Velcade, Vorinostat and Dexamethasone (V² D) in Relapsed Myeloma: Results of the Phase 2 Muk Four Trial

Introduction: Bortezomib (Velcade) and dexamethasone is a standard combination for relapsed myeloma. Both in vitro data and initial clinical trials signalled the efficacy of the combination of intravenous bortezomib and the oral histone deacetylase inhibitor vorinostat. Although the randomised phase 3 VANTAGE 088 trial identified an improvement in progression free survival with the combination of bortezomib and vorinostat compared to bortezomib monotherapy in relapsed myeloma, 50% of patients in the vorinostat group had at least one dose reduction compared with 25% in the placebo group, with potential impact on clinical outcomes. Subcutaneous bortezomib has now become the standard route of administration because of lower rates of peripheral neuropathy. MUK four is a single arm phase 2 multi-centre UK trial to evaluate the toxicity profile and efficacy of an alternative dosing schedule of vorinostat in combination with subcutaneous bortezomib and oral dexamethasone. We report the final analysis of toxicity and response data.

Methods: Patients with relapsed myeloma treated with 1-3 prior lines of therapy received up to 8 cycles of V² D (bortezomib 1.3 mg/m² subcutaneously days 1, 4, 8 and 11, vorinostat 400 mg orally days 1-4, 8-11 and 15-18 and dexamethasone 20 mg orally days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21 day cycle). Following completion of a minimum of 3 cycles of V² D, participants received maintenance vorinostat (400 mg days 1-4 and 15-18 of a 28 day cycle) until disease progression, intolerance or participant withdrawal. Responses were assessed using the modified IMWG response criteria and toxicities graded using CTCAE v4.0.

Results: Between August 2013 and November 2014, 16 participants were recruited to MUK four. Median age was 69.5 years (range 50.0-78.0) and median lines of prior treatment was 1 (1-3). Prior treatment included thalidomide-based combinations in 13/16 (81.3%), bortezomib-based in 7/16 (43.8%) and lenalidomide-based in 2/16 (12.5%). 9/16 (56.3%) participants had received prior high dose melphalan ASCT. Median time from diagnosis was 38.6 months (9.3-120.4).

At analysis in June 2015 8/16 (50%) participants continued on maintenance vorinostat. All 16 patients were evaluable for response within the first 8 cycles of V² D. Overall response rate was 81.3% (13/16, 95% CI [55.4-96.0]) consisting of CR in 4/16 (25.0%), VGPR 2/16 (12.5%) and PR in 7/16 (43.8%). The remaining 3/16 (18.8%) achieved MR giving a clinical benefit response rate of 16/16 (100%).

Participants received a median of 6 cycles of initial treatment with 6/16 (37.5%) receiving all 8 cycles. Treatment was discontinued in 4/8 (50%) because of disease progression, in 2/8 (25%) because of toxicity and in 2/8 (25%) for clinician discretion. Overall 12/16 (75%) participants experienced a dose reduction of either vorinostat or bortezomib or terminated treatment early as a result of toxicity. 11/16 (68.8%) reduced vorinostat and 10/16 (62.5%) reduced bortezomib. The most frequent grade 2 toxicities during the first 8 cycles were fatigue in 8/16 (50%), anaemia in 7/16 (43.8%), diarrhoea in 5/16 (31.3%), nausea in 4/16 (25.0%) and peripheral neuropathy in 4/16 (25.0%). The most frequent grade 3-4 toxicities encountered during the first 8 cycles were thrombocytopenia in 8/16 (50%), anaemia in 1/16 (6.3%), diarrhoea in 1/16 (6.3%) and fatigue in 1/16 (6.3%). During maintenance vorinostat only 1 participant experienced an adverse reaction above grade 2 (grade 3 neutropenia).

Conclusion: Bortezomib, vorinostat and dexamethasone is a highly effective combination in relapsed myeloma with good response rates. Maintenance vorinostat is well tolerated. Although toxicity and dose reductions are observed with combination therapy, this study demonstrates that the combination of proteasome inhibitor, HDAC inhibitor and dexamethasone offers promise. Further data on PFS will be presented.