High-Dose Therapy/Stem Cell Support (HDT), Including Tandem Transplant, for Primary Refractory Multiple Myeloma (MM): Results from the Spanish Myeloma Group (PETHEMA/GEM) in 49 Patients.
Authors: Rosinol L. , Garcia-Sanz R. , Lahuerta J. J. , Hernandez-Garcia M. , Sureda A. , de la Rubia J. , Ribera J. M. , Hernandez-Ruiz B. , Carreras D. , Navarro I. , Garcia-Ruiz J. C. , Gardella S. , Garcia-Larana J. , Diaz-Mediavilla J. , San Miguel J. F. , Blade J. 
Published: October 2019

Abstract
It is assumed that patients with primary refractory myeloma are the most likely to benefit from early HDT. In four series the CR rate was between 8 and 40% and the overall survival ranged from 4 to 6 years. However‚ the number of patients with progressive disease vs those with “stable disease” was not given in published series. The aim of our study was to investigate the efficacy in terms of response up-grading and survival of early HDT in patients with primary refractory myeloma. From October 1999 to December 2003 patients with MM younger than 70 years were given 6 courses of VBMCP/VBAD chemotherapy. Patients with refractory disease were scheduled to receive a tandem transplant‚ the first procedure intensified with busulphan-12 mg/kg-/melphalan-140 or melphalan-200 and the second with the CVB -cyclophosphamide‚ etoposide and BCNU- or with a dose-reduced intensity “allo” conditioned with fludarabine/melphalan-140‚ depending on sibling donor availability. Response and progression were defined according to the EBMT criteria. Forty-nine patients with primary refractory disease were identified. Twenty patients showed progression after their initial chemotherapy while 29 patients had “non-responding‚ non-progressive disease”. Eighty percent of the patients achieved some degree of response after the first autologous transplant (CR or near-CR: 8%‚ PR: 56%‚ MR: 16%) while 10% did not respond and 10% died from the procedure. Twenty-four patients were given a second transplant (autologous: 17‚ allogeneic: 7). Forty-six percent of the 17 patients who received a second autologous transplant upgraded their response (CR: 6%‚ PR: 17%‚ MR: 23%) while 41% had progressive disease or “no-change” and 13% died from the procedure. Three of the seven patients who underwent a dose-reduced intensity “allo” responded (2 CR‚ 1 PR) while two had progressive disease and two died from transplant-related complications. The median survival of the whole series of 49 patients was 32 months. Patients who had progressive disease after the initial chemotherapy had a significantly shorter survival than those who showed “non-responsive‚ non-progressive disease” (median 21 months vs. not reached‚ p=0.003). Finally‚ patients with “non-responding‚ non-progressive disease” had similar survival than those with chemosensitive disease intensified with HDT in the GEM trial.
Conclusions.
A high-dose therapy approach in patients with primary refractory myeloma results in a high overall response‚ but the CR rate is low‚ patients with progressive disease to the initial chemotherapy have short survival despite intensive therapy‚ and patients with “non-responding‚ non-progressive disease” have similar survival than chemosensitive patients.
Whether the good outcome of the latter patients is mainly due the effect of HDT or to the natural history of a more indolent disease remains to be determined.