The Efficacy and Toxicity of the RAD Regimen (Revlimid®, Adriamycin®, Dexamethasone) in Relapsed and Refractory Multiple Myeloma - A Phase I/II Trial of “Deutsche Studiengruppe Multiples Myelom”.

Background: Lenalidomide (Revlimid®; Len) has important efficacy in relapsed/refractory multiple myeloma (MM), with or without dexamethasone (Dex). Addition of Adriamycin® might further enhance antimyeloma activity of Len and Dex in patients (pts) with relapsed/refractory MM. We report data from a multicentre dose-finding phase I/II trial involving the RAD regimen (Revlimid®, Adriamycin®, Dex).

Methods: A modified Fibonacci design was chosen to enroll MM pts with measurable disease and <3 prior treatment lines. Pts were required to have adequate hematopoietic and organ function; prior Len treatment was an exclusion criterion. RAD was administered for 6 28-day cycles along with either aspirin® 100 mg/day or low-molecular-weight heparin for prophylaxis of venous thromboembolism (VTE). Phase I was a dose-escalating study with increasing doses of either Len (10–25 mg/day) or Adriamycin (4–9 mg/m²/day). Using pegfilgrastim support (G; 6 mg, day (d) 6), the maximum tolerated dose was not reached, even at the 5^th dose level (DL; 5+G: Len 25 mg d1–21; Adriamycin 9 mg/m² as a 24h infusion d1–4; and Dex 40 mg d1–4 and 17–20 of each 28-day cycle). This dose was next used in phase II.

Results: 69 pts with a median age of 65 (range, 46–77) years were included in the study and received at least 3 cycles. Prior anti-myeloma treatments included prior autologous stem cell transplantation (72%), prior allogeneic SCT (12%), bortezomib (57%), and thalidomide (20%). Grades 3/4 neutropenia and thrombocytopenia occurred in 44% and 32% of pts, respectively. Incidence of VTE was 7.5%. No neuropathy was diagnosed de novo. Three patients prematurely discontinued the trial due to catheter-related septicemia, thrombosis of basilar artery, and prolonged pneumonia. Fifty pts evaluable for response assessment were divided into 2 groups: 20 pts from phase I, who received doses up to DL 5+G and 30 pts on DL 5+G from both phase I and II. Using the European Group for Blood and Marrow Transplantation criteria, overall response rate (ORR) for DL 1–4 was 60% including 5 pts (25%) with near complete response (nCR). ORR for 30 pts on DL 5+G was 87%, including 7 pts (23%) with immunofixation-negative CR and an additional 18 pts (60%) with nCR. Median overall time to progression was 40 (4 to 75+) weeks with a very short median time to response of 4 (3–28) weeks. Several pts were evaluable for cytogenetic analysis performed by FISH: 17/37 (46%) had 13 q deletion (del[13q]). Partial response (PR) or better was seen in 12/17 pts (71%) with del(13q). Chromosomal translocation (4;14) was present in 4/25 (16%) evaluable pts with 1 having progressive disease (PD) and 3 PR. Del(17p) involving the tumor suppressor gene p53 and being associated with a particular adverse prognosis was found in 6/31 pts (19%): PR was noted in 2 pts, while 2 pts each had stable disease and PD.

Conclusion: RAD incorporating 25 mg of Len for 21 of 28 days demonstrated potential utility as a new combination regimen for heavily pre-treated myeloma pts. Toxicity was moderate and predictable. The efficacy of this regimen is considerable as a CR plus nCR rate of 83% was observed with DL 5+G. In addition, high responses were observed even in patients displaying high-risk cytogenetic abnormalities.