Results of a Phase I Study of Vorinostat In Combination with Pegylated Liposomal Doxorubicin and Bortezomib In Patients with Relapsed/Refractory Multiple Myeloma

The histone deacetylase inhibitor vorinostat has additive to synergistic activity in combination with anthracyclines and proteasome inhibitors in preclinical models of multiple myeloma (MM). We therefore sought to evaluate the safety of vorinostat in combination with pegylated liposomal doxorubicin (PLD) and bortezomib in patients with relapsed and/or refractory MM.

Treatment consisted of PLD 30mg/m² on D4, bortezomib 1.3mg/m² on D1,4,8,11 and escalating doses of vorinostat from either D4-11 or D1-14 of a 3-week cycle. Dose escalation followed a standard “3 + 3” design. Patients could remain on therapy until disease progression or unacceptable toxicity. Key eligibility criteria: relapsed and/or refractory MM, ANC≥1.0×10⁹/L. plts≥100×10⁹/L, CrCl≥30mL/min, adequate hepatic and cardiac function. The primary objective of the study was to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the regimen.

20 patients have enrolled at the following dose levels:

The median age was 60 (range 44–73), median time from diagnosis 42.5 months (9 to 117), and median number of prior lines of therapy 2 (1 to 7). 90% of patients received prior immunomodulatory drugs, 65% bortezomib, 65% autologous stem cell transplantation, and 50% anthracyclines. 55% of patients were relapsed; 45% relapsed and refractory. 9 of 13 patients had disease resistant to prior bortezomib-based therapy. Grade 3 and 4 neutropenia was seen in 35% and 5% of patients, respectively, while grade 3/4 lymphopenia and thrombocytopenia were seen in 30%/5% and 10%/20%, respectively. Two grade 3 infections were seen, 1 of which was attributable to study treatment, but no ≥grade 4 infections were encountered. Common non-hematologic toxicities of all grades regardless of attribution included fatigue (70%), anorexia (55%), nausea (80%), vomiting (60%), diarrhea (85%), constipation (70%) and peripheral neuropathy (75%), most of which was grade 1 or 2 in severity. Grade 3 fatigue, peripheral neuropathy and hand foot syndrome were seen in 10% of patients each, while grade 3 diarrhea was seen in 20%. 1 DLT of transient atrial flutter with grade 4 systolic dysfunction was seen at dose level 3. Two of six patients suffered DLTs at dose level 4 consisting of grade 4 thrombocytopenia without bleeding sequelae, thus establishing dose level 3 as the MTD. Serious adverse events included the above mentioned systolic dysfunction and a limited episode of diastolic dysfunction in one patient. No deaths have occurred on study. Using International Myeloma Working Group criteria, 38% of patients have had ≥VGPR and 61% ≥PR. Only 2 of 18 evaluable patients have had progressive disease on treatment. 7 of 10 patients with relapsed disease had ≥PRs, 6 of which were VGPRs, whereas 4 of 8 patients with relapsed and refractory disease responded. 4 of 5 bortezomib-naïve patients responded to treatment and 4 of 4 patients with bortezomib-pretreated but sensitive disease had PRs or better. 3 of 9 patients with bortezomib-refractory disease had ≥PRs but MRs were seen in an additional 3.

The MTD of vorinostat in combination with PLD and bortezomib was 400mg on D4-11. Constitutional, gastrointestinal, and neurologic toxicities were common, but predominantly grade 1 and 2 in severity, and largely manageable. Responses were seen in patients with bortezomib-resistant and -sensitive disease. Dose level 3 has been expanded to include an additional 12 patients. Our results support further clinical testing of this combination in patients with MM.

Voorhees:Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. Off Label Use: Vorinostat for the treatment of myeloma. Gasparetto:Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. Richards:Cephalon: Speakers Bureau; Merck/Shering-Plough: Consultancy. Orlowski:Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Hurd:Celgene: Research Funding.