A Phase II Trial of Doxil, Vincristine and Reduced Schedule Dexamethasone (DVd) for Patients with Relapsed or Refractory Multiple Myeloma.

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Abstract
Patients with newly diagnosed multiple myeloma (MM) typically have responses to initial cytotoxic or steroid based therapy. Disease relapse occurs in all patients. As high as 90% of patients with relapsed or refractory disease will have over-expression of the multi-drug resistance (MDR) gene. Pharmacokinetic data suggest that prolonged exposure to high concentrations of doxorubicin can overcome MDR. Pegylated liposomal doxorubicin can theoretically achieve this goal as the angiogenic activity of the MM bone marrow is significantly increased. We proceeded with a phase II trial to evaluate the response rate of patients with relapsed or refractory MM (R/R-MM) to the DVd regimen. Eligible patients had clinically active R/R-MM following at least one prior cytotoxic based treatment regimen. Patients received intravenous (IV) pegylated liposomal doxorubicin 40 mg/m2 day 1, vincristine 2 mg day 1 and oral or IV dexamethasone 40 mg daily days 1–4. Cycles were repeated every 28 days for a minimum of 6 cycles and 2 cycles after best response. Myeloma parameters were measured at the start of each cycle. SWOG criteria were used to determine response. Thirty-five patients (21 male and 14 female) with R/R-MM clinically active disease were enrolled. Median age was 59 years (range 43–87). Patients received a median of 2 (range 1–4) prior cytotoxic based treatments. All patients received at least one cycle of treatment (median=5; range 1–12) and were evaluable for response. Ten (29%) patients responded to therapy; 5 partial responses (PR > 50%) and 5 responses (R > 75%) were observed after a median of 2 cycles (range 1–9). Median progression free survival of responding patients (PR + R) was 4.5 mos. (range 0.67–44.8). Patients achieving R had a median progression free survival of 32.5 mos. (3.0–44.8). Thirteen (37%) patients had stable disease (SD) for a median of 1.4 mos. (range 0.8–9.9). Twelve (34%) patients had progressive disease after a median of 1 cycle (range 1–5). The most common toxicities were hematologic; there were four occurrences of febrile neutropenia. Three patients experienced grade 3 constipation and one grade 3 palmar-plantar erythrodysethesia was observed. This study suggests that in patients with R/R-MM, DVd alone yields response rates similar to bortezomib with patients achieving an R experiencing a durable plateau phase. Ongoing studies of DVd in combination with thalidomide or CC-5013 in patients with R/R-MM have resulted in higher and better quality response rates (comparable to autologous SCT) translating to a durable progression free survival. We would not recommend the DVd regimen in patients with R/R-MM without the addition of an immune modulator such as thalidomide.