Clinical Prognostic Factors in Chemosensitive Multiple Myeloma (MM) Patients Intensified with High Dose Therapy/Stem Cell Support (HDT/SCS): Results of the Spanish Trial (PETHEMA/GEM2000).
Authors: Mateos María-Victoria , Lahuerta Juán-José , Sureda Anna , de la Rubia Javier , García-Sanz Ramón , Martínez Rafael , García-Laraña José , de Arriba Felipe , Ribera Jose-María , Hernández Miguel-Teodoro , Escoda Lourdes , Carrera Dolores , Besalduch Joan , Hernández B. , Fernández P. , Blade Joan , Miguel J.F. San 
Published: October 2019

Abstract
Autologous stem cell transplantation (ASCT) has become the standard of care for young MM pts. The analysis of prognostic factors will contribute to identify which pts benefit more from this procedure. However, in this type of analysis it is important that all pts receive uniform treatment, and since primary refractory pts have a different prognosis from pts sensitive to initial chemotherapy, our policy was to use up-front a more intensive treatment approach for the refractory pts. In this report we will focus on the analysis of clinical prognostic factors in sensitive MM pts to induction chemotherapy. The Spanish PETHEMA/GEM2000 trial included untreated MM pts younger than 70 years and consisted on six alternating cycles of chemotherapy VBMCP/VBAD followed by high dose therapy (BuMel or Mel200) supported with ASCT. Pts achieving CR IF- or CR IF+ after the first transplant received maintenance treatment with interferon/prednisone, while pts with a remaining visible M-spike (partial or minimal response) received a second HDT/SCS with CBV (cyclophosphamide, etoposide and BCNU) or a dose-reduced intensity allogeneic transplant if donor is available. Between January 2000 and December 2004, 803 pts were considered to have chemosensitive disease and were transplanted as above described. Median age at time of diagnosis was 59 y (range: 31–70). Baseline characteristics were similar to those previously reported in other series in which young patients were included. Following initial chemotherapy, the response rate was: 13.6% CRIF-, 14% CRIF+ and 60% PR. Response rate increased after HDT/SCS: CRIF-, CRIF+ and PR rates were 38%, 20% and 35%, respectively. Early death rate, occurring during the first two months after ASCT was 3,5% (28 pts). 207 out of 803 pts received a second HDT/SCS. 531 pts (66%) started maintenance therapy after transplant with interpheron and prednisone in most of them (77%). After a median follow-up of 45 months (range: 6–91), the median EFS time for the 803 pts was 45 months (95% CI: 40,5–49,1), defining event as relapse/progression or death; median OS time has not been reached and the estimated 8-year EFS and OS were 30 and 53%, respectively. Univariate analysis identified the following adverse prognostic factors for EFS: age ≥ 59 y, advanced Durie and Salmon stage, advanced ISS stage, Monoclonal component ≥ 30g/l, Hemoglobin (Hb) level < 11 g/dl, creatinine > 1,5 mg/dl, Bone Marrow Plasma cells infiltration ≥ 45%, performance status according to EGOG 3–4, and failure to achieve CR IF- after induction chemotherapy or after the first transplant. The same prognostic factors were identified in the univariate analysis for OS. On multivariate analysis only five variables retained an independent prognostic influence on EFS and OS: age ≥ 59 y (p:0,04), Hb < 11 g/dl p:0,000), advanced ISS stage (p:0,03) and lack of CRIF- after transplant (p:0,000). The three ISS stages could be subdivided into two subgroups using the variables selected in the multivariate analysis. Thus pts who didn’t achieve CR IF- after transplantation and had an additional adverse factor (either age or anemia) showed a significant different outcome within the ISS stage I, II and III.