Non Pegylated Liposomal Doxorubicin in Combination with Dexamethasone and Lenalidomide (RMD) Is Active in Advanced MM
Authors: Buda Gabriele , Orciuolo Enrico , Rousseau Martina , Galimberti Sara , Cecconi Nadia , Petrini Mario 
Published: October 2019

Abstract
The pharmacology of liposomal doxorubicin gives rise to a compound with major advantages that could potentially improve response and decrease toxicity. 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. 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. In our hospital we treated 40 patients (24M/16F, see Table I) with of a combination regimen of lenalidomide, non pegylated liposomal doxorubicin (NPLD, Myocet®) and dexamethasone (RMD). All the patients had relapsed multiple myeloma and the majority of them were heavily pretreated (23/40 were resistant to ≥ 2 previous therapies). RMD was administered for a median of six 28-day cycles. Lenalidomide (25mg d 1-21), NPLD 40 mg/m2 d4, Dex 40 mg d1-4 and 17-20. The median age of patients was 61 years and the ORR of the combination was 58%, with 10% of patients achieving a complete or very good partial remission. In particular a high ORR (52%) resulted also in very refractory patients in third line of treatment or more. The median progression-free survival was 9.4 months, while the median overall survival was 21 months (see Table II). The most common side effect was haematological toxicity with grade neutropenia (33%), thrombocytopenia (33%) 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 (8%), diarrhoea (8%). Neither neurotoxicity nor constitutional symptoms of grade 3/4 were found. In our study, lenalidomide in combination with NPLD and dexamethason has shown encouraging activity in heavily pretreated patients with relapsed or refractory multiple myeloma. These schemes can be additional standard of care in the treatment of patients with relapsed or refractory multiple myeloma. The addition of NPLD can play a key role in overcoming anthracycline resistance and improving the quality of response without limiting toxicity. The pharmacology of NPLD gives rise to a compound with major advantages that could potentially improve response and decrease toxicity. Because increased angiogenic activity occurs in the bone marrow of patients with multiple myeloma, this non-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 without limiting toxicity, especially in patients who have already received at least one prior therapy.
Table Characteristics of MM Patients undergoing RMD therapy Characteristics Cases Age at diagnosis (median and range) 61 (30-73) Number of patients 40 (26 M, 14 F) Stage at diagnosis Durie-Salmon (II/III) 31/40 (78%) Number of previous therapies 1 17 (42,5%) 2 10 (25%) 3 8 (20%) 45 3 (7,5%) 2 (5%) Prognostic Markers b2-microglobulin (m/L.) 2.2 (1.1 – 35)a Creatinin (mg/dl.) 0.9 (0.5 – 4.4) a Albumin (g/dl)) 4.0 (2.1 – 4.9) a Hemoglobin (mg/dl) 11.3 (5.7 – 16.4) a .aMedian (Range)
Figure 1 Figure 1.
Figure 2 Figure 2.
Table II Progression Free Survival and Overall Survival (in months)

Disclosures
No relevant conflicts of interest to declare.