Final Results of the Phase I/II Trial of Weekly Bortezomib In Combination with Temsirolimus (CCI-779) In Relapsed or Relapsed/Refractory Multiple Myeloma Specifically In Patients Refractory to Bortezomib

This study aimed to determine activity and safety of weekly bortezomib (Takeda Inc) and temsirolimus (Pfizer Inc) in patients with relapsed/refractory Multiple Myeloma (MM).

Eligibility criteria included: 1) patients with relapsed or relapsed/refractory MM with any prior lines of therapy including bortezomib, 2) no chemotherapy within 3 weeks, or biological/novel therapy within 2 weeks. Primary endpoint was the percent of patients with at least a minimal response (MR).

Twenty patients were enrolled on the phase I study and 43 on the phase II study. The MTD was determined at 1.6 mg/m² bortezomib Days 1, 8, 15, and 22 every 35 days in combination with 25 mg IV temsirolimus Days 1, 8, 15, 22, and 29 every 35 days. Twenty % were stage III by ISS staging system in the phase I, and 21% in the phase II. The overall response rate of MR or better in the Phase II study was 20/43 (47%, 95%CI: 33,60), with 5% CR, 9% VGPR, 19% PR and 14% MR. Progression without any response occurred in just 1 patient (3%). One patient had an unconfirmed PR, but was included in the stable disease category. An additional 3 (6%) patients were unevaluable in the phase II trial because they did not complete their first cycle of therapy and had no follow up laboratory results for response. If these patients are excluded, the ORR including MR improves to 50% (95% CI: 36,64). The overall response rate in the phase I study was 20% with responses occurring in all the stages of the dose escalation. If three patients who were unevaluable in the phase I trial are excluded, then the response rate of evaluable phase I patients is 24% (95% CI: 9,46). Response was also evaluated by whether patients were bortezomib-refractory or not. These were defined as progressing while on therapy or progressing within 60 days of completing bortezomib therapy. Fifty-one patients had received bortezomib as part of prior treatment. Of these patients, 32 were refractory to bortezomib therapy immediately prior to study entry, and an additional 2 pts were refractory at prior time points. Responses observed among the 32 patients refractory to their most recent bortezomib therapy include 3 PR and 3 MR (ORR: 19%, 95% CI: 9,34). Another 21 patients had SD, 2 PD and 3 patients were unevaluable. Of the evaluable patients, the ORR was 6/29 (21%). Responses observed among the 19 patients who were not refractory to their last bortezomib treatment include 2 VGPR, 5 PR and 3 MR with 6 patients with SD, 0 PD and 3 unevaluable. The ORR among the evaluable patients who received bortezomib but were not refractory was 62%. Median time to response of MR or better (min, max) among all patients was 1.7 months (0.5,14.2) and among phase II patients 1.3 months (0.5,8.0). Median duration of MR or better (min, max) among all patients is 5.2 months (0.5,15.8) and among phase II patients is 4.6 months (0.5,10.8). Median duration of PR or better response (min, max) among all patients is 6.0 months (1.8,15.8) and among phase II patients is 5.2 months (1.8,10.8). The median time to progression for all patients in the phase I and II studies was 7.3 months (95% CI: 5.7 –17.2) and the median progression free survival was 6.4 months (95% CI: 4.8–7.4). The median overall survival in all phase I and II patients was 11.4 months (95%CI: 8.6-undetermined). Three deaths occurred during therapy in the phase I and II studies, 1 of septic shock, 1 with H1N1 infection, and 1 with cardiac amyloid and ventricular arrhythmia. The most common G1-4 toxicities that occurred in > 25% of patients included cytopenias, hypertrigyceridemia and diarrhea. Grade 3 and 4 thrombocytopenia occurred in 48% of patients in the phase I and II studies, G3 and 4 neutropenia occurred in 36%, and anemia in 26% of phase I and II patients. G3 and 4 hypertriglyceridemia occurred in 5% and diarrhea in 9%. Peripheral neuropathy (PN) was rare with no G3 or 4 neuropathy reported. Overall, there was 34% grade 1 and 2 PN seen.

The combination of weekly bortezomib and temsirolimus showed an encouraging response rate in heavily pretreated patients with relapsed or refractory MM, with an overall response rate in evaluable patients as part of the phase II portion of the trial of 50%, and a 21% ORR including MR or better in evaluable bortezomib refractory patients. Cytopenias were the most common toxicities, specifically thrombocytopenia, as well as GI toxicity, with side effects proving manageable. Significant PN was rare in this study.

Ghobrial:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Vij:Novartis: Honoraria; Eisai: Speakers Bureau. Munshi:Millennium Pharmaceuticals: Honoraria, Speakers Bureau. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees.