Lenalidomide, Bortezomib, and Dexamethasone (RVD) in Combination with Vorinostat As Front-Line Therapy for Patients with Multiple Myeloma (MM): Results of a Phase 1 Study

The combination of lenalidomide (R), bortezomib (V), and dexamethasone (D) (RVD) in newly diagnosed MM patients is well tolerated and associated with a very high overall response rate (Richardson et al, Blood 2010; Kumar et al, Blood 2012). The addition of a novel targeted agent to RVD may improve depth of response as reflected by an increase in complete remission (CR) rate. Preclinical studies have demonstrated that vorinostat (Vor), a histone deacetylase inhibitor, is synergistic with bortezomib, immunomodulatory compounds and dexamethasone. Clinical studies in the relapsed setting using either bortezomib or lenalidomide with vorinostat have yielded promising results with manageable toxicity. The aim of this study was to determine the tolerability and activity of the combination of RVD with vorinostat in newly diagnosed patients with symptomatic MM.

Patients (pts) received the classical RVD regimen (lenalidomide 25 mg days 1–14, bortezomib 1.3 mg/m2 days 1, 4, 8, 11 and dexamethasone 20/10 mg PO [cycles 1–4/5–8] days 1, 2, 4, 5, 8, 9, 11, 12 for up to 8 21 day cycles) combined with oral vorinostat (Vor), provided by Merck and Co. Inc., at 100, 200, 300 or 400 mg daily days 1 – 14 of each cycle. Pts were assigned to one of the four dosing cohorts according to the Bayesian Escalation with Overdose Control (EWOC) algorithm. Dose limiting toxicity (DLT) (Grade (G) 3 non hematologic toxicity, G4 hematologic toxicities defined as G4 thrombocytopenia of any duration; failure of recovery of neutrophils to 1,000/μL or platelets to 50,000/μL within 14 days of the last treatment; or inability to receive Day 1 dose for Cycle 2 due to continued drug-related toxicity from cycle 1) was determined in the first cycle of therapy. Toxicities were assessed and graded for all cycles using the NCI CTCAE v 3.0. Responses were assessed by modified European Group for Blood and Marrow Transplantation and Uniform Criteria. Pts with partial remission (PR) or better could proceed to autologous transplant after 4 cycles. After completion of 8 cycles, patients could continue maintenance with lenalidomide +/− bortezomib, with Vor not administered during maintenance therapy.

Thirty pts (median age 56 years [range 40–76], 63% men) were enrolled with 4 pts in cohort 1 (Vor 100mg), 15 pts in cohort 2 (Vor 200mg), 8 pts in cohort 3 (Vor 300 mg) and 3 pts in cohort 4 (Vor 400mg). The maximum tolerated dose was determined to be 200 mg Vor with RVD. Including maintenance, the median number of cycles completed was 4 (range <1 to 41) with 5 pts completing less than 4 cycles, 4 because of toxicity and one for non-compliance. Ten patients completed 4 cycles and discontinued study therapy and proceeded to autologous stem cell transplant. Eleven pts completed 8 cycles with 8 pts remaining on study having completed between 4 and 41 cycles. Five DLTs have occurred, one in cohort 1 (syncope), one in cohort 2 (venous thromboembolism [VTE]) and 3 in cohort 4 (reversible G4 thrombocytopenia without bleeding; G3 reversible, asymptomatic elevated transaminases and G5 cardiopulmonary arrest, suspected to be due to VTE but not confirmed). The most common G1 or higher toxicities included thrombocytopenia (n=30), constipation (n=25), diarrhea (n=20), fatigue (n=19), nausea (n=16), and neuropathy (n=8). Grade 3 toxicities that occurred in 10% or more of pts were thrombocytopenia (n=8), fatigue (n=5), neutropenia (n=3), cardiovascular (n=3) and neuropathy (n=3). The overall response rate (PR or better) was 100% for the 29 evaluable pts, with a very good PR (VGPR) or better of 52% and a CR rate of 28%. For those pts who completed 4 cycles, VGPR and CR rates were 60% and 32% respectively and for pts who completed 8 cycles, the rates were 64% (VGPR) and 55% (CR). At a median follow up of 11.5 months (range 1 – 31 months) there has been only one pt with progressive disease (asymptomatic relapse from CR).

The combination of RVD with vorinostat using the classical dose and schedule proved most tolerable at 200mg Vor dosing D1-14 every 21 days. The remarkably high VGPR/CR rate after 4 cycles and favorable progression free survival suggest that this combination is very effective. Alternative dosing and schedule of Vor may improve tolerability and so enhance clinical benefit, thus warranting further study.

Kaufman:Onyx: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Merck: Research Funding. Off Label Use: use of vorinostat in myeloma; use of lenalidomide as induction. Shah:Novartis: Honoraria, Research Funding, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harvey:Celgene: Research Funding. Heffner:Millenium: Research Funding. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Orlowski:Celgene: Honoraria, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lonial:Millennium, Celgene, Novartis, BMS, Onyx, Merck; all < $10,000 per year and disclosed to my institution: Consultancy.