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Combination of Revlimid and Velcade in the Treatment of Relapsed/Refractory Myeloma
By Paul G. Richardson, MD
12.17.06





Dr. Richardson presented the final results of a Phase I trial of the combination of Revlimid and Velcade (Rev-Vel). Rev-Vel with or without dexamethasone is well tolerated and did not produce significant peripheral neuropathy in any of the 38 patients in the study, even when dex was added. It produced durable responses even in patients who were heavily pretreated with Rev, Vel, thalidomide, and SCT.

ABSTRACT:

Lenalidomide Plus Bortezomib (Rev-Vel) in Relapsed and/or Refractory Multiple Myeloma (MM): Final Results of a Multicenter Phase 1 Trial. Session Type: Oral Session

Paul G. Richardson, S. Jagannath, D.E. Avigan, M. Alsina, R.L. Schlossman, A. Mazumder, N.C. Munshi, I. Ghobrial, D. Doss, M.L. McKenney, M.G. Farrell, D.L. Warren, L.E. Lunde, B. Gourley, S. Vaccaro, C. Delaney, S. Pountney, C.S. Mitsiades, T. Hideshima, C. Byrne, R. Knight, A. Birner, T. Myers, E. Weller, K.C. Anderson Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; St Vincents Comprehensive Cancer Center, New York, NY, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA; H. Lee Moffitt Cancer Center, Tampa, FL, USA; Celgene, Inc, Summitt, NJ, USA; Millennium Pharmaceuticals, Inc, Cambridge, MA, USA

Background: Bortezomib (VELCADE, Vel) and lenalidomide (Revlimid, Rev) are both highly effective agents in multiple myeloma (MM). Preclinical studies show Rev sensitizes MM cells to Vel and dexamethasone (Dex), suggesting combination therapy may enhance clinical activity. This phase 1 dose-escalation study aimed to determine MTD and activity of RevVel +/- Dex combination therapy in patients (pts) with relapsed and/or refractory MM. Methods: Eight cohorts (3 pts each) were planned, with dosing of Vel 1.0 or 1.3mg/m2 (d 1, 4, 8, 11) and Rev 5, 10, 15, or 20mg (d 114), in 21-d cycles. Dex 40mg (on day of and day after each Vel dose) could be added in pts with PD. NCI CTCAE v3.0 was used for toxicity assessment; DLT was defined as any grade (G) 3 non-hematologic toxicity, G4 neutropenia for 5 d and/or neutropenic fever, or platelets <10,000/mm3 on >1 occasion despite transfusion. Response was assessed by modified EBMT criteria. Results: 28 pts were enrolled in cohorts 16 (Rev 515mg, Vel 1.01.3mg/m2) plus 10 additional pts at the MTD (Dose Level 5), including 12 with relapsed and 26 with relapsed and refractory MM (n=38). Among 25 men and 13 women, median age was 60yrs (range: 3779), and median no. of prior therapies was 5 (range: 113), including 23 pts with prior SCT, 23 with prior Vel, 6 with prior Rev, and 36 with prior thalidomide (Thal). One DLT was observed in cohort 4 (Rev 10mgVel 1.3mg/m2; transient G3 hyponatremia). DLT was reached in cohort 6 (Rev 15mgVel 1.3mg/m2) with 1 episode of G3 HZV reactivation (successfully treated with acyclovir) and 1 G4 neutropenia (reversed with GCSF support and dose reduction). MTD was therefore declared at Rev 15mgVel 1.0mg/m2. In total, 5 pts had dose reductions for Vel, 6 pts for Rev, and 5 pts for both Rev and Vel. No significant (G3) fatigue or peripheral neuropathy has been seen. No anticoagulant prophylaxis was required and only 1 pt had DVT while on Rev alone. In 36 evaluable pts, the overall response rate (CR+PR+MR) is 58% (90% CI: 46%, 75%), including 6% CR/nCR (Table) after a median of 6 cycles (range: 417). Responses were durable (median 6 months, range: 126), and 11 pts remain on therapy beyond 1 year. Dex has been added in 14 pts with PD, resulting in PR/MR/SD in 10 (71%), with just 1 pt experiencing Dex-related G2 diarrhea and fatigue, which prompted discontinuation of therapy. Conclusions: RevVel +/- Dex is well tolerated and very active with durable responses seen in pts with heavily pretreated relapsed and/or refractory MM, including pts who have had prior Rev, Vel, Thal and SCT. An MTD of Rev 15mgVel 1.0mg/m2 has been defined, with Phase 2 studies now ongoing in both newly diagnosed and relapsed/refractory MM.

Best responses by RevVel cohort (EBMT criteria)
Cohort RevVel dose Vel 1.0mg/m Vel 1.3mg/m
12 Rev 5mg 2PR, 1MR 1CR, 2PR
34 Rev 10mg 1nCR, 2PR 2PR, 2MR, 1SD, 1PD
56 Rev 15mg 2PR, 4MR, 7SD, 1PD 2 PR, 5SD



Abstract #405 appears in Blood, Volume 108, issue 11, November 16, 2006