Bendamustine in Combination with Thalidomide and Prednisolone (BPT) in Patients with Refractory or Relapsed Multiple Myeloma (MM): Preliminary Results of a Phase I Clinical Trial.

Thalidomide is an active single agent in advanced relapsed or refractory MM. Treatment, however, is associated with significant dose-dependent toxicity limiting his application. Combination of low dose thalidomide with bendamustine and prednisolone might be a way to maintain efficacy of the drug without dose limiting toxicity. The cytotoxic agent bendamustine combines a purine-like benzimidazol with a bifunctionally alkylating nitrogen mustard group. The drug is active in a variety of lymphoproliferative disorders with modest non-hematological and hematological toxicities. Previous clinical studies confirmed the efficacy of bendamustine monotherapy and in combination with prednisolone in patients with newly diagnosed and relapsed MM. In a phase III study of newly diagnosed patients, overall response rate for bendamustine and prednisone was 75% and shown to be superior to melphalan and prednisone in regard to progression free survival and quality of life. The purpose of this phase I study was to test the feasibility of the combination of BPT in advanced MM patients.

The treatment consists of a fixed dose of bendamustine (60 mg/qm) i.v. day 1, 8, and 15 and prednisolone (100 mg) p.o. day 1, 8, 15, and 22. At the same time, thalidomide will be given orally in 4 patients cohorts with escalating doses, starting at 50 mg to a maximum of 200 mg daily. Cycles will be repeated every 28 days for a minimum of 2 and a maximum of 10 cycles until appearance of significant treatment-related toxicity or disease progression. Till now, four patients with stage IIIa MM were enrolled in the first dose level with 50 mg thalidomide daily. All patients had two prior treatment lines and three were refractory. Median age was 67 years (range 64 – 69 years).

Results: All four patients completed at least 2 cycles of BPT-treatment (2 completed 6 cycles, 1 completed 3 cycles and 1 completed 2 cycles) and were evaluable for toxicity and efficacy. All patients responded after the first two cycles of therapy in three of them with decrease of the myeloma protein of more than 90%. One showed a reduction of the myeloma protein of 30%. Although median follow up is still short, no progression of disease was observed yet.

Thalidomide in a dose of 50 mg daily given during 4.5 months median (range 2–6 months) was well tolerated. Most common site effects were constipation (three patients WHO grade 2) and somnolence (two patients WHO grade 1). None of the four patients developed dose-limiting hematotoxicity 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 1 patient (WHO grade 2) but no thrombocytopenia was observed. No grade 3 or 4 non-hematological toxicity was encountered and no dose modification was required.

BPT with a dose of 50 mg thalidomide daily is well tolerated in patients with relapsed or refractory MM. The next cohort of patients is currently treated with Thalidomide 100 mg daily to evaluate the maximal tolerable doses of the BPT regimen.