A Phase I/II Study of Bortezomib (VELCADE) in Combination with Pralatrexate in Relapsed/Refractory Multiple Myeloma

Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells accompanied by end organ damage. Although cytotoxic chemotherapy including high dose chemotherapy with stem cell support have improved survival of symptomatic patients, all patients invariably relapse. For patients with relapsed disease further chemotherapy is generally of limited benefit, indicating the need for novel therapies.

Pralatrexate is a folate antagonist which has been FDA approved for the treatment of peripheral T-cell lymphoma. It has been shown to be safe in combination with various cytotoxic agents. In preclinical studies, pralatrexate has been shown to be synergistic with the proteosome inhibitor bortezomib. This phase I/II study is being conducted with the support of the NCCN to determine the safety and maximum tolerated dose (MTD) of pralatrexate in combination with bortezomib in the treatment of relapsed/refractory MM.

The primary objectives were to determine the MTD and recommended phase II dose and toxicity profile of pralatrexate in combination with bortezomib. The secondary objectives were to determine clinical evidence of anti-myeloma activity based on response criteria of the International Myeloma Working Group Uniform Response Criteria (IMWGURC). Additionally, anti-tumor activity was measured by duration of response (DOR), progression free survival (PFS), and overall survival (OS). Eligible patients were age >18, with measurable MM that had relapsed following, or was refractory to at least 1 previous treatment. Refractoriness to bortezomib was allowed. Patients received pralatrexate intravenously on days 1, 8 & 15 in 3-dose cohorts of 10, 20 or 30 mg/m² and bortezomib intravenously on days 1, 8 & 15 at a fixed dose of 1.3 mg/m². Patients took folic acid 1mg daily as well as intramuscular vitamin B12 every 8–10 weeks. A standard 3+3 dose escalation was used for determining the MTD. In this study, dose-limiting toxicity (DLT) was determined during cycle 1 and defined as grade 3 febrile neutropenia, grade 3 or grade 4 non-hematologic treatment-related toxicity, or treatment delays exceeding 14 days in the first cycle of treatment. A maximum of 4 28-day cycles was planned.

Nine patients with a median age of 60 (55–74 years) have been enrolled on the study to date. The MTD has not been reached. Patients are currently enrolled in the 3^rddose cohort. The median number of previous therapies was 2 (range 1–4). Eight pts (88%) had received previous treatment with bortezomib, and 8 with immunomodulatory agents. Two patients had undergone autologous transplant. Six patients had refractory disease, including 5 refractory to bortezomib. Seven patients had bony disease, including 5 (55%) with >3 lesions. FISH studies revealed 2 patients with monosomy 13 and one with a p53 deletion. Patients received a median of 2 treatment cycles (range 1–4). The median follow-up time is 12.4 months (range 0.46–22.9). To date, the most common grade 3 or 4 adverse events occurring in more than 10% of patients, were thrombocytopenia (66%) and neutropenia (22%). Grade 3 mucositis was observed in 1 patient and constituted a DLT. Subsequent patients were given leucovorin to take at the first sign of mucositis. One patient had a grade 3 shingles infection. Of the eight patients evaluable for response, 2 achieved a partial response, 5 had stable disease, and 1 progressed. The median duration of response was 46 days (range 38–54). After completion of the study 1 patient started maintenance, and 7 patients started alternative therapy including transplant in 3 patients. The median time to next treatment was 23 days (range 13–196). There were no deaths on the study. The median PFS was 7.6 months (range 0.4–18.8). The median OS was 12.4 months (range 0.4–22.9)

The combination of pralatrexate 30mg/m² and bortezomib 1.3mg/m² on days 1, 8, and 15 appears to be a safe treatment option for heavily pre-treated patients with multiple myeloma. The main toxicities of this regimen are thrombocytopenia and mucositis.

Liedtke:Millennium: Research Funding.