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Introduction: Risk-adapted therapy in curable hematologic malignancies is commonly applied: low-risk patients (pts) may be cured with less intensive treatment, avoiding excessive toxicity, whereas high-riskpts require more intensive and toxic regimens. In multiple myeloma (MM), this model may not apply, since the disease is incurable. In recent years, there has been a marked improvement in patient outcome, due to the introduction of novel agents and optimized treatment strategies, including the use of transplant and maintenance. A better evaluation ofpts prognosis based on the new revised international staging system (R-ISS) has been also introduced in clinical practice. The objective of this analysis was to evaluate the impact of treatment intensification (specifically autologous stem cell transplantation [ASCT] and maintenance) inpts with different prognostic features. Methods: Data from 3 phase III randomized trials in newly diagnosed MMpts (RV-MM-209; EMN441; GIMEMA-MM0305) were pooled together and analyzed. Baseline patient risk assessment was estimated using R-ISS. We evaluated: 1) the impact of treatment intensification with high-dose therapy followed by ASCTvs no-ASCT inpts with R-ISS Stage Ivs Stage II/III; 2) the impact of treatment intensification with maintenancevs no maintenance inpts with R-ISS Stage Ivs Stage II/III. RV-MM-209 and EMN441 studies randomizedpts to ASCTvs no-ASCT; allpts in the GIMEMA-MM0305 trial did not receive ASCT and were excluded from the first comparison; RV-MM-209 and GIMEMA-MM0305 studies randomizedpts to maintenance or no maintenance after induction/consolidation; allpts in the EMN441 trial received maintenance and were excluded from the second comparison. We evaluated progression free survival-1 (PFS1), PFS2 and overall survival (OS). Cox proportional hazards models were used to estimate hazard ratios (HRs). To account for potential confounders, the comparisons between ASCTvs no-ASCT and maintenancevs no maintenance were adjusted for the trial effect and the main prognostic features. Results: Overall, 1302 pts were enrolled in the 3 trials. Median follow-up was 4 years.Comparison ASCTvs no-ASCT: 791pts were enrolled in the 2 trials, 529 were eligible for the ASCTvs no ASCT comparison. R-ISS Stage data were available for 419 pts. There was an overall advantage for ASCTvs no-ASCT in PFS1 (0.53; p Conclusions: Both ASCT and maintenance improved PFS1, PFS2 and OS in MM pts. The highest survival was reported in patients with R-ISS Stage I receiving ASCT and/or maintenance. Low-riskpts (R-ISS Stage I) not undergoing intensification with ASCT or maintenance lose their prognostic advantage over high-risk patients receiving the same intensification. Figure 1. Figure 1. Disclosures Gay: Janssen-Cilag: Other: Advisory Board; Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria, Other: Advisory Board; Mundipharma: Other: Advisory Board. Hajek:Novartis: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Bringhen:Mundipharma: Other: Advisory Board; Karyopharm: Other: Advisory Board; BMS: Honoraria; Janssen-Cilag: Honoraria; Amgen: Other: Advisory Board; Celgene: Honoraria. Gaidano:Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Caravita:Janssen-Cilag: Honoraria. Cavo:Millennium: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Foà:Pfizer: Speakers Bureau; Ariad: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Janssen-Cilag: Consultancy, Speakers Bureau; Genetech: Consultancy; Roche: Consultancy, Speakers Bureau. Patriarca:Bristol-Myers Squibb: Other: Advisory board; Mundipharma: Other: Advisory board; Janssen-Cilag: Other: Advisory board; MSD: Consultancy; Celgene: Consultancy. Ria:Italfarmaco: Consultancy, Speakers Bureau; Janssen-Cilag: Other: Advisory Board, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Binding Site: Speakers Bureau; BMS: Speakers Bureau; BMS: Speakers Bureau. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; SANOFI: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbivie: Honoraria; Amgen: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

Background: Minimal residual disease (MRD) is one of the most relevant prognostic factors in patients with multiple myeloma (MM); however, the impact of maintenance therapy on MRD levels remains unclear. Among patients with newly diagnosed MM (NDMM) who received lenalidomide maintenance until they developed disease progression, the role of MRD status as a predictor of progression-free survival (PFS) was evaluated by multiparameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) analysis. Methods: Seventy-three patients with NDMM enrolled in the RV-MM-EMN-441 (clinical trials.gov identifier, NCT01091831) and RV-MM-COOP-0556 (clinicaltrials.gov identifier, NCT01208766; European Myeloma Network EMN02/HO95 MM Trial) phase 3 trials who achieved at least a very good partial response after intensification/consolidation were included. The median patient age was 57 years (interquartile range, 53-61 years), and all patients received lenalidomide maintenance until they developed progression. MRD was evaluated on bone marrow after intensification/consolidation, after 6 courses of maintenance, and every 6 months thereafter until clinical relapse using both ASO-RQ-PCR (sensitivity, 10 −5 ) and MFC (sensitivity, from 10 −4 to 10 −5 ). Results: After intensification/consolidation, 33 of 72 patients (46%) achieved a molecular complete response (m-CR), and 44 of 70 (63%) achieved a flow complete response (flow-CR). Almost 27% of patients who were MRD-positive after consolidation became MRD-negative during maintenance. After a median follow-up of 38 months, PFS was prolonged in patients who achieved negative MRD status during maintenance according to results from both ASO-RQ-PCR analysis (hazard ratio, 0.29; 95% confidence interval, 0.14-0.62; P =.0013) and MFC (hazard ratio, 0.19; 95% confidence interval, 0.09-0.41; P