Background. Lenalidomide (Revlimid® ) is a novel, orally active immunomodulatory drug, effective in multiple myeloma (MM) patients. In newly diagnosed patients the addition of Thalidomide to the standard oral melphalan and prednisone (MP) significantly increase response rate and event free-survival compared with MP. No data are available on the clinical use of Revlimid® in combination with MP. In this multicenter phase I/II trial, we evaluate the dosing, safety and efficacy of the combination Revlimid® , melphalan and prednisone (R-MP).

Methods. Patients (pts) with newly diagnosed symptomatic MM older than 65 years were treated with 9 courses of Revlimid® (5–10 mg/day for 21days every 4–6 weeks) plus MP (melphalan 0.18–0.25 mg/kg and prednisone 2 mg/kg for 4 days every 4–6 weeks) followed by maintenance therapy with Revlimid® alone (10 mg/day for 21days every 4–6 weeks). Four different dose-levels were tested: 1.melphalan 0.18 mg/kg + Revlimid® 5 mg/day; 2.melphalan 0.25 mg/kg + Revlimid® 5 mg/day; 3.melphalan 0.18 mg/kg + Revlimid® 10 mg/day; 4.melphalan 0.25 mg/kg + Revlimid® 10 mg/day. Each cohort included 6 pts, with additional 15 pts enrolled at dose level 3 and 4. All pts received ciprofloxacin and aspirin (100 mg/day) as prophylaxis.

Results. Between January and October 2005, 54 pts (median age 71) were enrolled in the study. No DLTs were observed in the first 2 dose-levels. In dose-level 3, one pt experienced DLT (grade 4 neutropenia lasting>7 days). In dose-level 4, three pts showed DLTs (neutropenic fever, grade 3 cutaneous toxicity, pulmonary embolism, delay in the start of cycle 2) during the first cycle. The MTD was defined at dose-level 3 (melphalan 0.18 mg/kg+Revlimid® 10 mg/day).

In the dose-levels 3 and 4, after a median of 7 cycles, all patients showed at least a minimal response and 85.4% of patients showed at least a partial response (PR); 41.5% of patients achieved at least a very good partial response (VGPR) and 17.1% of patients reached immunofixation negative complete remission (CR). In the dose-level 3, defined as MTD, 85.6% of patients showed at least a PR, including 52.3% of patients who achieved at least a VGPR and 23.8% who showed immunofixation negative CR. After a median follow up of 9.6 months, the progression free survival (PFS) was 87% at 16 months. FISH informations on chromosome 13q deletion were available in 42 patients (79%): no difference in response rate and PFS was observed between patients with or without 13q deletion.

Toxicity was manageable, and occurred more frequently during early cycles. Major grade 3–4 adverse events consisted of hematological toxicities (neutropenia 66%, thrombocytopenia 34% and anemia 17%); major grade 3–4 non-hematological toxicities were cutaneous eruption (10%) and febrile neutropenia (8%). Three cases of tromboembolic events occurred: two of them after aspirin discontinuation, at cycle 7 and during maintenance.

Conclusions. R-MP induced a high proportion of responses and appeared to overcome the poor prognosis of patients with chromosome 13q deletion. It was well tolerated, toxicities were predictable and manageable. An update of these data will be presented.

Disclosures: Revlimid has the FDA approval for relapsed/refractory Multiple Myeloma. In the trial Revlimid is employed as first line therapy in Multiple Myeloma.; J. Zeldis and R. Knight are employees of Celgene.; A. Palumbo and M. Boccadoro are consulting for Celgene.; J. Zeldis and R. Knight are stockholder of Celgene.; The study was partially supported by Celgene.; J. Zeldis and R. Knight are expert testimony for Celgene.; A. Palumbo and M. Boccadoro have received scientific adviser board and lecture fees from Celgene.

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