Lenalidomide, Bortezomib, Pegylated Liposomal Doxorubicin, and Dexamethasone In Newly Diagnosed Multiple Myeloma (MM): Final Results of Phase I/II MMRC Trial

• Published in: Blood 2010-11, Vol.116 (21), p.1937-1937
• Main Authors: Jakubowiak, Andrzej J, Reece, Donna E., Hofmeister, Craig C., Lonial, Sagar, Zimmerman, Todd M, Campagnaro, Erica L., Schlossman, Robert L., Laubach, Jacob P., Raje, Noopur, Anderson, Tara B., Griffith, Kent A., Hill, Melissa A., Harvey, Colleen K., Wear, Sandra, Barrickman, Jennifer, Tendler, Craig L., Esseltine, Dixie-Lee, Kelley, Susan L., Kaminski, Mark S., Anderson, Kenneth C., Richardson, Paul G.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V116.21.1937.1937

Abstract 1937 Three-drug combinations with bortezomib (Bz) and/or either thalidomide or lenalidomide (Len) are highly active in frontline MM and appear superior to at least some 2-drug combinations with these agents. In an attempt to further improve treatment outcomes, we developed the 4-drug RVDD regimen of lenalidomide (Revlimid®, Len), Bz (Velcade®), pegylated liposomal doxorubicin (Doxil®, PLD), and dexamethasone (Dex), which demonstrates high activity in newly diagnosed MM. Here we present final results of this Phase I/II trial. Patients (Pts) received eight 3-week cycles with Len 15–25 mg (days 1–14), Bz 1.3 mg/m2 (days 1, 4, 8, 11), Dex 20/10 mg (cycles 1–4/5-8; days of and after Bz), PLD 20 or 30 mg/m2 (day 4) at 4 dose levels and the maximum tolerated dose (MTD; Phase II). Responses were assessed by modified EBMT and IMWG criteria with the addition of nCR. Pts could proceed to autologous stem cell transplant (ASCT) or continue treatment, which after 8 cycles consisted of 21-day maintenance cycles with Len (days 1–14), Bz (day 1 and 8), and Dex (days of and after Bz) at the doses tolerated by the end of initial treatment. The primary objectives were to evaluate MTD and VGPR rate at the end of 4 and 8 cycles. The study enrolled 72 pts with a median age 60 (range 29–77); 53% ISS II/III; 46% any of the del 13q, t(4;14), t(14;16), or del 17p, of which 37 were treated at the MTD (including 6 in Phase I). Pts received a median of 4.5 cycles (range 2–31); 70 pts completed at least 4 cycles and 20 at least 8 cycles. Five pts developed DLTs, including 2 pts grade (G) 3 asymptomatic neutropenia, 1 G3 elevation of transaminases, 1 G3 drug fever, and 1 G3 hypophosphatemia. Based on the pre-determined definition of MTD, the maximum planned doses of Len 25 mg, Bz 1.3 mg/m2, PLD 30 mg/m2, and Dex 20/10 mg were selected as the maximum tolerated dose (MTD) for the Phase II portion of the study as the closest to, but not exceeding, a target rate of 20% DLTs. The most common toxicities (all grades) were fatigue (83%), infections (72%), constipation (69%), and sensory neuropathy (65%) of which 8%, 14%, 1%, and 6% were G3, respectively. Other G3/4 toxicities included neutropenia (19%), infections (16 %), thrombocytopenia (11%), hyperglycemia (10%), and DVT/PE (3%). There was 25% G1/2 palmar-plantar erythrodysesthesia and 1 pt experienced G1 asymptomatic and reversible decrease in ejection fraction attributed to PLD. Importantly, there was no treatment-related mortality