Lenalidomide, Bortezomib, Pegylated Liposomal Doxorubicin, and Dexamethasone In Newly Diagnosed Multiple Myeloma (MM): Final Results of Phase I/II MMRC Trial
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. 
Published: October 2019

Abstract
Abstract 1937

Background:
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.

Methods:
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.

Results:
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. The best response rates for all pts were as follows: 96% ≥ PR, 66% ≥ VGPR, and 38% CR/nCR. At the end of 4 and 8 cycles, defined in the protocol for efficacy assessment, response rates were: 96% and 95% ≥ PR, 57% and 65% ≥VGPR and 29% and 35% CR/nCR; at the MTD ≥PR was 96%, ≥VGPR 66%, and CR/nCR 34%. Response rates were not statistically different in a subset of pts with any of del 13q, t(4;14), t(14;16), or del 17p. Forty-seven (65%) pts proceeded to ASCT, after collection of a median 6.7 × 106 CD34+ cells/kg (range 1.9–17.7). At 3 months post ASCT, ≥ VGPR and CR/nCR rates improved in 45 evaluable pts from 64% to 84% and from 38% to 60%, respectively. After a median of 15.5 months of follow-up, the estimated 18-month PFS for all pts is 84% and overall survival 99%.

Conclusion:
RVDD is generally well tolerated and highly active with rapid reduction of MM tumor burden seen (≥ PR 96%, ≥VGPR 57% and CR/nCR rate 29% at the completion of 4 cycles). Response rates further improved after additional treatment, both in pts who continued RVDD treatment (’VGPR 65%, CR/nCR 35%) and pts who proceeded to ASCT (≥VGPR 84%, and CR/nCR 60%), although some additional toxicity was noted. Whether the incorporation of a 4th agent in the form of PLD has made an impact in this pt population remains to be defined. At equivalent time points (i.e. at the completion of 4 and 8 cycles), the ≥VGPR and CR/nCR rates as well as the current estimated PFS appear to compare favorably to RVD, which provides the rationale for consideration of further studies with this regimen, including potential randomized trials in this setting.

Disclosures:
Jakubowiak: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide for newly diagnosed multiple myeloma. Reece:Celgene: Unrestricted educational lectures, research funding, ad hoc advisory boards. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau. Zimmerman:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Campagnaro:NIH: Research funding for NIH K12 CA076917. Raje:Celgene: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Acetylon: Research Funding. Anderson:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barrickman:Celgene: Employment, Equity Ownership. Tendler:Johnson & Johnson Pharmaceutical Services: Employment, Equity Ownership. Esseltine:Millennium: The Takeda Oncology Company: Employment; Johnson & Johnson: Equity Ownership. Anderson:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.