Combination of Bendamustine, Lenalidomide, and Dexamethasone (BLD) in Patients with Refractory or Relapsed Multiple Myeloma Is Safe and Highly Effective: Results of Phase I/II Open-Label, Dose Escalation Study

Abstract

304 Background: 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. Methods: 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. Results: 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. Conclusions: 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. Disclosures: 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.

Lenalidomide, bendamustine and prednisolone exhibits a favourable safety and efficacy profile in relapsed or refractory multiple myeloma: final results of a phase 1 clinical trial OSHO – #077

“…However, in contrast to the results reported here, the MTD of lenalidomide was only 10 mg when used in combination with 75 mg/m 2 bendamustine and dexamethasone (BLD) in patients with a median of three previous therapies (Lentzsch et al , ). This lower dose of lenalidomide in combination with bendamustine and corticosteroids resulted in a reduced ORR of approximately 50%.…”

“…The myeloma protein decreased rapidly in the majority of patients during the first two cycles. Moreover, the median time to first haematological response was 28 d, and the median time to best response was 56 d. This compares to a median of 1·6 months to reach response (including PR and VGPR) previously reported for a BLD protocol (Lentzsch et al , ).…”

“…The combination of bendamustine, lenalidomide and corticosteroids is being examined in three simultaneously conducted phase 1/2 studies involving relapsed/refractory MM patients. The first results of one of these studies with 25 evaluable patients were recently published (Lentzsch et al , ). The ORR achieved in this treatment regimen was 52% with 24% VGPR and 28% partial response (PR).…”

Dose‐intensified bendamustine and melphalan (BenMel) conditioning before second autologous transplantation in myeloma patients

“…The median duration of hospitalization was 18 days (range [15][16][17][18][19][20][21][22][23] after HDBenMel/ASCT2 versus 17 days (range 16-20) after HDMel/ ASCT1. Thus, the median and the maximum duration of hospitalization were only slightly longer for the HDBenMel regimen.…”

“…9,11 Bendamustine has an acceptable toxicity profile in both newly diagnosed and relapsed myeloma patients. [12][13][14][15][16] A phase I trial investigated escalating doses of bendamustine added to standard HDMel (HDBenMel) for conditioning before ASCT in myeloma patients. Adding bendamustine seemed not to increase HDMel-related toxicities, and the response rate was 80% at 100 days after ASCT including 45% of patients with CR.…”