Oral Melphalan, Prednisone, and Lenalidomide for Newly Diagnosed Multiple Myeloma Patients: Kinetics of Neutropenia/Thrombocytopenia and Time to Event Results

Background: The association of Melphalan, Prednisone and Lenalidomide (MPR) has shown significant anti-myeloma activity in newly diagnosed Multiple Myeloma (MM) patients. In this phase I/II study, the more frequent adverse events were neutropenia and thrombocytopenia. Non-hematologic toxicities were unusual.

Methods: We analyzed the kinetics and risk factors for neutropenia and thrombocytopenia in 21 patients (median age 69 years) who received nine four-week cycles of MPR at the maximum tolerated dose (melphalan 0.18 mg/Kg d 1–4, lenalidomide 10 mg d 1–21, prednisone 2 mg/Kg d 1–4, followed by maintenance period with lenalidomide 10 mg/day for 21 days every 4 weeks). We also up-dated efficacy end-point. At the occurrence of grade-3 neutropenia, G-CSF was administered for 5–7 days. The occurrence of grade-4 neutropenia despite G-CSF administration or any other grade-4 hematological toxicities required withholding of treatment and subsequent dose reduction at the start of the following cycle. A new cycle was allowed if the neutrophil count was >1×10⁹/L and platelet count >50×10⁹/L. A delay of 2 weeks was allowed, a delay beyond 2 weeks required dose reduction and a delay beyond 4 weeks required therapy discontinuation.

Results: Grade-3 neutropenia occurred in 38.1% of patients, grade-4 neutropenia in 14.2% of patients, but febrile neutropenia was 9.5%. G-CSF was administered in 42.3% of patients. The mean neutrophil count at the start of each MPR cycle was 2.69 × 10⁹/L (SD 1.4). The mean neutrophil count at nadir (day 15–21) of each cycle was 1.43 × 10⁹/L (SD 1.0). The incidence and depth of neutropenia did not increase with the number of cycles. The mean neutrophil count during maintenance was 2.11 × 10⁹/L (SD 1.0).

Grade-3 thrombocytopenia occurred in 14.2% of patients and grade-4 thrombocytopenia in 9.5%; one patient required platelet transfusion. The mean platelet count at the start of each MPR cycle was 174 × 10⁹/L (SD 63.9). The mean platelet count at nadir (day 15–21) of each cycle was 121 × 10⁹/L (SD 56.3). Thrombocytopenia was more pronounced after 9 cycles of treatment. The mean platelet count after 9 cycles was 109 × 10⁹/L (SD 53). The mean platelet count at the end of 6 months of lenalidomide maintenance therapy was 158 × 10⁹/L (SD 79.2).

One patient required lenalidomide dose reduction for severe neutropenia. Three patients discontinuated therapy for severe thrombocytopenia and neutropenia. Grade 3–4 hematologic toxicity was more frequent in patients with low baseline neutrophil count and in those with Bence-Jones myeloma. Neutropenic fever (9.5%), cutaneous reaction (9.5%), thromboembolism (4.8%) were the most frequent grade 3–4 non-hematologic adverse events.

After a median follow-up of 29.5 months, the median time-to-progression was 28.5 months, the median progression-free survival was 28.5 months and the 2-years overall survival was 90.5%. No death was reported in the first 18 months of treatment.

Conclusions: MPR is a promising first line regimen for elderly MM patients. Hematologic adverse events were frequent but manageable with the use of G-CSF.