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.

Lenalidomide (Len) is an immunomodulatory drug approved for use with high-dose dexamethasone (HD) as therapy for relapsed-refractory multiple myeloma (RRMM). Preliminary data suggest Len+HD may be even more active versus newly-diagnosed myeloma (NDMM). SWOG conducted 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/declining immediate autologous stem cell transplant), with interim analysis after accrual of 300 pts. The trial was closed after 198 pts were enrolled, due to external data affecting acceptability of 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 as maintenance 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 could crossover to Len+HD. After a high initial rate of thrombosis (TEE) was seen in pts on Len+HD, aspirin (ASA) 325 mg/d was mandated. Pts were stratified by ISS stage and SWOG performance status (PS). The primary endpoint is progression-free survival (PFS). Secondary endpoints reported here are overall response rate (ORR), major response rate (MRR), overall survival (OS), and toxicity.

Results: Between Oct 2004 and Mar 2007, 100 pts were randomized to Len+HD (arm A) and 98 pts to HD plus placebo (arm B), with no 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 high in both arms (93% vs 91% at 1 yr; p=NS). Forty pts on arm B crossed over to arm A. Of these, 23 are assessable for response: ORR is 70.4% (14.8% CR). Grade 3–4 neutropenia was more frequent 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+HD vs 7 on HD alone (p=0.089). Discussion: In NDMM, Len+HD is superior in terms of ORR, MRR, and PFS compared to HD alone. The 1-yr OS in both arms of this study is among the highest reported. ASA at this dose may not be optimal thromboprophylaxis for pts with NDMM treated with Len+HD, although pt compliance with ASA on this study is not known. With recent evidence that dex intensity may affect TEE risk, this study was modified to include lower dose dex (40 mg q wk) with no change in TEE prophylaxis.