Lenalidomide, Bortezomib, and Dexamethasone (Rev/Vel/Dex) in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Preliminary Results of a Phase II Study.

Background: Single-agent bortezomib (VELCADE®, Vel) and lenalidomide (Revlimid®, Rev) plus dexamethasone (Dex) are approved for relapsed MM patients (pts) following ≥1 prior therapy. Preclinical studies show Rev sensitizes MM cells to Vel and Dex, suggesting combination therapy may enhance clinical activity. In a phase 1 study, Rev/Vel (MTD 1.0mg/m²/15mg) ± Dex (20–40mg) was well tolerated and resulted in a response rate (CR+PR+MR) of 58% in relapsed and/or refractory MM pts. The aim of this multicenter phase 2 study was to evaluate the efficacy and safety of Rev/Vel/Dex (RVD) at the phase-1 MTD in up to 64 relapsed and/or refractory MM pts.

Methods: Pts with relapsed/refractory MM and 1–3 prior lines of therapy received up to eight 21-d cycles of Vel 1.0mg/m², d 1, 4, 8, 11, Rev 15mg, d 1–14 of a 21-d cycle, and Dex 40mg (cycles 1–4)/20mg (cycles 5–8), days of/after Vel dosing. After cycle 8, pts with stable or responding disease were allowed to continue on a maintenance schedule with Vel (d 1 and 8) and Rev (d 1–14) at the dose levels tolerated at the end of cycle 8, with Dex at 10mg (d 1, 2, 8, 9). Pts received concomitant antithrombotic and antiviral prophylaxis. Response was assessed according to modified EBMT and Uniform criteria with toxicities assessed using NCI CTCAE v3.0.

Results: 27 pts (19 men, 8 women) have been enrolled to date, including 16 with relapsed and 11 with relapsed and refractory MM. Median age was 71 yrs (range 51–83) and median no. of prior therapies was 2 (range 1–3), including prior SCT in 7, prior Vel in 18, prior Rev in 1, prior thalidomide in 21 and prior Dex in 22 pts. Pts received a median of 7 cycles (range 1–15); 10 pts completed 8 cycles and 5 pts continued on maintenance. Dose reductions were required for Rev in 4, Vel in 4 and Dex in 11 pts. Toxicities were manageable and consisted primarily of G1-2 myelosuppression. Attributable non-hematologic toxicities included 1 DVT in the context of air travel in a pt who had been receiving aspirin 81mg as thromboprophylaxis. Enoxaparin and Coumadin were administered and the pt continued on therapy. Two episodes of atrial fibrillation (G3) were reported, reversed with cardiac medication, attributed to Rev/Dex, prompted Dex dose reduction and have not recurred. G3 PN was reported in only 1 pt despite Vel dose reduction, resulting in treatment discontinuation. In 24 evaluable pts, ORR (CR/nCR+VGPR+PR+MR) is currently 79%, including 33% CR/nCR/VGPR.

Conclusions: RVD is very active in pts with relapsed and/or refractory MM, including pts with prior Rev, Vel, thalidomide, and SCT. Dex dose reduction was required in 11 pts and the protocol has been amended to use lower dose Dex at 20 mg, but the combination has been otherwise well tolerated, with low rates of DVT and PN. Accrual is ongoing.