Updated Report of T-Bird (thalidomide, clarithromycin/[Biaxin®], lenalidomide/[Revlimid^®], Dexamethasone) Therapy for Upfront Use In Symptomatic Multiple Myeloma

We hypothesized that the addition of thalidomide to BiRD therapy (clarithromycin/[Biaxin^®], lenalidomide/[Revlimid^®], dexamethasone) may improve the 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) therapy for use in up-front treatment of symptomatic multiple myeloma (MM).

Twenty-six patients with newly-diagnosed symptomatic MM were enrolled in a single-institution trial of T-BiRD. The T-BiRD regimen consists of clarithromycin 500mg twice daily, dexamethasone 40mg on days 1,8,15,22 of a 28-day cycle, and lenalidomide 25mg for days 1–21 of a 28-day cycle. Thalidomide is given at a dose of 50mg daily for the first week and thereafter at 100mg daily. All subjects had thromboprophylaxis with aspirin, 162 mg once weekly, 81mg on subsequent days throughout all treatment. Serum protein electrophoresis/immunofixation as well as free light chain determinations were done monthly. Bone marrow biopsy and skeletal imaging were done to confirm disease progression or complete response (CR).

Twenty-five patients had completed at least one cycle of T-BiRD and were evaluable. The median number of T-BiRD cycles was 5 (range 1–12). Response to T-BiRD, audited at time of autologous stem cell transplantation (ASCT) or other planned change in therapy, was: 1 (4%) progression of disease (PD), 4 (16%) stable disease (SD), 10 (40%) partial response (PR), 8 (32%) very good PR (VGPR), 1 (4%) complete response (CR), and 1 (4%) with unconfirmed CR, giving a overall response rate (ORR; ³PR) of 80% and a ³VGPR rate of 40%. Nine subjects subsequently underwent ASCT as part of a first line of therapy with T-BiRD induction. These subjects had an ORR of 100% to first-line therapy, with 2 maintaining PR (22%) 5 achieving VGPR (56%), and 2 achieving CR (22%). At three years of follow-up, median progression free survival (PFS) and event free survival (EFS) was not reached for first line therapy (median PFS and EFS censoring at time of ASCT were 65 and 53 weeks, respectively). Median overall survival (OS) was not reached; at 3-year follow-up, 2 patients had died of progressive myeloma, giving an overall survival rate of 92%. A total of 12 subjects (48%) experienced an adverse event (AE), 5 (20%) being study-drug related (RAE). Eight subjects (32%) withdrew from the study: 2 had grade 2 skin rash prior to initiation of full-dose thalidomide (RAE), 1 patient had grade 4 skin rash (Stevens-Johnsons syndrome, SJS) during cycle 1 (RAE), 1 had a TIA in cycle 2, 1 developed renal failure in cycle 1, 1 developed chest pain in cycle 3. Other toxicities include 1 patient with Grade 2 steroid myopathy (RAE), 1 patient with DVT of the leg (RAE), and 1 patient with atrial fibrillation. 2 subjects developed pneumonia (causitive organism not identified). 1 subject died of progressive myeloma prior to completion of 1 cycle.

T-BiRD has promising activity as an induction regimen as part of first-line therapy for MM, with prolonged responses; however, toxicity limited extended use. T-BiRD does not appear to be superior to BiRD in ORR, likely due to shorter average time of regimen exposure (median 5 cycles of T-BiRD versus 13 cycles of BiRD). These data continue to support the role of lenalidomide-based regimens in the upfront treatment of MM.

Mark:Celgene Corp: Speakers Bureau. Off Label Use: Lenalidomide - upfront use in myeloma. Coleman:Celgene Corp: Speakers Bureau. Zafar:Celgene Corp: Speakers Bureau. Leonard:BiogenIDEC: Consultancy; Genentech: Consultancy; Immunomedics: Consultancy. Niesvizky:Celgene Corp: Consultancy, Speakers Bureau.