Bendamustine, Bortezomib and Dexamethasone (BBD) As First-Line Treatment Of Patients (Pts) With Multiple Myeloma Who Are Not Candidates For High Dose Chemotherapy

Despite significant advances, multiple myeloma is an incurable plasma cell disorder with an eventual fatal outcome. In newly diagnosed MM, combinations of bortezomib, steroids and alkylating agents, such as melphalan and prednisone, have achieved response rates in excess of 70% and have been established as a standard of care in pts who are ineligible for high dose chemotherapy. Outcomes are more attenuated in pts > 75 yrs old. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective as a single agent and in various combinations for the treatment of relapsed/refractory MM (Poenisch et al, 2007, Fenk et al, 2007). In this study, the combination of bendamustine, bortezomib and dexamethasone (BBD) was evaluated as a first-line therapy for pts with MM. Here we present the updated results of this ongoing trial.

Pts with newly diagnosed active MM who were not candidates for high-dose chemotherapy and met standard eligibility criteria with regards to renal, hepatic and hematologic function were enrolled. The original treatment schema consisted of: bendamustine 80 mg/m² IV on days 1, 4; bortezomib 1.3 mg/m² IV on days 1, 4, 8, 11; and dexamethasone 40 mg on days 1, 2, 3, 4 with cycles repeating every 28 days. Pts had the option to continue treatment up to 8 cycles or 2 cycles beyond confirmed CR. An interim analysis found this combination to be efficacious but relatively toxic. As a result, the treatment schema was amended to the following: bendamustine 80 mg/m² IV on days 1, 2; bortezomib 1.3 mg/m² IV on days 1, 8, 15; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16 every 28 days for a total of 8 cycles or 2 cycles beyond documented CR, whichever occurred first. Pts achieving at least SD continued on to maintenance bortezomib 1.3 mg/m² IV/SQ every 2 weeks for 2 years. Acyclovir or equivalent viral prophylaxis was originally recommended and became required on the modified schema. Responses were assessed using the IMWG criteria. The overall response rate (ORR) was defined as ≥ PR. Adverse Events (AEs) were assessed using the CTCAE Version 4.0. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method.

As of 5/31/2013, 43 pts have been enrolled (18 on the original schema, 25 on the modified schema). The median age was 75 (45-89) and 39% of pts were > 75 (48% in the modified schema). Forty two percent of pts were ISS II and 32% were ISS III. Fifteen (35%) pts remain on treatment, all on the modified schema. Treatment-related Grade 3 hematologic AEs were seen in 30% of pts. Only 1 treatment-related Grade 4 hematologic AE of neutropenia was observed. Treatment-related Grade 3 non-hematologic AEs were seen in 21% of pts. The most common non-hematologic Grade 3 AE was neuropathy, seen in 12% of pts (all but 1 on the original schema). There was 1 treatment-related Grade 4 non-hematologic AE of atrial fibrillation and 1 treatment related death (congestive heart failure). Herpes Zoster was seen in 19% of the pts, all from the original treatment schema. A total of 40 pts were evaluable for response. The ORR was 83% (55% ≥VGPR, 28% PR) plus 17% SD and 0 PD. Of the 23 evaluable pts on the modified treatment schema, the ORR was 83% (52% ≥VGPR and 31% PR). For the 15 pts > 75, the ORR was 93% (60% ≥VGPR and 33% PR). At a median FU of 13.1 months, the 1-year PFS is 79% (0.53-0.92) and the 1-year OS is 83% (0.54-0.95).

The combination of bendamustine, bortezomib and dexamethasone is feasible and efficacious in this elderly pt population with a large number of pts over the age of 75 years. The modified schema is better tolerated allowing pts to proceed to maintenance treatment which may eventually translate to improved results. Enrollment is ongoing.

Off Label Use: Off-label use of Bendamustine in the Treatment of Multiple Myeloma. Chu:Teva: Research Funding; Millennium: Research Funding. Boccia:Teva: Research Funding; Millennium: Research Funding. Flinn:Teva: Research Funding; Millennium: Research Funding.