A Phase I-II Study of the Combination of Bendamustine and Pomalidomide with Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma.

Background

Bendamustine, a bifunctional mechlorethamine derivative with alkylating properties and pomalidomide, an IMiD® immunomodulatory agent, have both demonstrated efficacy as single agents or in combination with dexamethasone in relapsed/refractory multiple myeloma(RRMM). Bendamustine in combination with lenalidomide, thalidomide, and bortezomib have had high response rates and good tolerability. We combined bendamustine and pomalidomide with dexamethasone (Ben-Pom-d) and hypothesized that this regimen would be highly effective in patients with RRMM. Dose-escalation started with 120mg/m² bendamustine/3mg pomalidomide [or 4mg in the cohort 2]/40 mg dexamethasone using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. The MTD was 120mg/m² bendamustine/3mg pomalidomide/40 mg dexamethasone. Here, we report our findings to date from the phase I/II trial of Ben-Pom-d in patients with RRMM (NCT01754402).

Methods The primary objective of the phase I portion was to determine the MTD. Data for overall response, progression free survival, and overall survival, includes all patients treated on the phase I and II portions of the study. All patients had to be refractory to prior lenalidomide, and must have relapsed or were refractory to their most recent therapy. Patients had to be pomalidomide naïve. Treatment consisted of oral pomalidomide once daily on days 1-21, intravenous (IV) bendamustine given over 30 minutes on day 1 and dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria.

Results A total of 9 patients were enrolled in the phase I portion. The MTD was the starting dose level (bendamustine 120 mg/m², pomalidomide 3mg, dexamethasone 40 mg). In Phase II we enrolled an additional 16 patients resulting in a total study population of 25 patients evaluable for toxicity and 22 for efficacy, with 6 still receiving treatment.

The median age was 65 years (range 43-81), 46% were male. The median number of prior regimens was 3 (range 2-6), median time from diagnosis is 3.9 years (range 1.1-9.10 years), 88% of patients had a prior stem cell transplant, 100% had prior bortezomib, 20% had prior carfilzomib and all were lenalidomide-refractory. Fifteen patients had high risk cytogenetic, including 8 patients with del17. Patients received a median of 6 cycles of therapy (range 1-18 cycles). Best response assessments in 22 evaluable patients for efficacy, showed 5 (23%) VGPR, 12 (55%) PR, 3 (14%) MR, and 2 (9%) SD, for an ORR of 77% and a ≥MR rate of 91%. The median follow-up of survivors is 10 months (range: 2-19+ months). Median PFS and OS were 4.5 months (range 1-15+ months) and 9.5 months (range 2-19+ months), respectively, for the entire cohort with 13 of 22 still alive in follow-up. The Median PFS for patient with del 17 is 5.5 months (range 2-15 months) with >MR rate of 88%.

During the first cycle, 3 patients of all 25 evaluable enrolled experienced a DLT at the different doses, including 1 nausea/vomiting [cohort 1], and 2 with rash and fever in cohort 2. The therapy was tolerated well, but toxicities reported at any point while on therapy included 32% grade 4 neutropenia, 16% grade 4 thrombocytopenia, and half the patients requiring delay of subsequent cycles due to cytopenias and 17 of 22 (77%) had a dose reduction of pomalidomide per protocol guidelines at some point in the continuation cycles. The major non-hematologic Grade ≥3 drug-related AEs that occurred included febrile neutropenia in 12%, grade 3 mucositis in 8%, grade 3 pneumonia 16% and grade 4%, and grade 4 sepsis 4%.

Conclusions The Ben-Pom-d regimen is a well-tolerated regimen and achieves a high response rate (ORR of 77%; ≥MR rate of 91%) in a heavily pre-treated Lenalidomide-refractory population with prior bortezomib exposure. Therapy is ongoing for many and longer follow-up is needed to better assess the true durability of this approach.