A Phase III Study to Compare Melphalan, Prednisone, Lenalidomide (MPR) Versus Melphalan 200 Mg/m² and Autologous Transplantation (MEL200) In Newly Diagnosed Multiple Myeloma Patients

In this randomized study we question the role of HDT, when new drugs are incorporated in the conventional treatment or in the autologous transplant setting in newly diagnosed multiple myeloma (MM) patients.

To compare melphalan, prednisone and lenalidomide (MPR) with tandem melphalan (200 mg/m²) (MEL200) in MM patients younger than 65 years.

The induction treatment consisted of four 28-day cycles of lenalidomide (25 mg d 1–21) and low-dose dexamethasone (40 mg d 1,8,15,22) (Rd). Cyclophosphamide plus G-CSF was used to mobilize stem cells. As consolidation, patients were randomized to MPR (N=202) [six 28-day cycles of melphalan (0.18 mg/k g d 1–4), prednisone (2 mg/kg d 1–4) and lenalidomide (10 mg d 1–21))] or MEL200 (N=200)[tandem melphalan 200 mg/m² with stem-cell support]. All patients were also randomized to receive either aspirin or low-molecular weight heparin (enoxaparin) as thromboprophylaxis during Rd and MPR. Primary study endpoint was progression free survival (PFS). Data were analyzed in intention-to-treat.

From november 2007 to july 2009, 402 patients with newly diagnosed symptomatic MM younger than 65 years of age were recruited and randomized. All patients enrolled were stratified according to International Staging System (ISS) (stages 1 and 2 vs stage 3) and age (<60 vs ≥60 years).

On an intention to treat basis, best responses after Rd induction, were: partial response (PR) rate was 87%, very good partial response (VGPR) rate was 52%, including 13% complete responses (CR). The median yields of stem cells harvested was 8.7 ×10⁶ CD34+ cells/Kg; 91% of patients collected the minimum dose of 4×10⁶/kg CD34+ cells. As of August 10^th, 257 patients are evaluable for response after at least 3 cycles of MPR (124) and after the first MEL200 (133); best responses to consolidation: in the MPR group, the VGPR rate was 60% including 20% CR; in the MEL200 group the VGPR rate was 58% including 25% CRs. No differences in responses were reported according to chromosomal abnormalities, such as del13, t(4;14), t(14;16) or del17p. After a median follow-up of 14 months, the projected 2-year PFS and OS were similar in the two groups (table). The achievement of at least VGPR after consolidation was a predictive factor of longer PFS in both groups: in the MEL200 group, the 2-year PFS was 92% for patients with at least VGPR vs 70% for those with PR (p<.0001); in the MPR group 86% vs 61% respectively (p<.0001). MPR and MEL200 were equally effective in patients with chromosomal abnormalities (2-year PFS was 71% vs 77%; p=.39) or ISS 3 (2-year PFS was 58% vs 66%; p=.48). Induction with Rd was well tolerated: the most frequent grade 3–4 adverse events were neutropenia (8%), anemia (7%), infections (4%) and skin rash (5%). The incidence of thromboembolic events was similar in patients randomized to aspirin (2%) or low molecular weight heparin (1%) as thromboprophylaxis (p=.45). During consolidation, the incidence of grade 3–4 neutropenia (97% vs 32%;p <.001), thrombocytopenia (59% vs 5%; p<.001), infections (10% vs 1%, p<.001) and gastrointestinal (15% vs 1%, p<.001) complications was higher in MEL200 patients.

Our study confirms the efficacy and safety of Rd induction. Both MPR and MEL200 improved the quality of response, achieved by Rd induction. At present, PFS and OS are not significantly different in the two groups, but longer follow-up is needed. These data will be updated at the meeting.

Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janseen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo:Celgene: Honoraria. Patriarca:Celgene: Honoraria; Roche: Honoraria; Janssen-Cilag: Honoraria; Merck: Membership on an entity's Board of Directors or advisory committees. Caravita:Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janseen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.