Effect of Pre and Post-Transplantation Responses on Outcome of Multiple Myeloma Patients: CR and near-CR Should Not Be Considered as Equivalent Prognostic Markers. Results of a PETHEMA/Gem Prospective Study
Authors: Lahuerta Juan José , Mateos Maria Victoria , Martínez-López Joaquin , Rosinol Laura , Sureda Anna , de la Rubia Javier , García-Laraña José , Martínez-Martínez Rafael , Hernández-García Miguel-Teodoro , Carrera Dolores , Besalduch Juan , de Arriba Felipe , Ribera Jose-Maria , Escoda Lourdes , Hernández-Ruiz María-Belen , García-Frade Javier , Rivas-González Concepción , Alegre Adrian , Blade Joan , Miguel J.F. San 
Published: April 2020

Abstract
To achieve CR is an important goal in the treatment of most Hematological malignancies. In Multiple Myeloma (MM) although there is evidence demonstrating an association between CR and long-terms outcomes, some trials have failed to find such a correlation. In addition, it is not clear whether different responses categories, such as CR, near-CR (nCR) o Very Good Partial Response represent different prognostic subgroups or include an homogeneous group of patients with similar outcomes. Therefore, the confirmation of a possible association between different responses categories and long-term outcomes is required. We evaluated the prognostic influence on EFS and OS of pre- and post-transplant responses in newly diagnosed MM patients.
Patients and Methods: We analyzed 632 patients who had been included in the prospective GEM2000 trial. All were uniformly treated with VBCMP/VBAD induction followed by high-dose therapy and autologous stem cell transplant and maintenance therapy with interpheron plus prednisone. Disease response was assessed post-induction and post-transplant using EBMT criteria, modified to include nCR. CR required at least 6 weeks of negative immunofixation (IFx) in serum and urine plus less than 5% plasma cells in BM. nCR was defined as electrophoresis-negative but IFx-positive. Partial response (PR) required greater than 50% reduction in M-protein and Stable disease (SD) included patients with minimal response and no change by EBMT criteria.
Results: Probability of achieving CR post-transplant was significantly higher among patients achieving nCR versus PR (p= 0.004) versus SD or PD (p= 0.0003) pre-transplant. Patients achieving nCR or PR post-induction had similar outcomes, and both response categories showed a trend to have inferior EFS and OS as compared to patients in CR. After transplant, only borderline differences in EFS were detected upon comparing nCR with PR (nCR: median 40 months; PR median 34 months, p=0.07), by contrast the EFS of CR patients (median 61 months) was significantly longer than that of nCR or PR categories (both comparisons p&lt;10−5). OS was longer among patients achieving CR post-transplant (median NR) compared with patients achieving nCR (median NR, p= 0.01) or PR (61 months, p &lt; 10−5); it should be noted that nCR patients had longer OS than PR patients (p = 0.04). The multivariate analysis showed that achieving CR was associatted with significantly better EFS and OS while the EFS/OS influence of nCR was no statistically different from PR or SD. Within nCR patients, outcomes were significantly worse among those who achieved nCR post-induction and remained in nCR post-transplant compared with those who upgraded to nCR post-transplant after PR or SD post-induction. EFS and OS, and influence of response, were similar among elderly (65–70 years) and younger (&lt;65 years) patients. (both comparisons p&lt;10).
Conclusions: Our results confirm that the degree of response is highly associated with final survival, with higher benefit for patients achieving CR by IFx, which should not be pooled with the nCR patients. Although the impact in survival is more evident for the responses measures after HDT/SCT it is also evident after induction therapy, moreover, the quality of response post-induction clearly influences response post-transplant. Finally, patients between 65 and 70 years should not be completely discouraged from HDT/SCT.