Myeloma: Firstline Phase III Trials in Multiple Myeloma
Superiority of Lenalidomide (Len) Plus High-Dose Dexamethasone (HD) Compared to HD Alone as Treatment of Newly-Diagnosed Multiple Myeloma (NDMM): Results of the Randomized, Double-Blinded, Placebo-Controlled SWOG Trial S0232.
Jeffrey A. Zonder, MD1,
John Crowley, Ph.D.2,
Mohamad A. Hussein, M.D.3,
Vanessa Bolejack, Ph.D2,*,
Dennis F. Moore, Sr.M.D.4,
Brock F. Whittenberger, M.D.5,*,
Muneer H. Abidi, M.D.1,
Brian G.M. Durie, M.D.6 and
Bart Barlogie, M.D.7
1 Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA; 2 Southwest Oncology Group Statistical Center, Seattle, WA, USA; 3 H. Lee Moffitt Cancer Center, Tampa, FL, USA; 4 Wichita Community Clinical Oncology Program, Wichita, KS, USA; 5 Montana Community Clinical Oncology Program, Billings, MT, USA; 6 Salick Healthcare, Inc., Los Angeles, CA, USA and 7 University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Lenalidomide (Len) is an immunomodulatory drug approved foruse with high-dose dexamethasone (HD) as therapy for relapsed-refractorymultiple myeloma (RRMM). Preliminary data suggest Len+HD maybe even more active versus newly-diagnosed myeloma (NDMM). SWOGconducted a randomized, double-blinded, placebo-controlled trial(S0232) comparing Len+HD to HD alone.
Methods: Original study design: enrollment of 500 pts with NDMM(measurable disease, Cr 2.5 mg/dL, ineligible for/decliningimmediate autologous stem cell transplant), with interim analysisafter accrual of 300 pts. The trial was closed after 198 ptswere enrolled, due to external data affecting acceptabilityof HD as the control arm. Pts were randomized to Len 25 mg/d(28 of 35 days for 3 induction cycles, then 21 of 28 days asmaintenance thereafter) plus HD (40 mg days 1–4, 9–12,17–20 induction, then days 1–4, 15–18 maintenance)or HD (same induction and maintenance schedules) plus placebo.Therapy was unblinded for disease progression; pts on HD couldcrossover to Len+HD. After a high initial rate of thrombosis(TEE) was seen in pts on Len+HD, aspirin (ASA) 325 mg/d wasmandated. Pts were stratified by ISS stage and SWOG performancestatus (PS). The primary endpoint is progression-free survival(PFS). Secondary endpoints reported here are overall responserate (ORR), major response rate (MRR), overall survival (OS),and toxicity.
Results: Between Oct 2004 and Mar 2007, 100 pts were randomizedto Len+HD (arm A) and 98 pts to HD plus placebo (arm B), withno differences in age (median 64.6 yrs overall), sex, race,PS, or stage distribution between arms. As of July 18, 2007,61 pts on arm A and 72 pts on arm B were assessable for response.Estimated 1-yr PFS was 77% (arm A), vs 55% (arm B) (p=0.002).The ORR was 85.3% ( MR 79.4%, CR 22.1%) vs 51.3% ( MR 26.2%,CR 3.8%) on arms A and B, respectively (p = 0.001). OS was highin both arms (93% vs 91% at 1 yr; p=NS). Forty pts on arm Bcrossed over to arm A. Of these, 23 are assessable for response:ORR is 70.4% (14.8% CR). Grade 3–4 neutropenia was morefrequent on arm A (13.5% vs 2.4%; p=0.010), as were infections(arm A: n=38, Gr 3–4=13, Gr 5=1; arm B: n=23, Gr 3–4=8,Gr 5=0; p= 0.003). There were 20 TEEs on arm A (14 on ASA prophylaxis)and 12 on arm B (all on ASA; 5 after crossover to Len+HD). Thus,25 TEEs occurred during either blinded or open-label Len+HDvs 7 on HD alone (p=0.089). Discussion: In NDMM, Len+HD is superiorin terms of ORR, MRR, and PFS compared to HD alone. The 1-yrOS in both arms of this study is among the highest reported.ASA at this dose may not be optimal thromboprophylaxis for ptswith NDMM treated with Len+HD, although pt compliance with ASAon this study is not known. With recent evidence that dex intensitymay affect TEE risk, this study was modified to include lowerdose dex (40 mg q wk) with no change in TEE prophylaxis.
Disclosure:Research Funding: Jeffrey Zonder, Mohamad Hussein,Brian Durie, and Bart Barlogie have received research fundingfrom Celgene Corporation. Dr. Barlogie has also received researchfunding from Millennium. Honoraria Information: Brian Durieand Bart Barlogie have received honoraria from Celgene Corporationand also from Millennium. Membership Information: Jeffrey Zonderand Bart Barlogie are on the Speakers Bureau for Celgene Corporation;Dr. Barlogie is also on the Speakers Bureau for Millennium.Off Label Use: At the time of this submission, Lenalidomideplus dexamethasone is approved as therapy for relapsed/refractorymyeloma; this presentation addresses patients with newly-diagnosedmyeloma.