Abstract: The incidence of mutations within the MAPK pathway, the CRBN pathway, and TP53 is significantly increased in drug-refractory MM. Mutations in CRBN might contribute to IMiD resistance in drug-refractory MM.

Abstract: Mass spectrometry (MS) is a promising tool for monitoring monoclonal protein in plasma cell dyscrasias. We included 480 transplant-eligible newly-diagnosed multiple myeloma (MM) patients from the GMMG-MM5 trial (EudraCT No. 2010-019173-16) and performed a retrospective MS analysis at baseline (480 patients) and at the pre-defined, consecutive time points after induction (444 patients), prior to maintenance (305 patients) and after one year of maintenance (227 patients). We found that MS negativity was significantly associated with improved progression-free survival (PFS) even in patients with complete response (CR) at all investigated follow-up time points. The prognostic impact was independent of established risk factors, such as the revised International Staging System. Combining MS and baseline cytogenetics improved the prediction of outcome: MS-positive patients with high-risk cytogenetics had a dismal PFS of 1.9 years (95% confidence interval [CI] : 1.6–2.3 years) from the start of maintenance. Testing the value of sequential MS prior to and after one year of maintenance, patients converting from MS positivity to negativity had an excellent PFS (median not reached) while patients converting from MS negativity to positivity progressed early (median 0.6 years, 95% CI: 0.3-not reached). Among patients with sustained MS positivity, the baseline high-risk cytogenetic status had a significant impact and defined a group with poor PFS. Combining minimal residual disease (MRD) in the bone marrow and MS allowed the identification of double negative patients with a favorable PFS (median 3.33 years, 95% CI: 3.08-not reached) and no overall survival events. Our study provides strong evidence that MS is superior to conventional response monitoring, highlighting the potential of MS to become a new standard. Our data indicate that MS should be performed sequentially and combined with baseline disease features and MRD to improve its clinical value. Clinical Trials Register: EudraCT No. 2010-019173-16

Abstract: Introduction: Despite improvements in the prognosis of multiple myeloma (MM), most patients ultimately relapse and undergo multiple lines of therapy. Due to the immunocompromising effects of virtually all anti-myeloma agents as well as the disease itself, infections are a frequent complication during therapy and the most important cause of mortality in patients with MM. Establishment of clear predictors of infectious complications, especially under therapy with novel agents, is therefore of major clinical importance to identify patients at risk and to guide anti-infective prophylaxis. Methods: In this prospective, observational cohort study we examined the development of CD4+ T-cell numbers during anti-myeloma therapies which were based on the novel agents daratumumab, carfilzomib, elotuzumab, or pomalidomide and their impact on infectious complications in 96 patients with relapsed/refractory MM (median prior lines of therapy: 2 [1-13], median age: 70 years of age [42-90] ). Data on infectious events including CTC-AE severity grading, antimicrobial prophylaxis strategies and vaccination status was collected before start of therapy, after 3 months and after 6 months of therapy. Flow cytometry was used to identify T-cell subsets at all three timepoints. Results: Before start of therapy, 25 patients (26%) had CD4+ cell counts & lt; 200/µl, 75 patients (78%) had CD4+ cell counts & lt; 500/µl. In a multivariate linear regression model the number of previous lines of therapy had a significant negative impact on CD4+-cell numbers at start of relapse therapy (p=0.03), whereas age and active therapy within in the last 6 months did not. With regard to relapse therapy, both pomalidomide and carfilzomib led to a significant reduction in CD4+ cell count after 3 months of therapy (p=0.03 and p= 0.04, resp.) in a multivariate linear regression model. This effect was not noticeable in treatments based on daratumumab. In a multivariate logistic regression analysis with regard to the occurrence of infections ≥ CTC II° within the first 3 cycles of therapy, CD4+ cell count at start of relapse therapy was the only predictor with borderline statistical significance (p=0.06). Conclusions: A significant proportion of patients with relapsed refractory MM show a severe reduction of CD4+ T-cells already at start of relapse therapy, especially after multiple lines of therapy. CD4+ cell count at start of relapse therapy might indicate an increased risk of infectious complications. Additional studies with a larger number of patients are warranted to further elucidate the impact of CD4+ cell count at start of relapse therapy as a predictor of infectious complications in MM and whether it might serve to better identify patients at risk of infectious complications and steer antimicrobial prophylaxis strategies. Disclosures John: Proteona: Research Funding. Mueller-Tidow:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Jose-Carreras-Siftung: Research Funding; Bayer AG: Research Funding; BiolineRx: Research Funding; Wilhelm-Sander-Stiftung: Research Funding; BMBF: Research Funding; Deutsche Krebshilfe: Research Funding; Janssen-Cilag Gmbh: Membership on an entity's Board of Directors or advisory committees; Deutsche Forschungsgemeinschaft: Research Funding. Jordan:priME Oncology: Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Voluntis: Membership on an entity's Board of Directors or advisory committees; Pomme-med: Speakers Bureau; Hexal: Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dome: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; medupdate: Speakers Bureau; Helsinn: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tesaro: Membership on an entity's Board of Directors or advisory committees; ClinSolResearch: Membership on an entity's Board of Directors or advisory committees; Riemser: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Kreussler: Membership on an entity's Board of Directors or advisory committees; art-tempi: Speakers Bureau. Goldschmidt:Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Novartis: Honoraria, Research Funding; Mundipharma GmbH: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; Merck Sharp and Dohme (MSD): Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding. Raab:Heidelberg Pharma: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: Background: During the past decade, prognostic tools and outcomes of patients with newly-diagnosed multiple myeloma (NDMM) markedly improved. Data from clinical trials evaluating early morbidity and mortality including patients with transplant-eligible NDMM treated with novel agents are scarce. Thus, we aimed to analyze early morbidity and mortality in this patient cohort, devise and validate a predictive score to identify patients at risk. Patients and methods: Between July 2005 and January 2018, 1333 patients with transplant-eligible NDMM from three subsequent phase III trials, HD4, MM5 and HD6 from the German-speaking Myeloma Multicenter Group (GMMG), received a novel agent-based induction therapy with either bortezomib (BTZ) / doxorubicine / dexamethasone (DEX; PAD: n=192, HD4; PAd: n=296, MM5), BTZ / cyclophosphamide / DEX (VCD: n=300, MM5), BTZ / lenalidomide / DEX (VRD: n=272, HD6) or elotuzumab / VRD (ELO-VRD: n=273, HD6). Severe infections (SI) were defined as any infection grade ≥ 3 according to the Common Terminology Criteria for Adverse Events (CTCAE). SI and early deaths were counted on and up to 30 days post induction therapy. Uni-/multivariable logistic regression models were used to assess predictive factors for SI and early death and to account for trial effects. Data from the European Myeloma Network (EMN) 02 / Dutch-Belgian Cooperative Trial Group for Hematology Oncology Foundation (HOVON) 95 phase III trial including 1497 patients with transplant-eligible NDMM receiving induction therapy with VCD were used to validate a predictive score for SI and early mortality. Results: Overall, early mortality during induction therapy was low (n=24, 1.8%) in the GMMG cohort. SI were the most common cause for early deaths (n=15, 62.5%) as compared to MM progression-related death (n=5, 20.8%) and other causes (n=4, 16.7%). Rates of SI during induction therapy were 11.9% (n=159) and decreased in subsequent trial generations: HD4-PAD: 27.1%, MM5-PAd: 10.8%, MM5-VCD: 9.3%, HD6-VRD: 7.3% and HD6-ELO-VRD: 9.9% of patients. In the EMN02/HO95 trial, early mortality was 1.7% (n=25) and rates of SI were 6.8% (n=101). A multivariate model including patient and disease baseline characteristics identified four major risk factors for SI and/or early death on induction therapy in the GMMG cohort: age ( & gt;60 years; odds ratio [OR]=1.70, 95% confidence interval [95% CI] : 1.21-2.40, p=0.002), International Staging System (stage III; OR=1.92, 95% CI: 1.22-2.94, p=0.005), platelet count ( & lt;150/nl; OR=2.03, 95% CI: 1.27-3.30, p=0.004) and World Health Organization (WHO) performance status ( & gt;1; OR=1.82, 95% CI: 1.10-3.06, p=0.022). A sum score based on these four risk factors (one risk factor = one point) was built and included 519 (39.5%), 550 (41.9%) and 245 (18.6%) patients with a score of 0, 1 and ≥2 points. A higher score gradually predicted an increasing risk for SI and/or death during induction therapy: 0 points=7.9%, 1 point=11.5% and ≥2 points=23.2% (p & lt;0.001, Figure 1A); SI only: 0 points=7.7%, 1 point=10.9% and ≥2 points=21.6% (p & lt;0.001, Figure 1B) and early death only: 0 points=0.4%, 1 point=1.3% and ≥2 points=5.7% (p & lt;0.001, Figure 1C). In the EMN02/HO95 cohort, 673 (45.6%), 587 (39.7%) and 217 (14.7%) patients had a score of 0, 1 and ≥2 points. The score was successfully validated in the EMN02/HO95 cohort: SI and/or death during induction therapy: 0 points=5.0%, 1 point=8.3% and ≥2 points=11.9% (p & lt;0.001); SI only: 0 points=4.5%, 1 point=7.0% and ≥2 points=10.0% (p=0.006) and early death only: 0 points=0.5%, 1 point=2.2% and ≥2 points=2.5% (p=0.01). Conclusions: To date, this is the largest pooled analysis of individual patient data on early morbidity and mortality in patients with transplant-eligible NDMM treated with novel agent-based induction therapy. Our analysis highlights a decreasing incidence of SI and early mortality and proposes a validated, easy-to-use score to identify patients at excessive risk for SI and/or early death during induction therapy. This allows the implementation of intensive monitoring, preventive and supportive strategies for this subgroup of patients in further clinical trials and also routine care. Figure 1 Figure 1. Disclosures Mai: Celgene / BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Glaxo Smith Kline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding. Salwender: AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Takeda: Honoraria; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; GlaxoSmithKline: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen-Cilag: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Oncopeptides: Honoraria; Chugai: Honoraria; Pfizer: Honoraria. Zweegman: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munder: GSK: Consultancy; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Takeda: Consultancy, Honoraria; Amgen: Honoraria; Sanofi: Consultancy; Janssen: Consultancy, Honoraria; Incyte: Research Funding. Pantani: Janssen: Honoraria; Amgen: Honoraria. Brossart: BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; MSD: Honoraria. Beksac: Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Oncopeptides: Consultancy. Raab: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Abbvie: Consultancy, Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Dürig: Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Besemer: Takeda: Honoraria; Janssen: Honoraria; GSK: Honoraria. Fenk: GSK: Honoraria; Amgen: Honoraria; Janssen: Honoraria; BMS/Celgene: Honoraria; Takeda: Honoraria. Haenel: Bayer Vital: Honoraria; Jazz: Consultancy, Honoraria; GSK: Consultancy; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Metzler: Takeda: Consultancy; BMS: Consultancy; GSK: Consultancy; Amgen: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy. Graeven: Amgen: Honoraria; Sanofi Aventis: Honoraria; Celgene: Honoraria, Research Funding; Johnson and Johnson: Honoraria; Astra Zeneca: Honoraria; MSD: Consultancy; Boehringer Ingelheim: Honoraria; BMS: Honoraria; Fujifilm: Honoraria; Roche: Research Funding; Gilead: Research Funding; Ipsen Bioscience: Research Funding; MacroGenics: Research Funding. Boccadoro: Janssen and GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie: Honoraria; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma: Research Funding. Scheid: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Abbvie: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dimopoulos: Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Beigene: Honoraria. Weisel: Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Cavo: Adaptive Biotechnologies: Consultancy, Honoraria; Novartis: Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sonneveld: SkylineDx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Goldschmidt: Mundipharma: Research Funding; Incyte: Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grant; Molecular Partners: Research Funding; MSD: Research Funding; GSK: Honoraria; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding.

Abstract: The prospective, randomized phase III trial GMMG ‐ HD 2 aimed at demonstrating non‐inferiority of single (Arm A) versus tandem (Arm B) high‐dose melphalan followed by autologous transplantation ( HDM / ASCT ) with regard to 2‐year event‐free survival ( EFS ) in newly‐diagnosed multiple myeloma ( MM ) and included 358 evaluable patients [Intention‐to‐treat population, ( ITT ), single/tandem HDM / ASCT : n  = 177/181]. After a median follow‐up of more than 11 years, non‐inferiority of single versus tandem HDM / ASCT was demonstrated using the planned non‐inferiority threshold of 15% of the 2‐year EFS rate. Neither EFS ( P  = 0·53) nor overall survival ( OS ) ( P  = 0·33) differences were observed in the ITT population. In the tandem arm, 26% ( n  = 47/181) of patients refused a second HDM / ASCT due to non‐medical reasons. A per‐protocol ( PP ) analysis, including patients who received the intervention (single/tandem HDM / ASCT : n  = 156/93) and patients who did not receive a second HDM / ASCT due to medical reasons (12%, n  = 22/181), did not yield differences in EFS ( P  = 0·61) or OS ( P  = 0·16). In the ITT and PP set of the tandem arm, the rates of complete responses increased from first to second HDM / ASCT (both P  = 0·04). Ten‐year OS for the entire ITT was 34% (95% confidence interval: 29–40%). OS after first relapse was significantly shortened in the tandem arm ( P  = 0·04). In this study single HDM / ASCT was non‐inferior to tandem HDM / ASCT in MM .

Abstract: The discovery of new targets for tailored therapy is a major improvement in oncology, and tools for the rapid and reliable detection of these targets are essential. Clinical trials demonstrated the benefit of recently developed antibodies against antigens on malignant B‐cells. The aim of this study was to assess patients with plasma cell (PC) disorders for expression of antigens on malignant PCs that have exhibited promise in targeted cancer therapy. We retrospectively analyzed the expression of CD20, CD22, CD27, CD30, CD38, CD52, CD81, CD138, and SLAMF7 on PCs by flow cytometry in 103 patients with PC disorders. Furthermore, we studied cytogenetic data to correlate immunophenotyping and genetic parameters. The expression frequency of CD22, CD30, and CD52 was similar to other studies (12–35%, 0–19%, and 0–8%, respectively). Unexpectedly, we observed a high CD20 expression frequency in 37% of all AL‐amyloidosis cases. The presence of t(11;14) correlated positively with CD20 expression on PCs in AL‐amyloidosis ( p  = 0.018). Furthermore, the expression level of SLAMF7 was decreased in advanced PC disorders ( p  = 0.025) and a diminished expression of SLAMF7 is associated with low expression of CD27 and CD81 on malignant PCs in newly diagnosed multiple myeloma. This study provides a contribution to targeted therapy options in PC disorders. Particularly, the results put an emphasis on CD20 as therapeutic target in AL‐amyloidosis. Regarding the therapeutic options of the SLAMF7 antibody elotuzumab, these data advise that analysis of SLAMF7 expression before application of elotuzumab might help to estimate the efficacy of elotuzumab in clinical trials. © 2015 International Clinical Cytometry Society

Abstract: For multiple myeloma, high-dose chemotherapy and autologous blood stem-cell transplantation (ASCT) followed by lenalidomide maintenance (LenMT) at 10–15 mg/day is considered standard of care. However, dose reductions due to side effects are common and median LenMT doses achieved over time may remain lower. Dose response during LenMT has never been investigated. Patients and Methods: In a multicenter, randomized, open-label trial, patients with multiple myeloma after ASCT and high-dose lenalidomide consolidation therapy (CT) at 25 mg/day were randomized to receive LenMT at either 25 or 5 mg/day. Primary endpoint was progression-free survival (PFS). Results: Ninety-four patients (median age, 58 years) were randomized to either arm, with 22% having International Staging System (ISS) stage 3 and 22% being in complete remission (CR). After median follow-up of 46.7 months, median doses of 14.5 and 5 mg/day were achieved in the two arms; 53% of dose reductions occurring during CT. In the high- and the low-dose arm, median PFS was 44.8 and 33.0 months (HR, 0.65; 95% CI, 0.44–0.97; P = 0.032), 36% and 23% of patients had stringent CR as best response (P = 0.08), and 4-year OS was 79% and 67% (P = 0.16), respectively. Hematologic toxicity, grade ≥3 neutropenia, and infections were initially more common with LenMT 25 mg, but decreased after dose adjustments. SPM incidence and quality-of-life (QoL) scores in both arms were similar. Conclusions: LenMT dose correlated with efficacy and toxicity. High rates of dose reductions during CT argue against a high starting dose. However, continuous up- and down-titration for each patient to the current maximum tolerated dose is prudent.