Lenalidomide and vorinostat maintenance after autologous transplant in multiple myeloma.

UNLABELLED: 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.

A phase 1 study of vorinostat maintenance after autologous transplant in high-risk lymphoma.

Only a minority of patients with high risk lymphoma will be cured with autologous transplant, so maintenance with vorinostat, an oral agent with activity in relapsed lymphoma, was studied starting day + 60 for 21 consecutive days followed by a week off for up to 11 cycles. Twenty-three patients with lymphoma were treated. Ten patients completed the full 11-cycle treatment plan per protocol, four patients were removed due to progressive disease and seven withdrew or were removed from the study due to toxicities. Despite Prevnar vaccine administration every 2 months for three injections, the mean antibody concentration never reached protective levels (> 0.35 µg/mL). Fatigue and functional well-being measured by Brief Fatigue Inventory and Functional Assessment of Cancer Therapy-General improved significantly from cycle 1 to cycle 7, but depression scores from the Center for Epidemiologic Studies Depression scale did not change. Given the toxicities observed, this broad-spectrum deacetylase inhibitor at this schedule is not optimal for prolonged maintenance therapy.

A phase I trial of flavopiridol in relapsed multiple myeloma.

PURPOSE: Flavopiridol is primarily a cyclin-dependent kinase-9 inhibitor, and we performed a dose escalation trial to determine the maximum tolerated dose and safety and generate a pharmacokinetic (PK) profile. METHODS: Patients with a diagnosis of relapsed myeloma after at least two prior treatments were included. Flavopiridol was administered as a bolus and then continuous infusion weekly for 4 weeks in a 6-week cycle. RESULTS: Fifteen patients were treated at three dose levels (30 mg/m(2) bolus, 30 mg/m(2) CIV to 50 mg/m(2) bolus, and 50 mg/m(2) CIV). Cytopenias were significant, and elevated transaminases (grade 4 in 3 patients, grade 3 in 4 patients, and grade 2 in 3 patients) were noted but were transient. Diarrhea (grade 3 in 6 patients and grade 2 in 5 patients) did not lead to hospital admission. There were no confirmed partial responses although one patient with t(4;14) had a decrease in his monoclonal protein >50 % that did not persist. PK properties were similar to prior publications, and immunohistochemical staining for cyclin D1 and phospho-retinoblastoma did not predict response. CONCLUSIONS: Flavopiridol as a single agent given by bolus and then infusion caused significant diarrhea, cytopenias, and transaminase elevation but only achieved marginal responses in relapsed myeloma (ClinicalTrials.gov identifier NCT00112723).