Lenalidomide, Bortezomib, and Dexamethasone in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Encouraging Response Rates and Tolerability with Correlation of Outcome and Adverse Cytogenetics in a Phase II Study.

Background: Bortezomib (VELCADE^®, Bz) is approved for the treatment of multiple myeloma (MM). Lenalidomide (Revlimid^®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed MM pts following ≥ 1 prior therapy. In a phase 1 study, Len/Bz (maximum tolerated dose [MTD] 15 mg/1.0 mg/m²) with or without Dex (20–40 mg) 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 multi-center phase 2 study was to evaluate the efficacy and safety of Len/Bz/Dex (RVD) at the phase 1 MTD.

Methods: Pts with relapsed or relapsed and refractory MM with 1–3 prior lines of therapy received up to eight 21-day cycles of Bz 1.0 mg/m² (days 1, 4, 8, 11) Len 15 mg (days 1–14) and Dex 40/20 mg (cycles 1–4/5–8) on days of/after Bz dosing. After cycle 8, pts with stable or responding disease received maintenance therapy on a 21-day cycle; Bz (days 1 and 8) and Len (days 1–14) at the dose levels tolerated at the end of cycle 8, with Dex at 10 mg (days 1, 2, 8, 9) until disease progression or unacceptable toxicity. Pts received concomitant anti-thrombotic (aspirin 81 or 325 mg/day) and anti-viral prophylaxis. Pts with Grade (G) ≥ 2 peripheral neuropathy (PNY) were excluded. Response was assessed according to modified EBMT and Uniform Criteria with toxicities assessed using NCI CTCAE v3.0. Primary end point was time to progression (TTP).

Results: 64 pts have been enrolled; 38 (59%) with relapsed and 26 (41%) with relapsed and refractory MM. Median number of prior therapies was two, including Len (8%), Bz (55%), Dex (92%), thalidomide (77%), and stem cell transplant (SCT; 36%). Pts received a median of 8 cycles; 31 (48%) completed 8 cycles, 24 continue on maintenance. 4 pts proceeded to stem cell collection (median CD34+ yield of 4.58x10⁶/kg after median of 8 cycles of therapy) and 3 pts proceeded to stem cell transplant, with the 4^th pt currently undergoing salvage therapy to restore disease control. 19 pts discontinued prior to completing 8 cycles due to: progressive disease (10), toxicities (3) or other reason (2). Toxicities were manageable, consisting primarily of G1–2 myelosuppression. Attributable non-hematologic toxicities included deep vein thrombosis (two pts; attributed to Len, both pts remain on-study after antithrombotic therapy), and two episodes of atrial fibrillation (G3) prompting Dex dose reduction. G3 PNY was reported in one pt attributed to Bz and leading to treatment discontinuation despite Bz dose reduction. Dose reductions were required for: Len (13 pts); Bz (9 pts) and Dex (26 pts). One on-study death (thought to be due to fungal pneumonia) was reported during cycle 3: this was not attributed to either Bz or Len, but possibly Dex. In 63 response-evaluable pts, the overall response rate (CR/nCR+VGPR+ PR+ MR) is currently 86%, including 24% CR/nCR and 67% CR/nCR/VGPR/PR. Response rates according to baseline cytogenetics, disease stage, and prior therapies showed no significant differences according to adverse risk (Table). Similarly, analysis of evaluable pts with chromosome 13 deletion by FISH showed no significant difference in response rate compared to those without. Median DOR in responding pts is 21 weeks; range 6–72 weeks. Median TTP and overall survival have not yet been reached.

Conclusions: RVD is very active and well tolerated in pts with relapsed and/or refractory MM, including pts who have received prior Len, Bz, thalidomide, and SCT. Responses appeared independent of adverse cytogenetics, advanced disease stage at diagnosis, prior treatment, and being refractory to prior therapy. Durable responses have been observed. Surrogates and correlative studies are in progress.

Response rates* by baseline cytogenetics, disease stage at diagnosis, and prior treatment