By William B. Ershler, MD, Editor
SYNOPSIS: In a Phase 2 trial, Ludwig and colleagues present data on 79 patients with relapsed or refractory myeloma who were treated with bendamustine in combination with bortezomib and dexamethasone. The combination was well tolerated and resulted in a 75% response rate (including those with "minor" response). Responses occurred early (first noted at approximately 1 month) and progression-free survival was 9.7 months. Responses occurred in patients with adverse cytogenetics, higher stage, and prior exposure to bortezomib and/or lenalidomide.
SOURCE: Ludwig H, et al. Bendamustine-bortezomib-dexamethasone is an active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood 2014;123:985-991.
Recent advances in myeloma therapy have resulted in significant improvements in response rates and overall survival for patients with multiple myeloma. Yet the great majority of patients relapse and the optimal second-line therapy remains to be established. Typically second treatments are configured based on a number of patient-related factors as well as prior drug exposure. In this regard, bendamustine represents an attractive component for a second-line regimen. The bendamustine molecule is composed of three structural elements: a mechlorethamine (nitrogen mustard) group, a benzimidazole ring, and a butyric acid side chain. The mechlorethamine (nitrogen mustard) group is similar to other alkylators like cyclophosphamide and chlorambucil. The benzimidazole ring, which replaces the benzene ring present in chlorambucil, is unique and is similar in structure to some purine analogs such as 2-chlorodeoxyadenosine. This observation has led some to hypothesize that bendamustine may have purine analog activity as well. Laboratory studies indicate unique properties of this drug, especially when compared with other alkylators. DNA breaks induced by bendamustine are significantly greater in number than those produced by cyclophosphamide or carmustine and are more durable than those associated with melphalan, cyclophosphamide, or carmustine.1,2 Evidence in human breast carcinoma cells shows that bendamustine-induced DNA breaks are more difficult to repair than those induced by carmustine or cyclophosphamide, and that repair of DNA damage is slower than with other alkylating agents. Bendamustine lacks cross-reactivity with many other cancer drugs, including melphalan and several other cytotoxic drugs,3 and has been shown to overcome resistance to melphalan as well as dexamethasone in myeloma cell lines.4,5
The current Phase 2 trial was conducted throughout Austria and the Czech Republic. Bendamustine with bortezomib and dexamethasone was evaluated in 79 patients with relapsed/refractory multiple myeloma. The median age was 64 years, and all but four of the patients were ECOG performance status 0 or 1. Enrolled patients had a median of two prior treatment lines (range, 1 to 6 lines). Patients were given bendamustine 70 mg/m2 days 1 and 4; bortezomib 1.3 mg/m2 intravenously days 1, 4, 8, and 11; and dexamethasone 20 mg days 1, 4, 8, and 11 once every 28 days for up to eight cycles. Primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival, time to response, and toxicity. Myeloma response was assessed according to the International Uniform Response Criteria for Multiple Myeloma6 with the addition of the minor response category.7 The ORR was 60.8%, and when minor responses were included, 75.9%. Median time to response was 31 days. ORR rate was similar in patients previously exposed to bortezomib, lenalidomide, and bortezomib plus lenalidomide. PFS was 9.7 and OS was 25.6 months. Multivariate analysis showed high lactate dehydrogenase, three or more prior treatment lines, and low platelet count independently correlated with short survival. Grade 3/4 thrombocytopenia was noted in 38%, and grade 3/4/5 infections were noted in 23%. Grade 1 or 2 polyneuropathy increased from 19% at baseline to 52% at cycle 8, and grade 4 from 0% to 7%.
With the introduction of novel agents such as lenalidomide and bortezomib, prior alkylating agent exposure is less commonly encountered in patients with relapsed myeloma, particularly for those who were not treated with stem cell therapy. Bendamustine had previously been tested as single-agent (with prednisone) initial therapy and in combination with either lenalidomide or bortezomib in patients with relapsed or refractory myeloma. In this larger Phase 2 trial, bendamustine with bortezomib and dexamethasone resulted in an overall response rate (including minor responses) of > 75% with PFS of 9.7 months and OS of 25.6 months. Of particular interest was the relatively short time to response (31 days) and to best response (111 days), a feature that may well correlate with improved quality of life — although this was not measured in this trial. It is notable that comparable short time to response was also apparent when bendamustine was combined with lenalidomide and corticosteroids.8,9
Thus, bendamustine-bortezomib-dexamethasone is active and reasonably well tolerated in patients with relapsed/refractory myeloma. The patients enrolled in the current study, albeit with relapsed or refractory myeloma, were younger (median age 64 years) and healthier (ECOG PS 0-1 in 94%) than typically observed in most myeloma clinics. Thus, it remains to be seen whether this combination will be suitable for older patients, particularly those with existing comorbidities or significant functional impairment. In this regard, bendamustine in combination with carfilzomib might be an interesting comparator, in light of its favorable toxicity profile.10