Tanespimycin + Bortezomib Demonstrates Safety, Activity, and Effective Target Inhibition in Relapsed/Refractory Myeloma Patients: Updated Results of a Phase 1/2 Study.

Tanespimycin disrupts Hsp90, a key molecular chaperone for signal transduction proteins critical to myeloma growth, survival, and drug resistance. Increased Hsp70 expression is a pharmacodynamic (PD) marker for Hsp90 inhibition (Modi et al, J Clin Oncol, 2007). Tanespimycin + bortezomib has synergistic antitumor activity and enhanced proteasome inhibition in primary multiple myeloma (MM) cells. 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. In preclinical studies, tanespimycin protected against bortezomib-induced PN. Here we present PD data and updated efficacy and safety results of this phase 1/2 study of tanespimycin + bortezomib in patients with relapsed/refractory MM.

Patients with relapsed/refractory MM who had received ≥2 prior regimens were enrolled and received bortezomib (0.7, 1.0, or 1.3 mg/m²) intravenous (IV) bolus followed by a 1-hour infusion of tanespimycin (100, 150, 220, 275, or 340 mg/m²) on days 1, 4, 8, and 11 in each 21-day cycle. Peripheral blood mononuclear cells (PBMCs) were collected and lysates were analyzed for Hsp70 expression and 20S proteasome activity. Hsp70 levels, measured by Western blot, and 20S proteasome activity, measured as composite of chymotrypsin, trypsin, and caspase activity, were measured on days 1 and 11 at 0, 4, and 24 hours postdose and normalized to baseline pretreatment levels in each patient.

Seventy-two patients were enrolled with 42 patients treated at the highest doses (340 mg/m² tanespimycin, 1.3 mg/m² bortezomib). The median age was 60 years and 72% had IgG subtype. Median time since MM diagnosis was 51 months and the median number of prior regimens was 5 (range 1–15) including stem cell transplant (69%), thalidomide (74%), bortezomib (69%), lenalidomide (28%), and other Hsp90 inhibitors (13%). A total of 78% of patients had a history of PN prior to study entry. In the present study, overall response rates (ORR; minimal response or better by modified EBMT) were 48% in the 21 bortezomib-naive patients, 22% in the 23 bortezomib-pretreated patients, and 13% in the 23 bortezomib-refractory patients. ORR was 64% in bortezomib-naive patients who had '3 prior regimens. The median duration of response was 12 months (n=18 patients), including 3 bortezomib-refractory patients each with durable partial responses (PRs) through months 12, 22, and 27, respectively. Of these 3 bortezomib-refractory patients with long-term responses, 2 patients had progressed while being treated with prior bortezomib (bortezomib/dexamethasone and bortezomib/thalidomide/dexamethasone). Thrombocytopenia occurred in 40% of patients (25% Grade 3/4). In cycle 1, mean platelet counts decreased from 180,000/μL on day 1 to 154,000/μL on day 11. Neutropenia was observed in only 4% of patients (3% Grade 3/4). In cycle 1, mean absolute neutrophil counts (ANC) actually increased from 3.0 × 10⁹/L on day 1 to 4.2 × 10⁹/L on day 11. Grade 1 or 2 PN was observed in 15 patients (21%) and importantly no Grade 3/4 PN was observed. Similarly, no severe constipation or anorexia was observed. Hsp90 inhibition was achieved at tanespimycin doses of 275 mg/m² (n=3) and 340 mg/m² (n=15) as exhibited by 1.9-fold and 1.5-fold Hsp70 increases, respectively, from baseline to day 1 hour 4 and 1.7-fold and 2.0-fold Hsp70 increases, respectively, from baseline to day 11 hour 0. Proteasome activity decreased from 100% at baseline to 40%, 54%, 61%, and 53% at day 11 hour 1 with tanespimycin doses of 150 (n=2), 220 (n=3), 275 (n=5), and 340 mg/m² (n=23), and further decreased to 26%, 36%, 43%, and 34%, respectively, at day 11 hour 24.

Tanespimycin and bortezomib in combination is well tolerated with a low frequency of PN and neutropenia, which compares favorably with historical data on bortezomib monotherapy. Tanespimycin + bortezomib effectively targets the proteasome (with decreased 20S proteasome activity) and Hsp90 (as reflected by increased Hsp70 expression), and is associated with durable responses in heavily pretreated MM patients. Tanespimycin + bortezomib is currently being tested in a randomized phase 3 clinical trial.

Richardson:Millennium and Celgene: Speakers Bureau; Millennium Pharmaceuticals: Research Funding. Off Label Use: Combination uses. Chanan-Khan:Millennium, Celgene, Immunogen: Honoraria, Speakers Bureau. Lonial:Novartis: Consultancy; BMS: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy; Gloucester: Research Funding. Kopit:Bristol-Myers Squibb,: Employment, Equity Ownership. Berman:Bristol-Myers Squibb: Employment. Anderson:Celgene, Novartis, Millennium, BMS: Honoraria; Celgene, Novartis, Millennium, BMS: Research Funding; Celgene, Novartis, Millennium, BMS: Consultancy.