Impact of Novel Therapies on CD4-T-Cell-Numbers and Infectious Complications in Patients with Relapsed/Refractory Multiple Myeloma
Authors: John Lukas , Miah Kaya , Benner Axel , Mai Elias K , Kriegsmann Katharina , Hundemer Michael , Mueller-Tidow Carsten , Jordan Karin , Goldschmidt Hartmut , Raab Marc S. , Giesen Nicola 
Published: February 2021

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.