A Complete Remission (CR) Is Not a Prerequisite for Prolonged Survival after Autotransplants for Multiple Myeloma.
Authors: Tricot Guido , Reiner Maureen , Sawyer Jeffrey , Crowley John , Barlogie Bart 
Published: October 2019

Abstract
In acute leukemia prolonged survival is impossible without obtaining a CR. Based on the acute leukemia model, myeloma therapy has gradually been intensified with the aim to increase the CR rate as a first important step to improve overall survival (OS). Although patients with abnormal metaphase cytogenetics have a significantly inferior outcome in terms of event-free and overall survival, the CR rate is similar for patients with and without cytogenetic abnormalities, indicating that CR may not be a good prognostic indicator of ultimate outcome. To address the importance of obtaining a CR for OS, we analyzed our Total Therapy I (VADx3-high dose cyclophosphamide 6g/m2 with stem cell collection-EDAP-melphalan-based tandem transplants-α interferon maintenance) data in those patients who had not received any treatment prior to enrollment (N=155), received at least one transplant (N=135) and were alive one year after the first transplant (N=132). Kaplan-Meier curves were generated using a 1 year landmark to compensate for the guaranteed time of CR patients, but thereby excluding patients who died within the first year after the first autotransplant (N=3). The 1-year landmark was chosen because the large majority of CR patients (75%) had achieved their CR at 1 year after the first transplant. In addition, a time-dependent co-variate analysis for CR was performed, including the 135 patients. The median follow-up of these patients was 10.5 years. The 9 year OS after the landmark, i.e., 10 years after the first transplant, was 41% (95% confidence interval: 26, 55) for CR patients versus 37% (26, 47) for no CR patients (i.e., PR and <PR) with a logrank p value of 0.71 (Figure 1). Using a time-dependent co-variate analysis for CR, achieving a CR was not significantly related to OS (Hazard Ratio: 0.83; p value 0.39). Only the presence of metaphase cytogenetic abnormalities (HR: 2.0; p=0.005), LDH > 190 U/L (upper limit of normal) (HR: 2.0; p=0.01) and CRP >4.0mg/L (HR: 1.6; p=0.03) were significant for OS. When the importance of CR was assessed separately for patients with (N=43) and without (N=84) abnormal cytogenetic (cytogenetic information was missing on 5 patients), no survival benefit for CR patients was seen in either subgroup (p values 0.52 and 0.32, respectively) and similarly, using the time-dependent co-variate analysis for CR, there was no significant benefit for OS of attaining a CR in either group (p value: 0.7 and 0.5, respectively). We conclude that prolonged survival (>10 years) is observed in a substantial proportion of myeloma patients receiving a tandem autotransplant-based regimen, irrespective of the completeness of response to tandem transplants. The inherent genetic features of the myeloma and the impact on the micro-environment of the myeloma cells appear to be more important than the absolute tumor burden reduction accomplished by tandem transplants. Our findings may also be a reflection of the insensitivity of CR as an assessment of remaining tumor burden in myeloma and a new definition of CR may be required.
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