The Prognostic Impact of Complete Remission (CR) Plus Very Good Partial Remission (VGPR) in a Double-Transplantation Program for Newly Diagnosed Multiple Myeloma (MM). Combined Results of the IFM 99 Trials.
Authors: Harousseau Jean-Luc , Attal Michel , Moreau Philippe , Garban Frédéric , Facon Thierry , Avet-Loiseau Hervé 
Published: October 2019

Abstract
Introduction.
In MM, the impact of CR achievement is still a matter of debate. In the IFM 90 and IFM 94 trials the achievement of CR (negative electrophoresis with or without negative immunofixation) plus very good partial remission (90% reduction of the M-component) was significantly associated with longer overall survival (OS) (M. Attal et al: NEJM1996;348:1875–83 and M. Attal et al; NEJM2003; 349: 2495–502). We wanted to check the impact of this simple way of response assessment in a program of double transplantation designed with the objective of increasing the CR rate.
Methods.
In the risk-adapted IFM 99 trials, therapeutic strategy was based on the assessement of two adverse prognostic factors (β2 microglobulin > 3 mg/L; del (13) by FISH analysis). All patients up to 65 years of age were to receive a double transplantation after an induction treatment with 3–4 courses of VAD. In standard risk MM (0 or 1 adverse prognostic factors), patients received a double autologous stem-cell transplantation (ASCT) (Melphalan 140 mg/m2/Melphalan 200 mg/m2) and were there randomized between no further treatment, pamidronate, or Thalidomide plus pamidronate (IFM 99/02). In high risk MM (2 adverse prognostic factors), patients received a first ASCT (after Melphalan 200 mg/m2) followed by either a reduced-intensity allogeneic SCT if an HLA-identical sibling was available (IFM 99/03) or a second ASCT (after Melphalan 220 mg/m2 ± anti IL-6 antibody) (IFM 99/04).
Results.
With a median follow-up time of 47 months, the median event-free survival (EFS) was 39 months and the probability of 5-year OS was 62%. Best response to treatment was assessed in 849 patients: CR was achieved in 274 patients (32%) and VGPR in 191 patients (22.5%), while 311 patients (37%) had only a partial remission (PR) and 73 pts (8.5%) had a stable or progressive disease.
Median EFS and 5-year OS were respectively 42 months and 77% for patients who achieved CR, 38 months and 63% for patients with VGPR, 30 months and 55% for patients with PR. The outcome was significantly better for the 465 patients with at least 90% reduction of their M-component (CR+VGPR) than for the 384 patients with < PR (median EFS 40 months versus 28 months, p=7.10–6) and 5-year OS 72% versus 52%, p=6.10–6). Response to the induction treatment with VAD was assessed in 700 patients: 112 (16%) had at least a VGPR. As compared to the 588 with less than VGPR there was no difference in EFS or in OS (p=0.23 and p=0.67 respectively, logrank test).
Conclusion.
In the context of a double transplantation program, CR + VGPR is obtained in 54.5 % of patients. We confirm that the quality of response is significantly correlated to the outcome and that achievement of CR + VGPR which can be assessed by very simple means, has a strong prognostic impact. We were not able to show a benefit of achieving CR+ VGPR after the induction treatment with VAD but 353/465 (76%) achieved this status only after the double transplant program.