Vorinostat in Combination with Lenalidomide (L) and Dexamethasone (d) in Multiple Myeloma Patients Refractory to Previous Lenalidomide-Containing Regimens: Results of a Phase IIb Trial

Abstract

Background: Despite improvements in the treatment of relapsed/refractory multiple myeloma (RRMM), the disease remains incurable and new approaches to treatment are necessary. Clinical trials of vorinostat (V), a Class I/II pan-histone deacetylase (HDAC) inhibitor, in combination with proteasome inhibitors (PI) and immunomodulatory agents (IMiDs) have shown activity in RRMM. We report a Phase IIb, open-label, single institution study of V in combination with Ld in MM pts refractory to previous L-containing regimens.Patients and Methods: Eligibility criteria included pts with RRMM who had received ≥1 prior anti-MM regimen, no prior HDAC inhibitor, and must have been refractory to L, defined as either progression of disease (PD) on L therapy or no clinical response (< minimal response (MR) to at least 2 cycles on a previous L-containing regimen. LVd was administered in a 28-day cycle with oral V 400mg d 1-7 and 15-21, L 25mg d 1-21 and dexamethasone 40mg d 1,8,15, and 22. The primary endpoint was overall response rate (ORR).Results: 25 pts were enrolled from March 2012 to January 2014. Median age was 65 years (48-82), 18 (72%) were male. The median time from diagnosis to study entry was 4.95 yrs, median number of prior regimens was 5 (3-10); 24 (96%) had undergone at least 1 prior autologous transplant, 20 (80%) had prior PI exposure, and 9 (36%) had prior thalidomide. The last line of therapy prior to study entry was Ld in 16 (64%) and a non-L regimen in 9 (36%). Of pts on Ld prior to study entry, 11 were refractory and 5 relapsed/refractory to treatment. The last line of therapy in all 9 pts on a non-L regimen prior to study entry was a PI-containing therapy and in these pts the median time since last treatment with a L-containing regimen was 13.31 months (mos) (1.87-58.38).The ORR (≥ partial response (PR) was 24% (n=6); in addition 1 MR and 13 SD (52%) was observed for an overall objective response rate (≥ SD) of 80%. The median time to best response was 1.90 mos (0.93-3.67); median duration of response of pts in PR was 3.25 mos (95% CI 1.17-5.33). Five pts (20%) had PD after the first cycle of therapy. Of the 5 pts who were relapsed/refractory to Ld therapy prior to study entry, 1 achieved PR, 1 MR, and 3 SD. The median PFS of the entire cohort was 5.4 mos (95% CI 1.58-9.15), with 6-month (mo) PFS rate 48% and 12-mo PFS rate 6% (Figure 1). There was no significant difference in ORR between pts whose last line of therapy prior to study entry was Ld vs. a non-L regimen: ORR 19% and 33%, respectively (p=0.42). Median PFS was 3.80 mos (95% CI 3.16-4.44) vs. 6.97 mos (95% CI 3.06-10.87) in pts whose last line of therapy prior to study entry was Ld vs. a non-L regimen, respectively (p = 0.084, log rank test).All 25 pts (100%) had at least 1 drug-related adverse event (AE). Common AEs (any grade, most of which were Grade 1/2) at least possibly attributable to the study drugs included diarrhea (72%), fatigue (72%), anorexia (28%), nausea (28%), dysgeusia (28%). Most grade 3/4 AEs were related to hematologic toxicities with Grade 3/4 anemia, neutropenia, and thrombocytopenia occurring in 20%, 48%, and 32%, respectively. Dose modifications for either V or L were necessary in 18 pts (72%) due to thrombocytopenia, neutropenia, and/or diarrhea. 8 pts (32%) experienced at least one serious AE, of which only 2 were considered possibly related to therapy.Only one patient was withdrawn from study due to toxicities (cytopenias), other reasons for study discontinuation included PD 20 pts (80%) and consent withdrawal in 3 (12%). Median OS was 23.4 mos (95% CI 16.42-30.45), with 12-mo and 24-mo OS 72% and 49%, respectively (Figure 2).Conclusions: The combination of V with Ld resulted in ORR 24% and overall objective response rate of 80%, an appreciable clinical benefit considering the study group was a heavily pre-treated population with RRMM. Notably, in pts progressing on Ld immediately prior to study entry, the addition of V to Ld appears to enhance the anti-myeloma effect of L and re-sensitize pts to Ld therapy. Further studies are warranted to better characterize the role of vorinostat and other novel HDAC inhibitors in combination with IMiDs and PIs in RR MM. [Display omitted] [Display omitted] DisclosuresMcBride:Celgene: Speakers Bureau. Bilotti:Pharmacyclics LLC, an AbbVie Company: Employment. Vesole:Idera Pharmaceuticals: Research Funding; Celgene Corporation: Speakers Bureau. Biran:Celgene: Speakers Bureau. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau.