Bendamustine in Combination with Thalidomide and Prednisolone (BPT) in Patients with Refractory or Relapsed Multiple Myeloma after Conventional Chemotherapy: Final Results of a Phase I Study.

Thalidomide is a remarkably active agent in patients with advanced relapsed or refractory multiple myeloma (MM), but with a significant co morbidity due to side-effects such as neuropathy. We investigated whether lower doses of thalidomide in combination with weekly doses of bendamustine and prednisolone might be a more effective regimen with fewer side-effects especially in relation to neurotoxicity. Clinical studies in patients with newly diagnosed and relapsed MM have shown that bendamustine is effective as single agent as well as in combination with prednisolone. In a phase III study, overall response rate for bendamustine and prednisone was 75% as first line therapy.

The purpose of this phase I study was the assessment of toxicity of the combination bendamustine, prednisolone, and thalidomide (BPT) in patients with advanced MM. The treatment consisted of a fixed dose of bendamustine (60 mg/qm) i.v. days 1, 8, and 15 and prednisolone (100 mg) p.o. days 1, 8, 15, and 22. Thalidomide was given to patient cohorts at escalating doses, starting with 50 mg up to a maximum of 200 mg daily. Four patients were enrolled at each dose level. If one dose limiting toxicity (DLT) occurred, additional two patients would be enrolled at that dose level. Cycles were repeated every 28 days for a minimum of 2 and a maximum of 10 cycles until maximum response, DLT, or progressive disease.

Fourteen patients (4 in the first thalidomide dose level with 50 mg, 4 in the second dose level with 100 mg, and 6 patients in the third dose level with 200 mg) were enrolled. Median age was 69 years (range 61 - 78). The number of prior treatment regimens was 2 or more in all patients. Six younger patients were included who had failed VAD-like induction therapy (n=5) or stem cell mobilization (n=1). Six patients had been refractory to the last treatment.

Results: All patients completed 2 cycles of BPT (1 completed 7 cycles, 4 completed 6 cycles, 3 completed 5 cycles, 3 completed 4 cycles, 2 completed 3 cycles, and 1 completed 2 cycles). Response was assessed using EBMT criteria modified to include near complete remission (nCR) and very good partial remission (VGPR). After at least 2 cycles of chemotherapy, 12 of 14 patients responded with 2 CR, 2 VGPR, 7 PR, and 1 MR (ORR 85%). Two patients had a stable disease.

No DLT was observed at any dose level. Most common side-effects were constipation (7 patients WHO grade 1; 6 patients WHO grade 2), somnolence (4 patients WHO grade 1), and peripheral neuropathy (2 patients WHO grade 1; 2 patients WHO grade 2). None of the 14 patients developed dose-limiting hematological toxicity as defined by an ANC < 1,0 x 10⁹/l for > 7 days or an ANC < 0,5 x 10⁹/l for > 3 days or platelet count < 25 x 10⁹/l. Neutropenia was reported in 4 patients (WHO grade 4) but no thrombocytopenia was observed. No grade 3 or 4 non-hematological toxicity was encountered and no dose modification was required.

BPT with daily thalidomide between 50 mg and 200 mg is well tolerated in patients with relapsed or refractory MM after conventional chemotherapy.