Prolongation of Post Relapse and Overall Survival in Patients with Multiple Myeloma by Salvage Strategy with the Combination of Thalidomide and Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation Based on the Nature of Disease Progression after Autologous Bone Marrow Transplantation.
Authors: Hardan Izhar , Shimoni Avichai , Kneller Abraham , Avigdor Abraham , Shemtov Noga , Berkowicz Miriam , Davidowitz Yaron , Yeshurun Moshe , Yerushalmi Ronit , Meirav Leiba , Michal Bar-Nathan , Izaac Ben-Bassat , Arnon Nagler 
Published: April 2020

Abstract
The impact of the use of autologous BMT (ABMT) as an up-front therapy on the natural history of multiple myeloma (MM) is limited, mainly due to the course of disease at progression after ABMT. Conventional salvage at that stage was reported to offer overall survival of only 14–17 months. The benefit of thalidomide and reduced intensity allogeneic stem cell transplantation (RIC SCT), which were introduced at that stage, is limited by the duration of response and toxicity. It was shown, however, that the aggressiveness of relapse clearly predicts for outcome in this set-up.
Methods. Patients (pt’s) with progression after ABMT were treated according to a strategy based on the nature of relapse, with thalidomide (Thal) and reduced intensity conditioning allogeneic stem cell transplantation (RIC SCT) as following: all progressing patients had Thal ± Dexa for induction of response, but only at a clinical indication for therapy. DTPACE combination was given to those who failed to respond to Thal. Pt’s with aggressive progression were offered a RIC SCT at response, while patients with an indolent progression were offered a RIC SCT only at escape from response to Thal or if being resistant to Thal+Dexa. Re-induction therapy was delivered prior to transplant. The post transplant therapy included DLI and/or Thal according to the findings in minimal residual disease (MRD) studies and base line chromosomal studies.
Results. Seventy five pts (age 36–66, median 58 y) with indolent (n= 46, 61%) or aggressive (n=29, 39%) progression, were treated according to this strategy. The overall response rate (= or &gt;PR) to Thal ± Dexa was 58.6%. Thirty six pt’s (48%) subsequently underwent RIC SCT (27 related, 9 unrelated donor) and 10 pts with an indication but no matched donor had a 2nd ABMT. Treatment related mortality was 9.3% (7 pt, all after RIC SCT, giving transplant related mortality rate of 16.6% for RIC SCT in this setting). RIC SCT reversed resistant to Thal in 7 pt. The median overall survival (OS) from progression of the entire group is 39 months with a projected 3-years survival rate of 52% (follow-up 19m-74m, median= 34m). The nature of relapse was found to be a strong independent favorable prognostic factor with a median post relapse OS of &gt;62m (not yet reached) vers. 24m, for pt’s with indolent compared with aggressive relapse (p=0.00002). In 24 patients (32%), the duration of response exceeded the first progression free period (from ABMT until progression). The median OS from ABMT of this group of patients is 85m, compared with a median OS rate of 56m from ABMT in a comparable historical group of 62 patients from our center that relapsed after ABMT prior to the introduction of the Thal /RIC SCT strategy.
Conclusion. The therapy with Thal and RIC SCT with a strategy based on the nature of disease progression after ABMT can improve post relapse and overall survival of MM patients. This may significantly add to the contribution of ABMT to the outcome of therapy in MM.