Lenalidomide Induced Myelosupression Is Potentially Associated with Renal Dysfunction in Treatment Naïve Myeloma (MM) Patients Receiving BiRD (Biaxin®/Revlimid®/Dexamethasone) Combination Therapy (Rx).

Lenalidomide or Revlimid® has recently been approved for the treatment of relapsed or refractory MM. It has been demonstrated that Biaxin(Bi) augments tumor mass reduction and improves responses in patients (pts) receiving low-dose thalidomide and/or Dexamethosone (D). The results of a phase II trial exploring the combination of Bi, R & D in newly diagnosed MM are reported here. The planned accrual target was met and additional patients accrued for correlative studies. The BiRD regimen consists of R 25 mg po daily on days 1–21 of a 28-day cycle. D 40 mg once weekly and Bi 500 mg po twice daily. All pts received low dose aspirin (ASA)(81mg) once daily as thrombosis prophylaxis, prophylactic sulfamethoxazole/ trimethoprim, and a proton pump inhibitor.

PATIENTS: 58 pts[median follow-up 9 months (range 2–21)] have been accrued. Median age of 62.5 years (range 36–80), hemoglobin of 10.9 g/dL (range 7.2–15.1), platelets of 242 k/uL (range 51–526), B2M of 3mg/L (range 0.8–12.8), CRP of 0.56 mg/dL (range 0.12–14.2), creatinine (Cr) of 1.2 mg/dL (range 0.6–3.1), albumin of 3.55g/dL (range 2.3–4.9), and calcium of 9.3mg/dL (range 6.9–11.2). 50% of the pts are stage IIIa, 7% are stage IIIb, 41.4% are stage Iia. According to ISS classification 28/58 are stage I (48%), 18/58 are stage II (31%) & 12/58 are stage III (20%).

RESULTS: This combination yielded a 95% overall response rate (EBMTR) by ITT with 38% of the pts achieving either a CR(16/58) or a nCR(6/58). Of the remaining 36 pts, 92% achieved a PR. Of those PR pts, 11/36 pts had >90% reduction in the initial paraprotein, while 12/36 pts had >75% decrease. All R dose reductions were due to myelosupression. R dose reduction scheme for myelosupression was defined as follows: Grade≥ 3 Neutropenia: Level −1: 25 mg po daily + G-CSF. Level −2 : 15 mg po daily and Level −3: 10 mg po daily. Thrombocytopenia: Level −2 : 15 mg po daily. Level −3: 10 mg po daily. 18% of the pts required at least one dose reduction. Of these patients, 6% required further dose reductions to level 2, and 2 patients were reduced to level 3. Mean time to R dose reduction level 1 was 65.1 days (range 15 to 142), to level 2 was 113 days (range 35 to 166) and to level 3 was 170 days (range 95 to 244). Baseline Cr level correlated with R dose reductions. Of the 11 patients who were dose-reduced, 1 had a baseline serum Cr level of ≤1.4 mg/dL, while the rest had a baseline serum Cr level >1.4 mg/dL (p<0.0001). Using baseline Cr level as a continuous variable in a Cox proportional hazards regression model results in a hazard ratio of 6.4 (95% CI = 2.1, 19.1), p=0.0009. This indicates a 6.4-fold increased likelihood of a dose reduction for each 1-unit increase in baseline serum creatinine level. Similarly, a Cr clearance (Cl) of ≤40, was associated with R dose-reductions (KM log-rank analysis ≤40 (n=12) versus >40 (p=0.0014). Other toxicities included PE (4%), DVT (9%), AMI (2%), and sudden death (2%). Other non-hematological toxicities included myopathy (6%), diverticular abscess (10%), hand tremor, weakness and hyperglycemia.

Conclusions: BiRD is highly effective and safe in the initial Rx of MM. Myelosuppression & renal dysfunction potentiated the need for R dose reduction.