS of 20% (95% CI, 6%-41%). Grade 3/4 adverse events included neutropenia, thrombocytopenia, anemia, hyperglycemia, and fatigue. This first phase 1/2 trial testing bendamustine, lenalidomide, and dexamethasone as treatment of relapsed refractory MM was feasible and highly active. This study is registered at www.clinicaltrials.govas #NCT01042704.

This multicenter phase 1/2 trial investigated the combination of bendamustine, lenalidomide, and dexamethasone in repeating 4-week cycles as treatment for relapsed refractory multiple myeloma (MM). Phase 1 established maximum tolerated dose (MTD). Phase 2 assessed overall response rate at the MTD. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A total of 29 evaluable patients were enrolled. Median age was 63 years (range, 38-80 years). Median number of prior therapies was 3 (range, 1-6). MTD was bendamustine 75 mg/m2 (days 1 and 2), lenalidomide 10 mg (days 1-21), and dexamethasone 40 mg (weekly) of a 28-day cycle. Partial response rate was 52%, with very good partial response achieved in 24%, and minimal response in an additional 24% of patients. Median follow-up was 13 months; median OS has not been reached. One-year OS is 93% (95% confidence interval [CI], 59%-99%). Median PFS is 6.1 months (95% CI, 3.7-9.4 months) with one-year PFS of 20% (95% CI, 6%-41%). Grade 3/4 adverse events included neutropenia, thrombocytopenia, anemia, hyperglycemia, and fatigue. This first phase 1/2 trial testing bendamustine, lenalidomide, and dexamethasone as treatment of relapsed refractory MM was feasible and highly active. This study is registered at www.clinicaltrials.gov as #NCT01042704.

Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma. This first multicenter, phase I/II trial investigated the combination of bendamustine, lenalidomide and dexamethasone (BLD) as a potentially effective treatment option for multiple myeloma (MM) patients, particularly for those with pre-existing or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM.We conducted an open-label, dose escalation study (Table 1). Patients were enrolled from June 2008 through February 2011. Eligible patients were aged ≥ 18 years with confirmed, measurable stage II or III MM that was refractory to or progressed after 1 or more prior therapies including lenalidomide. Patients were assigned to their dose levels in a classical 3+3 cohort design. Phase I was to assess the safety and to establish the MTD of the combination treatment. The phase II portion of the study was to assess the overall response rate (ORR) at the MTD. Intravenous bendamustine was given on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of the 28-day cycle. Treatment was given until plateau of best response as determined by the International Myeloma Working Group uniform response criteria for a maximum of 8 cycles. The study doses were escalated through 3 levels, in a 3+3 dose escalation scheme. The MTD was defined as the dose level at which ≤1 of 6 patients experienced dose-limiting toxicity (DLT) during the first cycle of therapy when the next higher dose level was associated with DLTs in ≥ 2 patients. Primary endpoint was the MTD. After determining the MTD, up to 12 additional patients were enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival.36 patients with a median age of 63 years (range 38 to 80) were enrolled. The median number of prior therapies was 3 with a range of from 2–9; 79% of the patients had prior lenalidomide, 48% had prior thalidomide, and 34% had both. 69% of the patients had a prior autologous stem cell transplant. The MTD was 75 mg/m2 for bendamustine and 10 mg for lenalidomide. DLTs included at dose level 2: 1 grade 4 neutropenia; at dose level 3: 2 grade 4 neutropenias and 1 delayed platelet recovery from grade 3 thrombocytopenia. 25 received at least 2 cycles and were included into the response assessment. A partial response or better was observed in 52% (n=13) of the patients, including 24% (n=6) VGPR. MR was observed in 24% (n=6), SD 16% (n=4), and PD 8% (n=2). BLD induced fast responses with a time to best response of 1.6 months (range 0.7–7.4). The response was independent of prior exposure to lenalidomide evidenced by the fact that 84% of patients with VGPR/PR had prior treatment with lenalidomide. The median follow up for patients at risk of progression is 8 months (range 4–13). The estimated median progression free survival (PFS) is 4.4 months (95% CI (3.4, 9.2). 4 patients have died and the median follow up for patients who are still alive is 13 months (range 6–33). The median OS survival has not been reached yet. We did not observe any unanticipated DLTs. The only grade 4 adverse events for all patients for all cycles included 24.1% neutropenia and 7% thrombocytopenia. No infection was associated with the neutropenia and all AE resolved successfully. This is the first phase I/II trial testing bendamustine, lenalidomide and dexamethasone in combination for relapsed and refractory MM. This regimen is safe and well tolerated even in older patients up to 80 years. Based on the mainly myelosuppressive side effects, concomitant treatment with filgastrim is recommended. This regimen induced fast responses and high response rates even in heavily pretreated MM patients. The high responses were also achieved in patients with prior exposure to lenalidomide suggesting that BLD overcomes resistance to lenalidomide and is a highly active regimen.Lentzsch: Celgene Corp: Consultancy, Research Funding; Onyx: Consultancy; Genzyme: Consultancy; prIME Oncology: Honoraria; Imedex: Honoraria; Clinical Care Options: Honoraria. Burt:Celgene Corp: Honoraria, Speakers Bureau; Cephalon: Honoraria, Speakers Bureau. Roodman:Amgen: Consultancy; Millennium Pharmaceuticals: Consultancy. Agha:Novartis: Consultancy. Zonder:Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy.

Abstract 304

Lenalidomide is an analog of thalidomide that has significant clinical activity in combination with dexamethasone in patients with relapsed or refractory multiple myeloma (MM). Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. This multicenter phase I trial is the first to investigate the combination of bendamustine, lenalidomide, and dexamethasone. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM.Patients aged ≥18 years with confirmed, measurable symptomatic MM that was refractory to or progressed after 1 or more prior therapies were treated with bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau or best response, as determined by the International Myeloma Working Group uniform response criteria, was reached. Study drug doses were escalated through 3 levels (Table 1) in a 3+3 dose-escalation scheme. The MTD was defined as the dose level at which ≤1 of 6 patients experienced dose-limiting toxicity (DLT) during the first cycle of therapy when the next higher dose level is associated with DLTs in ≥2 patients. After determining the MTD, an expansion cohort of 12 additional patients at the MTD will be treated to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy as evidenced by objective response, time to disease progression, and overall survival.Twenty-six patients with a median age of 63 years (range, 38 to 81 years) were enrolled. The mean number of prior therapies was 3 (range, 2–7); 81% of the patients had prior lenalidomide, 48% had prior thalidomide, and 29% had both. The MTD was identified at dose level 2: 75 mg/m2 bendamustine and 10 mg lenalidomide. Four DLTs were recorded: at dose level 2 (n = 6), 1 patient with grade 4 neutropenia; at dose level 3 (n = 6), 2 patients with grade 4 neutropenia and another with delayed platelet recovery from grade 3 thrombocytopenia. Currently 9 patients have been enrolled in the expansion cohort. Twenty-one of 26 patients received at least 2 cycles and were included in the response assessment. A partial response (PR) or better was observed in 63% (n = 12) of the patients, including 16% (n = 3) achieving a very good PR (VGPR). In addition to these 12 patients, another 3 (15%) had a minor response (25%-49% reduction in M-protein). Stable disease was observed in 32% (n = 6), and only 5% (n = 1) had disease progression. The median time to next treatment was 8.1 months (range, 1.9–27.3 months). Other grade 3/4 adverse events occurring after the first cycles of treatment included prolonged QTc in 1 patient.This is the first phase I trial testing the combination of bendamustine, lenalidomide, and dexamethasone for relapsed and refractory MM. This regimen is well tolerated even in older patients up to 81 years. With a PR/VGPR rate of 63%, this combination is a highly active regimen even in heavily pretreated MM patients, and its side effect profile makes it an attractive treatment option for MM patients especially with pre-existing therapy-related peripheral sensory neuropathy. Final data on response and overall survival will be available at the time of presentation.Lentzsch: Celgene Corp: Research Funding. Roodman:Amgen, Novartis, Celgene, Acceleron: Consultancy. Zonder:Amgen, Celgene, Cephalon: Consultancy; Millennium: Research Funding; Millennium: CME only, no promotional work.

Abstract 989

Lenalidomide is an analog of thalidomide that has shown significant clinical activity in patients with relapsed or refractory multiple myeloma (MM), both as a single agent and in combination with dexamethasone. Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. Bendamustine combined with lenalidomide may be an effective treatment option for MM patients, particularly those with preexisting or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM.Patients aged ≥18 years with confirmed, measurable stage 2 or 3 MM that was refractory to or progressed after 1 or more prior therapies, including lenalidomide, received bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau of best response, as determined by the IBMTR/ABMTR, was reached. Study drug doses were escalated through 4 levels (Table), with 3–6 patients enrolled at each level depending on the rate of dose-limiting toxicity (DLT). After determining the MTD, up to an additional 12 patients will be enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival.To date, 11 patients have been enrolled, with a median age of 63 years (range, 38–75 years). The MTD of bendamustine and lenalidomide has not been identified at this point; currently, patients are enrolling on dose level 3 with 100 mg/m2 bendamustine and 10 mg lenalidomide. Thus far, DLT included 1 grade 4 neutropenia at dose level 2. Nine of 11 patients are currently eligible for response assessment. A partial response was observed in 67% of patients, including 1 very good partial response and 5 partial responses (PR). Two patients experienced stable disease and 1 exhibited progressive disease. Grade 3/4 adverse events included grade 3 neutropenia, thrombocytopenia, anemia, hyperglycemia, and prolonged QTC, and 1 grade 4 neutropenia.Bendamustine, lenalidomide, and dexamethasone form a well-tolerated and highly active regimen even in heavily pretreated MM patients, with a PR rate of 67%. Additional updates on response and MTD will be available at the time of presentation.Lentzsch: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bendamustine is not FDA approved for the treatment of multiple myeloma in the USA. Burt:Millennium: Honoraria; Celgene: Honoraria. Mapara:Resolvyx: Consultancy, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees; Gentium: Equity Ownership; Celgene: Spouse is consultant , has received research funding, and participates on advisory board; Cephalon: Spouse has received funding for clinical trial and participates on advisory board. Redner:Biogen: Equity Ownership; Wyeth: Equity Ownership; Glaxo-Smith-Kline: Equity Ownership; Pfizer: Equity Ownership; Genzyme: Membership on an entity's Board of Directors or advisory committees. Roodman:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Acceleron: Consultancy. Zonder:Amgen: Consultancy; Pfizer: Consultancy; Cephalon: Consultancy; Millennium: Consultancy, Speaking (CME only); no promotional talks.

Abstract 1856