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Activating BRAF mutations are found in a small subset of patients with newly diagnosed multiple myeloma, but prevalence increases in late-stage, refractory disease, and the mutations are associated with adverse outcome. This prospective single-arm, open-label, multicenter phase 2 trial assessed the efficacy and safety of combined BRAF/MEK inhibition, using encorafenib and binimetinib, in patients with relapsed/refractory multiple myeloma (RRMM) carrying a BRAFV600E mutation. Patients received 450 mg encorafenib once daily and binimetinib 45 mg twice daily. The primary end point was the overall response rate achieved within the first year after start of treatment according to International Myeloma Working Group criteria. Twelve RRMM patients with a median of 5 prior lines of therapy were enrolled. The overall response rate was 83.3%, with 10 patients achieving at least a partial response. The median progression-free survival was 5.6 months, and overall survival was 55% at 24 months. Emerging resistance to therapy was driven by RAS mutations and structural variants involving the BRAF locus. This is the first prospective clinical trial to demonstrate that combined BRAF/MEK inhibition is highly effective in patients with BRAFV600E-mutated RRMM, and it represents a successful targeted precision medicine approach in this disease. This trial was registered at www.clinicaltrials.gov as #NCT02834364.

Activating BRAF mutations are found in a small subset of patients with newly diagnosed multiple myeloma but prevalence increases in late stage, refractory disease, and are associated with adverse outcome. This prospective single-arm, open-label, multicenter phase II trial assessed the efficacy and safety of combined BRAF/MEK inhibition, using encorafenib and binimetinib, in patients with relapsed/refractory multiple myeloma (RRMM) carrying a BRAFV600E mutation (ClinicalTrials.gov identifier: NCT02834364). Patients received 450 mg encorafenib once daily and binimetinib 45 mg twice daily. The primary end point was the overall response rate achieved within the first year after start of treatment according to IMWG criteria. Twelve RRMM patients with a median of 5 prior lines of therapy were enrolled. The overall response rate was 83.3% with 10 patients achieving at least a partial response. The median progression-free survival (PFS) was 5.6 months and overall survival was 55% at 24 months. Emerging resistance to therapy was driven by RAS mutations and structural variants involving the BRAF locus. This is the first prospective clinical trial to demonstrate that combined BRAF/MEK inhibition is highly effective in patients with BRAFV600E mutated RRMM and represents a successful targeted precision medicine approach in this disease.

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

Intensive upfront therapy in newly-diagnosed multiple myeloma (MM) including induction therapy (IT), high-dose melphalan (MEL200), and autologous blood stem cell transplantation (ASCT) followed by consolidation and/or maintenance is mostly restricted to patients up to 65 years of age. Prospective phase III trial data in the era of novel agents for patients up to 70 years of age are not available. The GMMG-MM5 trial included 601 patients between 18 and 70 years of age, divided in three groups for the present analysis: ≤60 years (S1, n = 353), 61–65 years (S2, n = 107) and 66–70 years (S3, n = 141). Treatment consisted of a bortezomib-containing IT, MEL200/ASCT, consolidation, and maintenance with lenalidomide. Adherence to treatment was similar among patients of the three age groups. Overall toxicity during all treatment phases was increased in S2 and S3 compared to S1 (any adverse event/any serious adverse event: S1:81.7/41.8% vs. S2:90.7/56.5% vs. S3:87.2/68.1%, p = 0.05/p = 0.73), overall survival (log-rank p = 0.54) as well as time-to-progression (Gray’s p = 0.83) and non-relapse mortality (Gray’s p = 0.25), no differences were found between the three age groups. Our results imply that an intensive upfront therapy with a bortezomib-containing IT, MEL200/ASCT, lenalidomide consolidation, and maintenance should be applied to transplant-eligible MM patients up to 70 years of age.

The article Bortezomib-based induction, high-dose melphalan and lenalidomide maintenance in myeloma up to 70 years of age, written by Elias K. Mai, Kaya Miah, Uta Bertsch, Jan Dürig, Christof Scheid, Katja C. Weisel, Christina Kunz, Markus Munder, Hans- Walter Lindemann, Maximilian Merz, Dirk Hose, Anna Jauch, Anja Seckinger, Steffen Luntz, Sandra Sauer, Stephan Fuhrmann, Peter Brossart, Ahmet Elmaagacli, Martin Goerner, Helga Bernhard, Martin Hoffmann, Marc S. Raab, Igor W. Blau, Mathias Hänel, Axel Benner, Hans J. Salwender, and Hartmut Goldschmidt for the German-speaking Myeloma Multicenter Group (GMMG), was originally published Online First without Open Access. After publication in volume 35, pages 809–822, the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2020 and the article is forthwith distributed under the terms of the Creative Commons Attribution. FUNDING Open Access funding enabled and organized by Projekt DEAL.

Circulating microRNAs (miRNAs) could improve colorectal cancer (CRC) risk prediction. Here, we derive a blood-based miRNA panel and evaluate its ability to predict CRC occurrence in a population-based cohort of adults aged 50–75 years. Forty-one miRNAs are preselected from independent studies and measured by quantitative-real-time-polymerase-chain-reaction in serum collected at baseline of 198 participants who develop CRC during 14 years of follow-up and 178 randomly selected controls. A 7-miRNA score is derived by logistic regression. Its predictive ability, quantified by the optimism-corrected area-under-the-receiver-operating-characteristic-curve (AUC) using .632+ bootstrap is 0.794. Predictive ability is compared to that of an environmental risk score (ERS) based on known risk factors and a polygenic risk score (PRS) based on 140 previously identified single-nucleotide-polymorphisms. In participants with all scores available, optimism-corrected-AUC is 0.802 for the 7-miRNA score, while AUC (95% CI) is 0.557 (0.498–0.616) for the ERS and 0.622 (0.564–0.681) for the PRS., Appropriate risk models could facilitate risk stratification for colorectal cancer (CRC) screening. Here, the authors propose a blood-based microRNA signature observed to have altered expression in pre-diagnostic samples, which might be useful to identify high-risk populations for colorectal cancer screening.

Background: Treatment regimens including a proteasome inhibitor, immunomodulating agent and a monoclonal antibody (moAb) play an emerging role in the treatment of newly-diagnosed multiple myeloma (NDMM). This multicenter phase III trial of the German-speaking Myeloma Multicenter Group (GMMG HD6) investigated the addition of the anti-SLAMF7 moAb elotuzumab to lenalidomide / bortezomib / dexamethasone (RVd) in induction and consolidation therapy as well as to lenalidomide maintenance treatment in transplant-eligible NDMM. Patients and Methods: Patients were equally randomized into four treatment arms, stratified by International Staging System (ISS). Treatment consisted of four 21-day cycles of RVd (arms A1/A2) or elotuzumab-RVd (arms B1/B2) induction therapy, respectively. High-dose melphalan (HDM) and autologous blood stem cell transplantation (ASCT) were followed by two 21-day cycles of RVd or elotuzumab-RVd consolidation and lenalidomide or elotuzumab-lenalidomide maintenance for two years (arms A1/B1 vs. A2/B2). Primary objective of the trial was determination of the best of four treatment strategies regarding progression-free survival (PFS) from randomization. Secondary endpoints included overall survival (OS), response rates and safety. Results: Between 06/2015 and 09/2017, 564 patients were included in the trial. The evaluable intention-to-treat (ITT) and safety population comprised 559 and 555 patients (A1: n=139/137; A2: n=141/138; B1: n=137/138; B2: n=142/142). Median age at randomization was 59 (range 27-70) years. Baseline characteristics were well balanced between the four treatment arms. Four cycles of induction therapy were completed by 517 patients (92.5% of ITT). At least one HDM/ASCT was applied in 495 (88.6%), of which 116 patients (20.8%) received tandem HDM/ASCT. Consolidation and maintenance therapy were initiated in 469 (83.9%) and 454 (81.2%) patients, respectively. Rates of very good partial response or better (≥VGPR) prior to start of consolidation therapy were 78.9%, 78.2%, 81.5% and 80.7% in arms A1, A2, B1 and B2, respectively (p=0.95). With a median follow-up time of 49.8 months, PFS was not significantly different between the four treatment arms (adjusted log-rank p value stratified by ISS, p=0.86; primary endpoint). OS was similar in all treatment arms (stratified log-rank p=0.43). 3-year PFS/OS rates are 68.8%/89.4%, 68.5%/89.1%, 66.2%/92.5% and 67.2%/89.7% in arm A1, A2, B1 and B2, respectively. Multivariate analyses including age, sex, ISS stage, performance status, serum lactate dehydrogenase level, renal impairment at diagnosis, adverse cytogenetics (del17p, t[4;14] and t[14;16]) and treatment arms identified ISS stages II and III (hazard ratio [HR]=1.42/2.04, 95% confidence interval [95% CI]= 1.00-2.02/1.36-3.07, p=0.048/ On induction, consolidation and maintenance treatment, at least one (serious) adverse event (grade ≥3 for all AE or ≥2 for infections and infestations, neuropathy, cardiac disorders and thromboembolic events, and any grade for serious AE) occurred in 95.6%, 91.3%, 92.8% and 89.4% of patients in arm A1, A2, B1 and B2, respectively (p=0.25). Most common system organ classes (SOCs) were "infections and infestations", "neurological disorders", "blood and lymphatic system disorders", and "investigations" with no significant differences between the four treatment arms (p=0.39/0.64/0.13/0.42). Overall AE/SAE during lenalidomide vs. elotuzumab-lenalidomide maintenance were comparable (A1/B1: 65.5% vs. A2/B2: 66.4%,p=0.86), though SOC "infections and infestations" was increased in the elotuzumab-lenalidomide arms (A1/B1: 42.9% vs. A2/B2: 51.4%, p=0.05). Conclusions: This is the first phase III trial evaluating elotuzumab in patients with transplant-eligible NDMM. The addition of elotuzumab to RVd induction/consolidation therapy and lenalidomide maintenance did not result in improved PFS or OS. This is in line with previous reports from the ELOQUENT-1 and SWOG-1211 trials, investigating elotuzumab in non-transplant-eligible and high-risk NDMM, while elotuzumab-based combination therapies are effective in relapsed MM (ELOQUENT-2/-3 trials). Further analyses to identify potential subgroups that benefit from elotuzumab-based treatment in our trial are ongoing. Disclosures Goldschmidt: Incyte: Research Funding; BMS: Consultancy, 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; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; GSK: Honoraria; 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; Mundipharma: 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; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding. Mai: Takeda: 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; Celgene / BMS: 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. Besemer: GSK: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Fenk: Janssen: Honoraria; Amgen: Honoraria; GSK: Honoraria; Takeda: Honoraria; BMS/Celgene: Honoraria. Munder: Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Takeda: Consultancy, Honoraria; Amgen: Honoraria; Sanofi: Consultancy; GSK: Consultancy; Incyte: Research Funding. 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. Hose: LamKap Bio: Consultancy, Current Employment; BMS: Research Funding. Scheid: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria; Amgen: Consultancy, 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Schroers: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Honoraria. Metzler: GSK: Consultancy; Amgen: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; BMS: Consultancy; Takeda: Consultancy. Schieferdecker: Sebia: Consultancy. Mahlberg: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; BMS: Honoraria; GSK: Honoraria. Graeven: Amgen: Honoraria; Sanofi Aventis: Honoraria; Celgene: Honoraria, Research Funding; Johnson & 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. Martens: Celgene: Consultancy; Sanofi-Aventis: Consultancy. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: 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; GSK: 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; Janssen: 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; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Raab: Roche: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, 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, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Salwender: Takeda: Honoraria; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; GlaxoSmithKline: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Oncopeptides: Honoraria; Chugai: Honoraria; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen-Cilag: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Pfizer: Honoraria. OffLabel Disclosure: Lenalidomide and ELotuzumab in first line therapy prior to autologous stem cell transplantation, Elotuzumab in maintenance after autologous transplantation.

Introduction: The treatment of patients (pts) with rrMM remains challenging and response is often limited in depth and duration. In contrast to many other malignant diseases, targeted therapy in MM is hampered by the limited number of actionable targets. Activating mutations of BRAF have been found in 2-4% of newly diagnosed MM and in up to 8% of rrMM. Several case reports have reported clinical efficacy of downstream pathway inhibition in MM. This phase II trial is evaluating the safety and efficacy of combined BRAF/MEK inhibition in rrMM pts with BRAF V600E mutation. Aims: The primary objective of this study was to demonstrate the therapeutic efficacy of encorafenib in combination with binimetinib. The primary endpoint was the overall response rate (ORR), defined as best response within 1 year of treatment. Main secondary endpoints included progression-free survival (PFS) and duration of response. Safety analyses included all adverse events (AEs) with those of grade 1/2 only being assessed further if considered to be related to study medications by the investigator. Methods: A total of 15 pts with rrMM who have failed at least 2 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMID), were planned to be enrolled in this open-label phase II multicenter trial. Key inclusion criteria were presence of a BRAF V600E/K mutation confirmed by both mutation-specific immunohistochemistry (IHC) and next-generation sequencing in more than 50% of MM cells. Exclusion criteria included plasma cell leukemia, CNS involvement, cardiac dysfunction, or a history of retinal vein occlusion. Pts received encorafenib 450mg p.o. daily and binimetinib 45mg p.o. twice daily. Responses were assessed using IMWG 2016 criteria. The primary endpoint was analyzed by testing the one-sided null hypothesis of ORR Results: As of July 2020, 12 pts have been enrolled and were evaluable for safety and 11 pts were evaluable for response as 1 pt had just completed cycle 1 with confirmation of response pending at the time of data lock. Subtypes of MM were IgG in 6 pts, IgA in 2 pts, and Bence Jones in 4 pts. Pts had received a median of 5 prior lines of therapy (range 2-14). All pts had failed previous treatment with both a PI and an IMID and in addition carfilzomib, pomalidomid, and/or anti-CD38 antibodies in 8/4/6 pts, respectively. The study already reached its primary endpoint. The ORR was 82% (lower limit of the 95% CI 56.4%, one-sided exact binomial test, p Adverse events of all grades, assessed to be at least possibly related to a study drug, occurred in 9/12 pts and included blurred vision, macula edema, cramps, arthralgia, diarrhea, skin rash, and decreased left ventricular function. Grade 3 or 4 AEs irrespective of causality occurring in more than 1 pt were reported in 8 pts with anemia, hypertension and thrombocytopenia (3/ 3/ 2 pts, respectively). SAEs were reported in 2 pts, respiratory tract infection in both pts and tooth decay in 1 pt that was not related to the study medication. No deaths occurred while on treatment or within 30 days of the end of treatment. Preliminary results of biomarker assessments reveal new RAS mutations and amplification of the BRAF locus at the time of relapse while on study treatment as potential markers of resistance. Analysis of pharmacodynamic markers by phospho-IHC reveals suppression of BRAF/MEK signaling at cycle 1 / day 28 and restoration of expression at the time of relapse. Conclusion: Targeting activating BRAF mutations in rrMM by combining the BRAF inhibitor, encorafenib, and the MEK inhibitor, binimetinib, induces rapid and deep responses in the majority of pts. No new safety signal has been observed when compared to prior reports on these compounds. The study reached its primary endpoint with fewer pts than expected. The primary efficacy and safety analysis will be presented at the conference. Disclosures Raab: Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Celgene: 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; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Scheid:BMS: Honoraria; Amgen: Honoraria; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Besemer:GSK: Honoraria; Janssen: Honoraria. Metzler:Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; GSK: Consultancy; BMS: Consultancy. Khandanpour:Astra Zeneca: Research Funding; Sanofi: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy. Trautmann-Grill:Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Honoraria; GSK: Consultancy; BMS: Honoraria. Goldschmidt:Mundipharma GmbH: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp and Dohme (MSD): Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, 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; Janssen: 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; Molecular Partners: Research Funding; Incyte: Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:. Weisel:Abbvie: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. OffLabel Disclosure: Encorafenib and Binimetinib in BRAF V600E mutant multiple myeloma

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 < 200/µl, 75 patients (78%) had CD4+ cell counts < 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.