Type of Relapse in 91 Newly Diagnosed MM Patients Treated with High Dose Chemotherapy Followed by Autologous Stem Cell Transplantation.
Authors: Petrucci Maria Teresa , Avvisati Giuseppe , Annibali Ombretta , Capria Saveria , De Propris Maria S. , Del Bianco Patrizia , Federico Vincenzo , Gallucci Cristiano , Gozzer Maria , Gregorj Chiara , Natale Annalisa , Romeo Azzurra , Meloni Giovanna , Foa Robert 
Published: October 2019

Abstract
High dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) is now considered standard therapy in patients (pts) with Multiple Myeloma (MM) aged less than 65–70 years. Using this therapeutic approach, newly diagnosed MM pts may achieve a complete remission rate of 30–50% associated to prolonged disease-free and overall survival (OS) rates. Unfortunately, HDT followed by ASCT is not curative and only a small fraction of pts remains free of disease after a long follow-up. In this study we analysed the different patterns of relapse after HDT and ASCT in 91 previously untreated MM pts (M/F : 46/45; median age: 54 years, range 32 – 69). As for stage, according to Durie and Salmon criteria, 4 pts (4%) were stage IA, 26 (29%) IIA, 57 (63%) IIIA and 4 (4%) were stage IIIB. The monoclonal component (MC) was: IgG in 54 pts (60%), IgA in 23 pts (25%), IgD in 2 pts (2%); 11 pts (12%) had a micromolecular MM (k/l were 8/3). Only one patient had a non-secretory MM. Median bone marrow plasma cells were 43%. Of the 91 pts, 5 were not evaluable for response because had died early during the transplantation procedure. Causes of death were: hepatic toxicity (1 patient), cardiac complications (1 patient) and hemorrhagic complications (3 pts). Of the remaining 86 evaluable pts, 84 (98%) achieved an objective response and 2 (2%) showed a progressive extramedullary disease (cutaneous and thoracic). After a median follow-up of 49 months (range 6–169) from the HDT-ASCT, 45/84 (54%) responding pts have relapsed and 38/84 (46%) are still alive and responding, the remaining patient was lost to follow-up and considered as event in both OS and event free survival (EFS) curves. The relapse type was “classical” (bone marrow + increase in MC) in 34 (75%) pts, extramedullary in 8 (18%) pts and of both type in 3 (7%) pts. Extramedullary relapse was defined by the presence of normal bone marrow, no increase in MC and presence of plasma cell tumour masses outside the bone marrow demonstrated by clinical examination, imaging and histology. As of July 31 2006, the median OS was not yet reached with 66% of pts still alive. The median overall EFS and time to progression (TTP) were: 82 and 89 months, respectively. As for the 34 pts with “classical” relapse and the 8 pts with extramedullary relapse, median OS and EFS were 120 and 29 months versus not reached and 85 months, respectively. The median time from HDT-ASCT to extramedullary relapse was 85 months. Sites of extramedullary relapse included vertebral and para-vertebral localization (7 pts), humeral localization (2 pts) and thoracic localization (1 patient); one patient presented humeral and pancreatic localization. The 8 pts with isolated extramedullary relapses were treated by local radiotherapy (4 pts), radiotherapy combined to Melphalan-Prednisone (MP) (3 pts) and a combination of surgical treatment + MP (1 patient). In conclusion, HDT-ASCT has greatly improved the prognosis of MM pts, however about 10%–15% of transplanted pts experience an extramedullary relapse probably due to sub-clinical seeding of tumor cells suggestive of the presence of an extramedullary clone of plasma cells with a high degree of chemo resistance responding, however, to radiotherapy.