Lenalidomide and vorinostat maintenance after autologous transplant in multiple myeloma

Abstract

Single-agent post-autologous transplant maintenance therapy with lenalidomide is standard of care for patients with multiple myeloma. The tolerability and effectiveness of combination post-transplant maintenance therapy is unknown, so we investigated lenalidomide and vorinostat (suberoylanilide hydroxamic acid) in this setting, hypothesizing that the regimen would be well tolerated and associated with an improved post-transplant response. This trial followed a standard 3 × 3 dose escalation phase 1 design. Vorinostat was administered beginning day +90 post-haematopoietic stem cell transplantation for days 1-7 and 15-21, and lenalidomide was started at 10 mg days 1-21, both on a 28-d cycle. The primary endpoint was maximum tolerated dose and dose limiting toxicities were assessed during the first cycle. Treatment was well tolerated in 16 enrolled patients. During Cycle 1, the most common toxicities included cytopenias, gastrointestinal complaints and fatigue. Seven patients improved their transplant response after starting combination therapy. The median follow-up was 38·4 months, and the median progression-free survival and overall survival have yet to be reached. This oral post-transplant maintenance regimen was well tolerated. This is the first trial to publish results on the use of a histone deacetylase inhibitor in the maintenance setting, and it provides rationale for the ongoing randomized trial in maintenance (ISRCTN 49407852).

Trial registration: NCT00729118.

Keywords: autologous transplant; deacetylase inhibition; immunomodulatory agent; myeloma.

© 2015 John Wiley & Sons Ltd.

Figures

Fig 1

Ten worst grade adverse events occurring during Cycle 1. Treatment was generally well tolerated and no grade 4 events were experienced by any patient. Grade 3 events included neutropenia, fatigue and hypokalaemia. Grade 2 events included neutropenia, nausea, diarrhoea, fatigue, lymphopenia and emesis. The most frequently experienced grade 1 events included cytopenias (neutropenia, leucopenia and thrombocytopenia), nausea, diarrhoea and hypokalaemia.

Fig 2

Changes in response from transplant to trial discontinuation. Seven of the evaluable 16 patients had an improvement of response following treatment. Two patients improved from stable disease (SD) to partial response (PR), one patient improved from SD to stringent complete response (sCR), two patients improved from PR to very good partial response (VGPR), one patient improved from VGPR to complete response and one patient improved from VGPR to sCR. The remaining nine patients did not have an improvement in response, but all had VGPR or better following autologous stem cell transplantation. *Deceased patients.

Fig 3

Changes in monoclonal protein from before transplant to the end of treatment. The predominant clone for each patient is depicted over time from prior to transplant to screening and through the duration of treatment. 100% represents the pre-transplant baseline and each subsequent data point is the monoclonal protein at a specific time point divided by this baseline value. For example, if a patient had a 50% decrease of the monoclonal protein from the pre-transplant baseline, this would be represented as a monoclonal protein of 50%, and if a patient had evidence of no monoclonal spike, then this would be depicted as 0%. Six patients continue therapy as of 1 September 2014 (dark solid lines). Four patients discontinued study treatment due to toxicities (light solid line) and six patients were found to have disease progression (dotted line). Although patient M’s monoclonal protein more than doubled by Cycle 14, the patient did not meet criteria for progressive disease. C, cycle; D, day (e.g., C1D1 = Cycle 1, Day 1)

Fig 4

Progression-free and overall survival. At the time of analysis (1 September 2014), median progression-free survival (PFS) and overall survival (OS) had not been reached (median days on treatment = 965).