A Phase I/II Study of the Tolerability of Lenalidomide and Low Dose Dexamethasone in Previously Treated Multiple Myeloma Patients with Impaired Renal Function: Pre1003, a Precog LLC Study

Lenalidomide has proven to be a highly effective treatment in relapsed multiple myeloma (MM), particularly when used in combination with dexamethasone. However, over 30% of patients with myeloma have renal insufficiency and as lenalidomide is renally excreted, little information is available about its use in myeloma patients with impaired kidney function. Defining a safe and effective dose of lenalidomide in this context is critical.

We undertook this study to establish the maximum tolerated dose of lenalidomide in three cohorts of patients with different levels of impaired renal function: Group A - patients with creatinine clearance (CrCl) between 30 and 60 mL/min, Group B - patients with CrCl <30 mL/min not on dialysis, and Group C - patients with CrCl < 30mL/min who are on dialysis. Secondary endpoints included response rate, progression free survival and overall survival.

Eligible patients had previously treated MM with renal impairment defined as creatinine clearance < 60 mL/min measured within 21 days prior to registration. Patients previously treated with lenalidomide were required to demonstrate clinical response (any duration) or stable disease with progression-free interval of > 6 months from start of that therapy. All patients received dexamethasone 40 mg orally on days 1, 8, 15 and 22 of a 28-day cycle. Prophylactic anticoagulation consisted of either 81 mg or 325 mg per day of aspirin. Patients also received lenalidomide orally every 1 or 2 days on days 1 through 21 of a 28-day cycle, as described below (Table 1). Starting doses were as in US Product Insert. Dose escalation follows a standard 3+3 design.

There have been 23 patients enrolled into groups and cohorts as shown in Table 1. Median age was 73 (range 49–89) and 13 (57%) were women. ISS stage was advanced in all patients, 0 in stage 1, 4 (18%) in stage 2 and 19 (82%) in stage 3. The regimen was well tolerated. Indeed, the MTD has not been reached in any of the groups, as no DLTs have occurred to date. The most commonly reported clinical adverse events (all grades, independent of attribution) across all patients included infections, hyperglycemia, constipation, dizziness, hyponatremia, hypocalcemia and tremor. Hematological toxicities (grade 3–4) occurred in 13 out of 21 pts (62%), mostly neutropenia and thrombocytopenia. Grade 3–4 events at least possibly related to the regimen occurred in 70% and included pneumonia (26%) and otitis media (9%).

Response was seen in 14 patients, resulting in an overall response rate of 61%. CR was seen in 1 patient (4%), VGPR in 2 patients (9%), PR in 11 patients (43%), and SD for 9 patients. With median follow-up of 15.5 months, median progression-free survival is 9.8 months and median overall survival is 22 months.

Lenalidomide and dexamethasone is a safe and effective regimen in patients with multiple myeloma and renal insufficiency. It is also very well tolerated, although cytopenias are common but manageable. MTD has yet to be reached in each group, allowing for higher doses to be given than previously thought, including 25mg daily (for 21/28 days) in patients with CrCl 30–60 mL/min, 25 mg every other day (for 21/28 days) in patients with CrCl < 30 mL/min not on dialysis, and 10mg daily (for 21/28 days) in patients with CrCl < 30 mL/min on dialysis. These results will provide needed, clinically relevant dosing for lenalidomide in MM patients with renal insufficiency.

Kaufman:Millenium: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Novartis: Consultancy.