Safety and Efficacy of Pegylated Liposomal Doxorubicin In Combination with Dexamethasone and Bortezomib (VMD) or Lenalidomide (RMD) In Multiple Myeloma Refractory/Relapsed Patients

Abstract 5033

The pharmacology of pegylated liposomal doxorubicin (PLD) gives rise to a compound with major advantages that could potentially improve response and decrease toxicity. PLD comprises doxorubicin incorporated into polyethylene-glycol-coated liposomes, resulting in a longer circulation time in the body compared with the conventional formulation and a unique toxicity profile. The lower toxicity, especially less cardiotoxicity, is also related to the encapsulation of doxorubicin into microscopic liposomes, which preferentially penetrate and accumulate in tumour vasculature. Because increased angiogenic activity occurs in the bone marrow of patients with multiple myeloma, this pegylated formulation can enhance the delivery of doxorubicin to the tumour site. In addition, because myeloma cells divide slowly, the increased exposure of these cells to doxorubicin has the potential of overcoming resistance and increasing tumour cell killing capacity, theoretically resulting in improved response rates.

Between December 2008 and May 2010, we treated a total of 39 MM resistant/refractory patients with two different scheme including PLD. Twenty-five patients were resistant/relapsed after at least one prior therapy including conventional doxorubicin. The scheme therapy was based on VMD: bortezomib (Velcade®: 1.3 mg/m²) as intravenous bolus twice a week for 2 weeks (on days 1, 4, 8 and 11 of each cycle) in a 28-day cycle for a total of 4 cycles; oral dexamethasone (40 mg) on the day of each bortezomib dose and the day after, and PLD (Myocet® 30 mg/m²) on day 4 of each cycle, 1 h after bortezomib infusion. Baseline characteristics are shown in table 1. All 25 patients were evaluable for response. Response rates following VMD showed: 2 patients in nCR (10%), 4 in VGPR (20%), 14 in PR (70%) resulting in an overall response rate (ORR) of 80% (20 patients). Global toxicities were lower and included neutropenia (12.5%), fatigue (25%), thrombocytopenia (25%) and neuropathy (37.5%).

In the other group, fourteen patients were treated with RMD a combination regimen of lenalidomide (Revlimid®), PLD (Myocet®) and dexamethasone and 11 patients were eligible for evaluation. All the patients had multiple myeloma resistant or progressed after 1 to 5 previous anti-myeloma regimens including at least one doxorubicin containing scheme. RMD was administered for six 28-day cycle. Lenalidomide 25mg d1-21, Liposomal doxorubicin 30 mg/m² d4, Dex 40 mg d1-4 and d17-20. Eight of eleven patients (73%) achieved an objective response to the therapy. Respectively, 2 patients (25%) obtained a VGPR and additional 6 patients (75%) a PR. The most common side effects was haematological toxicity with grade neutropenia (32%), thrombocytopenia (32%) and anaemia (18%). Under thrombosis prophylaxis with aspirin 100 mg per day we observed thrombembolic complications in only in one patients. Other non haematological side effects were pain (9%), diarrhoea (9%). Neither neurotoxicity nor constitutional symptoms of grade 3/4 were found.

In both of groups no cardiovascular events were reported. Additionally 12 patients of RVM group and 4 patients of RMD group underwent to high dose chemotherapy and successfully collected an adequate number of peripherals stem cells at the first attempt.

The introduction of pegylated liposomal doxorubicin, in bortezomib or lenalidomide based regimens, can play a key role in overcoming anthracycline resistance and improving the quality of response without limiting toxicity, especially in patients who have already received at least one prior therapy. We believe that there is a rational basis for the use of PLD as a second-, third-, or fourth-line therapy in patients with advanced MM.