Response to Lenalidomide, Doxorubicin and Dexamethasone (RAD) in Newly Diagnosed Multiple Myeloma Is Independent of Cytogenetic Risk and Retained after Double Stem Cell Transplant
Authors: Knop Stefan , Langer Christian , Engelhardt Monika , Mügge Lars-Olof , Reichle Albrecht , Rösler Wolf , Bassermann Florian , Hertenstein Bernd , Sturm Isrid , Röllig Christoph , Ostermann Helmut , Schäfer-Eckart Kerstin , Ringhoffer Mark , Günther Andreas , Junghanss Christian , Biersack Harald , Strifler Susanne , Bachinger Andreas , Einsele Hermann , Bargou Ralf C. 
Published: October 2019

Abstract

Background Induction triplets with at least one of the “novel drugs” and steroids with or without chemotherapy are deemed standard of care in newly diagnosed multiple myeloma (MM). Medically fit patients (pts) remain candidates for subsequent autologous (auto) stem cell transplant (SCT) while the use of allogeneic (allo) SCT is an ongoing matter of debate. We had previously shown the RAD regimen to be well tolerated and highly effective in relapsed and relapsed/refractory disease. Based on the overall results we decided to further evaluate the combination in first-line treatment. Methods The current phase II trial was designed to include pts up to 65 years of age with newly diagnosed, symptomatic MM. Four 4-week RAD induction cycles (lenalidomide 25 mg/day, d 1-21; infusional adriamycin 9 mg/m², d1-4; oral dexamethasone 40 mg, d1-4 and 17-20; pegfilgrastim 6 mg, d 6) were followed by stem cell chemomobilization. Pts received either tandem auto SCT (melphalan 200 mg/m²; Mel) or auto followed by allo SCT. Allo SCT (conditioning 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. Target dose for subsequent lenalidomide maintenance (R-maint; for one year) was 10 mg/d for tandem Mel and 5mg/d for auto/allo pts. Primary endpoint was response (at least VGPR) following second SCT. Results 190 pts with a median age of 55 (range, 30-66) years were recruited by 17 German centers between 8/2009 and 4/2012. 103 pts (56%) had ISS stage II/III disease and 165 pts are evaluable for molecular cytogenetic abnormalities assessed by fluorescence in situ hybridisation (FISH). Incidences were as follows: 29.6% had deletion of (del) chromosome 13q, 11.5% showed translocation (t) (4;14), 9% presented with del 17p, and 0.6% had a t(14;16). 163 pts completed all 4 RAD cycles and 47 underwent allogeneic SCT. 60 pts following tandem Mel and 15 pts after auto-allo SCT proceeded to R-maint. Median number of maintenance cycles was significantly higher in tandem Mel compared with auto-allo pts (12 versus 3; p=.01). Rate of at least (≥) VGPR increased from 47.9% following RAD induction to 60.6% following double SCT. Accordingly, post-induction complete response (CR)/stringent CR rate of 7.9% increased to 31%. In pts with FISH results, ≥ VGPR rate was 44% with t(4;14)/t(14;16)/del 17p versus 53% without those abnormalities, respectively (p=.34). Following double SCT, ≥ VGPR was increased to 63% [t(4;14)/t(14;16)/del 17 pts.] versus 65%, respectively (p=.84). Response was not different with either transplant strategy. No treatment-related mortality occurred during RAD induction, while non-relapse mortality at one year from allo SCT was 10.6%. Incidences of pneumonia, venous thromboembolism, and febrile neutropenia were 11, 7.2, and 5.3%, respectively. Preliminary overall survival results will be presented. Conclusions Our data show RAD induction to be very effective in newly diagnosed MM and to be well tolerated. By subsequent double SCT, a high number of CR/sCR was added. Correlative studies suggests response to be independent of known unfavourable cytogenetic prognosticators, such as t(4;14) and del 17p while time-to-event data will be needed to ultimately confirm a lenalidomide-based triple regimen being able to overcome adverse cytogenetic risk. Administration of R-maint to auto-allo pts was challenging despite a lenalidomide target dose of 5 mg/day.

Disclosures
Knop: Celgene GmbH: Consultancy, Honoraria. Off Label Use: Use of lenalidomide, doxorubicin, and dexamethasone in newly diagnosed multiple myeloma. Einsele:Celgene GmbH: Consultancy, Research Funding. Bargou:Amgen Inc.: Consultancy, Honoraria, Other.