Lenalidomide, Adriamycin and Dexamethasone (RAD) As An Induction Regimen In Newly Diagnosed Multiple Myeloma – Interim Results From a German Multicenter Phase II Trial

Abstract

Background Induction triplets utilizing at least one of the “novel drugs” and steroids with or without chemotherapy are considered current standard of care in newly diagnosed, symptomatic multiple myeloma (MM). Medically fit patients (pts) remain candidates for subsequent autologous (auto) stem cell transplant (SCT) while use of allogeneic (allo) SCT remains a matter of debate. As we had previously shown the RAD regimen to be well tolerated and highly effective in relapsed and relapsed/refractory MM, we evaluated this combination in first-line treatment. Methods The current phase II trial (DSMM XII) was designed to include a total of 190 pts up to 65 years of age with symptomatic MM. Four 4-week cycles of RAD (lenalidomide 25 mg/day, d 1-21; adriamycin 9 mg/m² as 24-hour infusion, d1-4; oral dexamethasone 40 mg, d1-4 and 17-20; pegfilgrastim 6 mg, d 6) preceded stem cell chemomobilization. Low-molecular weight heparin for prophylaxis of venous thromboembolic events (VTE) was mandatory. Pts received either tandem auto SCT (melphalan 200 mg/m²; Mel200) or auto followed by allo SCT. Allo SCT (preparative regimen: treosulfan/fludarabine) was reserved for pts featuring at least one cytogenetic or serologic risk factor who had a matched sibling or unrelated donor available. Lenalidomide maintenance was administered for one year following both tandem auto and auto/allo SCT. This is the second pre-planned interim safety and efficacy analysis. Results Eighty-nine pts with a median age of 54 (range, 30-65) years, who were recruited between August 2009 and October 2010, are evaluable. Fifty pts (56.2%) had ISS stage II/III disease and in all except three, molecular cytogenetic analysis was performed. Incidences of chromosomal abnormalities were as follows: deletion of (del) 13q, 24.7%; translocation t(4;14), 12.4%; t(14;16), 3.4%; and del 17p, 5.6%. Treatment-related mortality with RAD induction was 0% while 61.8% of pts had treatment-emergent SAEs. Seventeen pts (19%) experienced neutropenia of grades 1 to 4. Incidences of severe (grades 3/4) and febrile neutropenia were 5.6 and 1%, respectively. Seven pts each (8%) had pneumonia and VTE, respectively. Post-RAD-induction CR/sCR and at least VGPR rates were 9% and 47.2%, respectively. All 78 pts with at least stable disease successfully mobilized stem cells. Overall response rate (at least partial response, PR) following first SCT on an intention-to-treat basis was 83%. Twelve pts each (13.5%) achieved centrally confirmed complete response (CR) or stringent (s)CR, respectively, and 54 pts (60.7%) had at least very good PR (VGPR). Conclusions This interim analysis shows RAD to be very well tolerated and effective in first line treatment of symptomatic MM. Mel200 further increased rates of deep response (at least VGPR) achieved by RAD induction. We are currently comparing this regimen to bortezomib, lenalidomide and dexamethasone (VRd) in a phase III trial. Disclosures: Knop: Celgene GmbH: Honoraria. Off Label Use: Lenalidomide and doxorubicin in newly diagnosed multiple myeloma. Engelhardt:MSD, Janssen-Cilag: Research Funding. Einsele:Celgene GmbH: Consultancy, Honoraria, Research Funding. Bargou:Celgene GmbH: Research Funding.

Effect of induction therapy with lenalidomide, doxorubicin and dexamethasone on bone remodeling and angiogenesis in newly diagnosed multiple myeloma

“…The observed discrepancies in the depth of responses between the present study and the German study may be attributed to differences in baseline patient characteristics such as ISS stage, performance status and renal function . In the study by Knop et al ., 78/89 (87%) patients with at least stable disease successfully mobilized stem cells; this result was totally comparable to our study in which 89% of patients had adequate stem cell collection. The ORR in the German study following first SCT on an intention‐to‐treat basis was 83% (13.5% achieved CR or stringent sCR, and 60.7% had at least VGPR) .…”

“…In the study by Knop et al ., 78/89 (87%) patients with at least stable disease successfully mobilized stem cells; this result was totally comparable to our study in which 89% of patients had adequate stem cell collection. The ORR in the German study following first SCT on an intention‐to‐treat basis was 83% (13.5% achieved CR or stringent sCR, and 60.7% had at least VGPR) . Our data showed a comparable ORR of 84.4% but with lower VGPR rate (42%) after ASCT.…”

“…Furthermore, our results show that RAD combination is an effective induction regimen for proceeding to high‐dose therapy and ASCT, because it does not seem to affect the quality of stem cell collection. More specifically, the number of stem cells collected per patient, and consequently the outcome of ASCT, is similar to other reports in the literature with the use of similar or other induction regimens such as VAD, PAD, dexamethasone, thalidomide and dexamethasone or lenalidomide and dexamethasone …”

“…This may be attributed to the combined positive effect of both antimyeloma and antiresorptive agents. The toxicity profile of RAD regimen in our study was similar to that reported in clinical trials with lenalidomide‐based combinations …”

“…After a median follow up of 29 months, 11 patients had progressed whereas median values of survival outcomes (PFS, TTP and OS) had not been reached. To the best of our knowledge, RAD regimen has been previously evaluated in only one study for NDMM patients . Following induction with four cycles of RAD, an ORR of 78.4% was observed with 48.4 and 8.4% of the patients achieving at least VGPR and CR, respectively .…”