Histone deacetylase inhibitors potentiate the efficacy of anthracyclines and proteasome inhibitors in preclinical models of multiple myeloma (MM). We therefore conducted a phase I clinical trial to evaluate the safety of the histone deacetylase inhibitor, vorinostat, in combination with pegylated liposomal doxorubicin (PLD) and bortezomib for patients with relapsed/refractory MM.
Patients received bortezomib at 1.3mg/m2 on days 1, 4, 8, and 11; PLD at 30mg/m2 on day 4, and escalating doses of vorinostat (200 to 400mg once daily) on days 4 through 11 of a 3-week cycle. Dose escalation followed a standard “3 + 3” design. Patients remained on therapy until disease progression or unacceptable toxicity. Eligibility criteria included an ANC of ≥1.0×109/L, platelets of ≥100×109/L, a CrCl of ≥30 mL/min., and adequate hepatic and cardiac function. The primary objectives of the study were to establish dose limiting toxicities (DLTs) in cycle 1 and the maximum tolerated dose (MTD) for future phase II testing.
Nine patients have enrolled thus far at vorinostat dose levels of 200mg (n=3), 300mg (n=4), and 400mg (n=2). Six patients had relapsed disease, while 3 had relapsed disease that was refractory to their last prior therapy. The median age was 56 (range 44–73), median time from diagnosis was 66 months (range 28 to 117), and median prior number of lines of therapy was 2 (1 to 7). Six of 9 patients received prior bortezomib, 3 of whom were refractory, 7 of 9 had received anthracyclines, 9 of 9 were treated with corticosteroids, 8 of 9 were treated with immunomodulatory agents, and 7 of 9 had undergone autologous stem cell transplantation. One patient was removed from the study at the 300mg vorinostat dose level due to a grade 3 infusion reaction with the first dose of PLD and was not evaluable for DLT or response. Otherwise, there have been no DLTs, serious adverse events, or deaths to date. Common non-hematologic toxicities of all grades have included fatigue (44%), constipation (67%), diarrhea (67%), nausea (56%), vomiting (33%), and peripheral neuropathy (56%), the majority of which were grade 1 and 2 in severity. Grade 3 sensory neuropathy was seen in 2 patients. Common hematologic toxicities of all grades have included neutropenia (44%), lymphopenia (44%), and thrombocytopenia (67%). Grade 3/4 neutropenia, lymphopenia and thrombocytopenia were seen in 2, 3, and 2 patients, respectively. Dose reductions for non-hematologic toxicities have been necessary for 3 patients thus far. Using International Myeloma Working Group criteria, 6 out of 7 evaluable patients have responded to treatment, including 1 complete remission (CR), 1 very good partial remission, and 4 partial remissions (PRs). The only non-responder was assigned to the 200mg vorinostat dose level. PRs were seen in 2 of 3 patients with bortezomib-refractory disease.
At the dose levels tested thus far, the addition of vorinostat to the PLD/bortezomib backbone is safe and efficacious in relapsed/refractory MM patients, including those with bortezomib-refractory disease. Cumulative constitutional, gastrointestinal, and neurologic toxicities are common but manageable, and will need to be considered when determining the optimal phase II dose moving forward. Enrollment into the 400mg dose cohort continues.
Voorhees:Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: Speakers Bureau. Off Label Use: Vorinostat for the treatment of multiple myeloma. Gasparetto:Millennium Pharmaceuticals: Consultancy, Speakers Bureau. Richards:Cephalon, Inc.: Speakers Bureau. Garcia:Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. MacLean:Novartis: Speakers Bureau. Foster:Genzyme: Consultancy, Research Funding. Shea:Otsuka: Research Funding; Novartis: Consultancy, Research Funding; Millennium Pharmaceuticals: Research Funding; Genzyme: Consultancy, Research Funding; Genetech: Consultancy. Rizvi:Merck: Employment.
Asterisk with author names denotes non-ASH members.