ORLANDO, Fla.—Despite prior therapy with novel agents, the combination of lenalidomide, bortezomib, and dexamethasone (RVD) is very active and well tolerated in patients with relapsed and relapsed/refractory multiple myeloma after >2 years of follow-up have shown.

Based on 32 patients who remained alive at data cutoff, overall survival (OS) results are also encouraging, noted Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston, Mass. A previous phase 1/2 study demonstrated that as front-line therapy, the combination of lenalidomide 25 mg, bortezomib 1.3 mg/m2, and dexamethasone 20/10 mg generated high response rates (Richardson et al. Blood. 2010.). A phase 1 study found the combination to be well tolerated, with 58% ≥ minimal response (MR) and maximum tolerated doses (MTDs) of bortezomib 1.0 mg/m2 and lenalidomide 15 mg (Richardson et al. J Clin Oncol. 2009.).

The goal of this multicenter, phase 2 study was to evaluate further the efficacy of RVD in patients with relapsed or relapsed/refractory multiple myeloma at the MTD, the investigators outlined in a poster presentation during the 52nd American Society of Hematology Annual Meeting and Exposition.

Eligibility included relapsed or relapsed/refractory multiple myeloma following 1 to 3 prior therapies, age ≥18 years, and Karnofsky Performance Status ≥60%. Patients with peripheral neuropathy grade ≥2 were excluded. Patients received up to 8, 21-day cycles of bortezomib 1.0 mg/m2 (days 1, 4, 8, 11); lenalidomide 15 mg/day (days 1-14); dexamethasone 40/20 mg/day (cycles 1-4); and 20/10 mg/day (cycles 5-8) (days 1, 2, 4, 5, 8, 9, 11, 12). Patients who responded could receive maintenance therapy: 21-day cycles of bortezomib (days 1, 8), lenalidomide (days 1-14), and dexamethasone (days 1, 2, 8, 9), all at doses tolerated at end of cycle 8.

Patients were required to take anticoagulation therapy (aspirin 81 or 325 mg/d) and prophylactic antivirals. Primary end point was proportion of patients alive and progression free (PFS) at 6 months. Secondary end points included objective response rate (modified EBMT [European Group for Blood and Marrow Transplantation] criteria), time to response (TTR), duration of response (DOR), time to progression (TTP), OS, and safety/tolerability.

Sixty-four patients were treated. Median age was 65 years (range, 32-83 years)—66% were men; 58% had relapsed and 42% had relapsed/refractory multiple myeloma; 59% had Durie-Salmon stage 3 disease at diagnosis. Median number of prior therapies was 2; 53% had received bortezomib; 73% thalidomide; 6% lenalidomide; and 89% dexamethasone. A median of 11 cycles (range, 1-48 cycles) was administered; the median was 11 (1-48) for lenalidomide; 9 (1-48) for bortezomib; and 9 (1-48) cycles for dexamethasone. A total of 42 patients (66%) received ≥8 cycles (maintenance). Reasons for discontinuation before cycle 8 included progressive disease (PD; n=11) and toxicity (n=3). Eighteen patients (28%) were on study for >1 year and 6 remained on study at 16-34 months from treatment initiation.

Dexamethasone starting dose was 40 mg in 19 patients and 20 mg in 45. In total, 40 (62%) required dose reductions.

At ≥6 months from treatment initiation, 43 patients (74%) were alive without PD (90% CI, 65, 84); 50 (78%) achieved ≥MR and 41 (64%) ≥ partial response (PR); 16 (25%) achieved complete response (CR)/near CR. No difference (P=0.8) was detected in ≥PR rate between patients with relapsed (62%) or relapsed/refractory (67%) disease.

In patients with ≥MR or ≥PR, median time to best response was 1.9 and 2.1 months, and median DOR was 8.3 and 8.4 months, respectively. After median follow-up of 26 months, 55 patients have PD, and 32 have died. Median TTP was 9.5 months; estimated 6-, 12-, and 24-month TTP rates were 76%, 37%, and 16%, respectively. Median PFS was 9.5 months; with respective 6-, 12- and 24-month rates of 75%, 36%, and 15%. Median OS was 26 months, with respective 12- and 24-month OS rates of 86% and 55%. Preliminary analysis suggests no significant difference in outcome (PFS/OS) between patients with abnormal cytogenetics by metaphase karyotyping or FISH.

Common treatment-related toxicities included sensory peripheral neuropathy (64%), fatigue (48%), neutropenia (42%), diarrhea, muscle pain (both 39%), and hyperglycemia (36%); most common grade 3/4 toxicities included neutropenia (30%), thrombocytopenia (22%), lymphopenia (11%), hyperglycemia, leukopenia (both 9%), hyponatremia, and hypophosphatemia (both 8%). No grade 3/4 sensory peripheral neuropathy or neuropathic pain was reported; 3% grade 3 motor peripheral neuropathy (2 patients) was observed. Two patients (3%) developed thrombosis, attributed to lenalidomide. Peripheral neuropathy was manageable and reversible in most patients. Only 5 patients (8%) discontinued treatment due to toxicity of any cause.

The investigators concluded further investigation of this regimen is warranted, both at the higher lenalidomide and bortezomib doses in the front-line setting—with subsequent dose reductions and schedule change as required for potential toxicities—as well as in combination with other agents.

Off Label Use: Bortezomib and lenalidomide in novel combination.