Bendamustine, thalidomide and dexamethasone combination therapy for relapsed/refractory myeloma patients: results of the MUKone randomized dose selection trial

Abstract

SummaryThere is a significant unmet need in effective therapy for relapsed myeloma patients once they become refractory to bortezomib and lenalidomide. While data from the front line setting suggest bendamustine is superior to melphalan, there is no information defining optimal bendamustine dose in multiply-treated patients. We report a multi-centre randomized two-stage phase 2 trial simultaneously assessing deliverability and activity of two doses of bendamustine (60 mg/m 2 vs. 100 mg/m 2 ) days 1 and 8, thalidomide (100 mg) days 1-21 and low dose dexamethasone (20 mg) days 1, 8, 15 and 22 of a 28-d cycle. Ninety-four relapsing patients were treated on trial, with a median three prior treatment lines. A pre-planned interim deliverability and activity assessment led to closure of the 100 mg/m 2 arm due to excess cytopenias, and led to amendment of entry criteria for cytopenias. Non-haematological toxicities including thromboembolism and neurotoxicity were infrequent. In the 60 mg/m 2 arm, treatment was deliverable in 61Á1% subjects and the partial response rate was 46Á3% in the study eligible population, with 7Á5 months progression-free survival. This study demonstrates bendamustine at 60 mg/m 2 twice per month with thalidomide and dexamethasone is deliverable for repeated cycles in heavily pretreated myeloma patients and has substantial clinical activity.

Phase II trial to investigate efficacy and safety of bendamustine, dexamethasone and thalidomide in relapsed or refractory multiple myeloma patients after treatment with lenalidomide and bortezomib

“…In the present study, BDT was able to induce a VGPR in three patients (11%) and a PR in 7 patients (27%), leading to an ORR of 10 patients (37%) and so the null hypothesis was refused, confirming the efficacy of the investigated regimen. However, the ORR was slightly inferior than that reported in the MUKone trial (Schey et al , ) where 41·5% responded to B60TD. Of the remaining patients, three (11%) achieved stable disease and nine (35%) progressed during treatment.…”

“…Grade 3/4 anaemia occurred in three patients (12%), neutropenia in nine cases (35%) and thrombocytopenia in three (12%). Although patients received three doses of bendamustine 60 mg/m 2 at each cycle compared to two doses in the 60‐mg arm (B60TD) of the MUKone trial (Schey et al , ), where patients in the 60‐mg arm suffered ≥grade 3 anaemia (22%), ≥grade 3 neutropenia (33%) and ≥grade3 thrombocytopenia (31%), in the present study the haematological toxicity was similar to the MUKone trial. This suggests that higher doses of bendamustine can be delivered but must be subdivided into smaller single doses.…”

“…In the last decade several reports regarding the administration of bendamustine in relapsed/refractory multiple myeloma have been published in this journal (Ponisch et al , ; Ramasamy et al , ; Grey‐Davies et al , ). The last one was the two‐step phase II trial MUKone (Schey et al , ), which evaluated the deliverability and activity of two doses of bendamustine (60 mg/m 2 vs. 100 mg/m 2 ) days 1 and 8, thalidomide (100 mg) days 1–21 and low dose dexamethasone (20 mg) days 1, 8, 15 and 22 of a 28‐day cycle. In 2013, based on these positive experiences, we designed a phase II trial (EudraCT #: 2011‐001775‐39) to determine the efficacy and feasibility of the combination of bendamustine, dexamethasone and thalidomide, as these had not been evaluated prospectively at that time.…”

“…During the observation period of 18 months after induction treatment, 10 more patients progressed, leading to an overall rate of progression of 73%. While DFS was not applicable because no patient achieved a CR, the TTF and OS at 18 months were 22% (median 6·2 months, range 3·5–18·7 months) and 40% (median 9·1 months), respectively (Fig B, C) compared to a 12‐month OS and PFS of 45·3% and 6·5%, respectively, in the MUKone trial (Schey et al , ).…”

Bendamustine in multiple myeloma

“…After an interim analysis, the enrolment in the bendamustine 100 mg/m 2 arm stopped due to excess of cytopenias. The bendamustine 60 mg/m 2 arm resulted deliverable in 61.1% of cases and the ORR was 46.3% (1.9% of CR), with a PFS of 7.5 months . Overall, these data demonstrated the safety and efficacy of the combination between bendamustine, thalidomide and steroid in relapsed/refractory MM patients.…”