Tanespimycin + Bortezomib in Relapsed/Refractory Myeloma Patients: Results From the Time-2 Study.

Tanespimycin is an inhibitor of Hsp90, a molecular chaperone for proteins critical to growth, survival, and drug resistance of multiple myeloma (MM) cells. Increased Hsp70 expression is a pharmacodynamic (PD) marker of Hsp90 inhibition (Modi et al, J Clin Oncol, 2007). In primary MM cells, tanespimycin synergizes with bortezomib resulting in increased antitumor activity and enhanced proteasome inhibition. Tanespimycin + bortezomib has demonstrated durable responses in patients with relapsed/refractory MM with low rates of neutropenia and peripheral neuropathy (PN) relative to historical data on bortezomib monotherapy. Here we present the clinical and PD results of a randomized phase 2 study of tanespimycin + bortezomib in patients with relapsed/refractory MM that was truncated early for reasons unrelated to safety and efficacy.

Patients with MM aged ≥18 years with Karnofsky performance status ≥70% and measurable disease who relapsed or progressed following ≥3 prior treatments (must have included lenalidomide and bortezomib) were eligible. Patients were randomized to 1 of 3 treatment arms with bortezomib 1.3 mg/m² included in each arm: (1) tanespimycin 340 mg/m², (2) tanespimycin 175 mg/m², and (3) tanespimycin 50 mg/m². Tanespimycin + bortezomib was administered on days 1, 4, 8, and 11 of each 21-day cycle. Treatment continued for at least 4 cycles and then until progression. Plasma Hsp70 levels and 20S proteasome activity as determined by chymotrypsin-like and caspase-like activity, were measured on days 1 and 11 at 0 and 4 hours postdose.

Twenty-two patients were randomized: 8 patients each in arm 1 and arm 2, and 6 patients in arm 3. Patients had a median age of 63 years; 64% were men, 46% had IgG subtype, 18% had IgA subtype, and 64% had heavy chain disease. At baseline, 3 patients had chromosome 13 deletion, 1 patient had t(11;14), 1 patient had t(14;16), 2 patients had other translocations, and 1 patient had p53 mutation. The median time since diagnosis was 81 months and the median number of prior regimens was 5 (range 3–12; 50% had received 5 or more prior regimens) and 96% had received prior thalidomide. A total of 72% of patients had had a prior stem cell transplant and 18% had not been candidates for transplant. For 68% of patients, the best response to the bortezomib-containing regimen prior to randomization had been stable disease or progressive disease. In the present study with tanespimycin + bortezomib, the overall response rate (≥ minimal response [MR]) was 14% including: 1 MR at 340 mg/m² dose, and 1 very good partial response and 1 partial response (PR) at 175 mg/m² dose. In addition, 10 patients had a best response of stable disease. The patient who achieved a PR had had 10 prior regimens including 3 bortezomib-containing regimens and had been refractory to the most recent regimen that included bortezomib + vorinostat. The most common adverse events (AEs) (any grade) were fatigue 73%, nausea 68%, diarrhea 64%, constipation 50%, and vomiting 46%; most AEs were Grade 1 or 2. PN was observed in 27% of patients; only 1 patient had Grade 3 PN that occurred after the patient had discontinued tanespimycin and was receiving bortezomib alone. Neutropenia (Grade 3) occurred in 18% of patients. Thrombocytopenia (any grade) occurred in 32% of patients; Grade 3/4 in 27%. From day 1 hour 0 to day 11 hour 0, Hsp70 levels increased 3.2-fold, 5.0-fold, and 6.3-fold in the 50 (n=3), 175 (n=3), and 340 mg/m² (n=4) arms, respectively. Plasma chymotrypsin activity per μg proteasome at day 1 hour 4 was 90%, 77%, and 61% of baseline (day 1 hour 0) for the 50, 175, and 340 mg/m² arms, respectively; at day 11 hour 4, chymotrypsin activity was 93%, 33%, and 40% of baseline for the 3 doses, respectively. A similar trend was observed for caspase activity per μg proteasome.

In this randomized study, tanespimycin + bortezomib treatment resulted in a low frequency of PN and neutropenia, similar to a prior phase 1/2 study in patients with relapsed/refractory myeloma. Tanespimycin + bortezomib had activity in heavily pretreated myeloma patients (median 5 prior regimens; median 81 months since diagnosis), including a PR in a patient refractory to prior bortezomib + vorinostat. PD analysis confirms that tanespimycin + bortezomib effectively targets Hsp90 and the proteasome.

Richardson:Millennium and Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: Research Funding. Jagannath:Millennium and Merck: Membership on an entity's Board of Directors or advisory committees. Berman:Bristol-Myers Squibb: Employment. Anderson:Celgene, Novartis, Millennium, BMS : Honoraria; Celgene, Novartis, Millennium, BMS: Research Funding; Celgene, Novartis, Millennium, BMS: Consultancy.