Background: The addition of thalidomide to BiRD therapy (clarithromycin/[Biaxin®], lenalidomide/[Revlimid®], dexamethasone) may enhance anti-myeloma activity of the combination while not adding to overall regimen toxicity, given the different side effect profiles of thalidomide and lenalidomide. We now report an update of the phase 2 trial of T-BiRD (thalidomide/Thalomid®, clarithromycin/[Biaxin®], lenalidomide/[Revlimid®], dexamethasone) in up-front treatment of symptomatic multiple myeloma (MM).
Methods: Twenty-six patients with newly diagnosed symptomatic MM received T-BiRD. T-BiRD is clarithromycin 500mg twice daily; dexamethasone 40mg on days 1,8,15,22; and lenalidomide 25mg for days 1-21 of a 28-day cycle. Thalidomide was given at a dose of 50mg daily for the first week and thereafter at 100mg daily. All subjects had thromboprophylaxis with aspirin. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patients until disease progression.
Results: Twenty-six patients were enrolled. The median number of T-BiRD cycles delivered was 6.5 (range 0-17). The overall response rate (ORR) to T-BiRD (audited at time of autologous stem cell transplant [ASCT] or other planned change in therapy) was 77% (4% progressive disease (PD), 19% stable disease (SD), 42% partial response (PR), 31% very good partial response (VGPR), 4% CR). Eight patients (31%) withdrew from study, including 4 (15%) early withdrawals prior to completion of cycle 2 (1 due to Grade 4 rash, 2 due to Grade 3 rash, and 1 due to renal failure secondary to MM). Excluding these early withdrawals, ORR was 86% (5% PD, 10% SD, 45% PR, 36% VGPR, 5% CR). In these patients, median time to PR was 1 cycle [range 1-5]; the median time to max response was 4 cycles [range 1-7]. All eighteen patients who electively underwent autologous stem cell collection were successful, with median 16.317 CD34+ cells/kg collected [range 5.8-43.9] over a median of 1.5 apheresis sessions [range 1-5]. Eleven subjects underwent ASCT as part of a first line of therapy with T-BiRD induction; ORR to first line therapy in these subjects was 100%, with 18% PR, 46% VGPR, and 36% CR. At 4 years of study follow-up for 1st line therapy, median progression free survival (PFS) and event free survival (EFS) was 135.6 and 65.3 weeks respectively. Median overall survival (OS) was not reached; at 4-year follow-up, 4 patients had died of progressive myeloma, giving an overall survival rate of 84.5%. Twelve patients experienced grade 3 non-hematologic toxicity (weakness: 4; rash: 3; popliteal vein thrombosis: 2; respiratory infection: 1; hyperglycemia: 1; anorexia/dysgeusia: 1; renal insufficiency: 1; dizziness: 1; psychomotor agitation: 1; myocardial infarction: 1). One subject had grade 4 rash during cycle 1. 1 subject died of progressive myeloma prior to completion of 10 days of cycle 1.
Conclusions: T-BiRD is a highly active regimen in treatment-naïve multiple myeloma, with prolonged responses achieved; however, early treatment toxicity precluded extended use in up to a third of patients. Responding patients achieved PR within 1 cycle, indicating that this regimen may be useful when a swift drop in paraprotein is desired. T-BiRD allows for successful autologous stem cell collection and transplant outcomes. These data support the use of immunomodulatory-based regimens in the upfront treatment of MM and highlight the potential additive toxicities of the simultaneous administration of thalidomide and lenalidomide.