Lenalidomide, Adriamycin and Dexamethason (RAD) in Relapsed and Refractory Multiple Myeloma: Final Results from a Phase I/II Trial of “Deutsche Studiengruppe Multiples Myelom”

Background: Lenalidomide (Revlimid®) is an analogue of thalidomide, with immunomodulatory properties and is effective and safe in the treatment of multiple myeloma. We report follow-up data of effects of a combination regimen of lenalidomide, adriamycin and dexamethasone (RAD) on toxicity, prognostic factors, time to progression, and overall survival in patients with multiple myeloma.

Patients and Methods: From January 2005 through June 2007 we enrolled 69 patients, 66 patients between 46 and 77 (median age 65) were eligible for evaluation. To be included, patients had to have multiple myeloma with Durie-Salmon stage II or III and considered to have disease progression after 1 to 3 previous anti-myeloma regimens. The feasibility of administering lenalidomide in combination with Doxorubicin and Dexamethasone and the MTD of the combination were determined in the phase I part of the study (Part A). RAD was administered for six 28-day cycle. The MTD was not reached at the highest dose level G5 (R 25 mg d1–21, Adriamycin 9 mg/m² d1–4 as a 24h infusion, Dex 40 mg d1–4 and 17–20) This dose was used for the phase II part.

Results: Forty-eight of 66 patients (73%) achieved an objective response to therapy. Respectively, 10 (15%) of 66 patients achieved a immunofixation-negativ CR, 30 patients (45%) a VGPR and additional 8 patients (12%) a PR. The median follow up was 14,6 (range 7–35) months. Median time to disease progression (TTP) was 45 weeks (95% confidence interval [39,3 to 50,7 weeks] and the one-year survival probability was 88%. 63/66 patients (95%) were evaluable for β2-Microglobulin serum level. Forty-four patients had a level lower than 3,5 mg/l and 19 patients had a higher level than 3,5 mg/l. Subgroup analyses showed a statistical benefit for the group with β2-Microglobulin level < 3,5 mg/l in terms of response (p = 0,002). 37 patients were evaluable for cytogenetic abnormalities with FISH analyses. We found in 15 patients (41%) a Del 13q, four patients (11%) had a t(4;14) and 5 patients (14%) had a Del 17p. There was no significant correlation between response to treatment and the Del 13q (p = 0,40) and the t(4;14) translocation (p = 0,176). Although absolute numbers of patients were low, presence of Del 17p was identified as adverse prognostic factor: 87% without versus 20% with Del 17p responded (p = 0,001). The most common side effects was haematological toxicity with grade 3/4 neutropenia (48%), thrombocytopenia (38%) and anemia (16,6%). Under thrombosis prophylaxis with aspirin 100 mg or enoxaparin 40 mg per day we observed thrombembolic complications in 3 patients (4,5%). Other non haematological side effects were pain (grade 3/4-1 patient), infection (grade 3/4-7 patients), diarrhoea (grade 3/4-1 patient). Neither neurotoxicity nor constitutional symptoms of grade 3/4 was found.

Conclusion: In our study, lenalidomide in combination with doxorubicin and dexamethason has shown encouraging activity in heavily pretreated patients with relapsed or refractory multiple myeloma. The combination was well tolerated with a mild toxicity profile. Lower level of β2-Microglobulin and the absence of the deletion 17p had a statistical benefit in terms of response. An update of these data will be presented at the meeting.