High Response Rate for Lenalidomide Plus Melphalan and Prednisone in Newly Diagnosed Multiple Myeloma Patients

• ORLANDO—The combination of lenalidomide (R) (Revlimid) with oral melphalan and prednisone (MP) induces responses in a high proportion of patients with newly diagnosed multiple myeloma. R-MP is well tolerated with predictable, manageable toxicities, according to a presentation at the 48th Annual Meeting of the American Society of Hematology (abstract 800).

Antonio Palumbo, MD, of the University of Torino, Italy, and his colleagues tested four dose combinations among 54 patients (median age, 71 years). Chromosome deletion 13q, which confers high risk, was identified in 38% of patients. The median β2-microglobulin level was 11.2 g/L, with levels above 3.5 g/L conferring high risk.

Patients were treated with nine courses of lenalidomide for 21 days every 4 to 6 weeks plus MP for 4 days every 4 to 6 weeks. The dose levels tested were: melphalan at either 0.18 or 0.25 mg/kg/d plus lenalidomide 5 mg/d (cohorts 1 and 2); or the same two doses of melphalan with lenalidomide 10 mg/d (cohorts 3 and 4). Prednisone was given at 2 mg/kg.

Lower vs Higher Dose

Analysis of dose-limiting toxicities (DLTs) identified the cohort 3 dose (lenalidomide 10 mg/d, melphalan 0.18 mg/kg/d) as the maximum tolerated dose (MTD). In cohort 4, which had the higher melphalan dose, DLTs occurred in half the patients. Most of the toxicities, however, occurred in the first three cycles, and results therefore were compared between the two lower-dose (5 mg) and two higher-dose (10 mg) lenalidomide cohorts.

For the lower-dose group, 17% of patients had a complete response (CR) or a very good partial response (VGPR), with the rest (83%) having a partial (PR) or minimal response (MR). CR+VGPR was 44% in the higher-dose group, with 56% having PR or MR. "There seems to be a relationship between response rate and Revlimid dose in this small cohort of patients," Dr. Palumbo said.

He emphasized that all patients had at least a minimal response and that responses were rapid, with MRs and PRs occurring within the first two cycles. He underscored, also, that the higher best response rate seen in cohort 3 vs cohort 4 (CR+VGPR, 48% vs 40%), which had occurred similarly in his earlier research, suggests a lack of dose response for melphalan. Responses were similar for those with or without 13q deletions, but were significantly better (P = .02) for patients with lower β2-microglobulin levels.

Dr. Palumbo characterized R-MP as "well tolerated, with toxicities that were predictable and manageable." For the MTD, neutropenia rates were about 40%, thrombocytopenia about 20%, anemia about 5%, and need for G-CSF about 40%. Thrombosis was less than 5% and did not occur during aspirin treatment. One thrombosis was reported in a patient who stopped aspirin as a consequence of thrombocytopenia. The infections rate was under 10%, with one pneumonia and the rest neutropenic fever. Cutaneous toxicities were also under 10%. The deep vein thrombosis rate was below 5%.

Dr. Palumbo concluded: R-MP induced a high proportion of responses in newly diagnosed multiple myeloma. For the MTD, the combined CR+VGPR rate was 48% and the CR+PR rate was 81%. The combination appeared to overcome the poor prognosis of patients with chromosome 13q deletion.

Investigators are going forward with a large randomized trial comparing nine courses of R-MP with or without maintenance lenalidomide against nine courses of melphalan alone.