Chander, A.; Rachid Zaim, S.; Dillon, M. A.; Genge, P. C.; Moss, N.; McGrath, P. I.; Kopp, M. S.; Lee, K. J.; Kuan, E. L.; Reading, J.; Hernandez, V.; Song, X.; Singh, M.; Garber, J.; LaFrance, C. M.; Kong, G. L.; Glass, M. C.; Davis, E. L. W.; Glass, D.; He, Y. D.; Heubeck, A. T.; Kawelo, E. K.; Krishnan, U.; Lord, C.; Meijer, P.; Mettey, R. R.; Musgrove, B.; Okada, L. Y.; Parthasarathy, V.; Peng, T.; Phalen, C. G.; Riddell, S.; Roll, C. R.; Stuckey, T. J.; Swanson, E. G.; Thomson, Z. J.; Weiss, M. D. A.; Wittig, P. J.; Anover-Sombke, S. D.; Coffey, E. M.; Becker, L. A.; Bumol, T. F.; Goldrat

Infections are the most common cause of non-relapse mortality in multiple myeloma (MM), but the basis of persistent immune dysfunction is obscured by patient heterogeneity and complex treatment regimens, including autologous stem cell transplant (ASCT). We performed longitudinal multi-omic profiling of matched bone marrow and peripheral blood from MM patients across diagnosis, induction, ASCT, and recovery. We found the tumor imposes a compartment-specific immune program where the marrow exhibits metabolic and inflammatory changes that bias hematopoiesis and alter cytotoxic effector programs not mirrored in blood. Adaptive immune reconstitution is impaired up to two years post-ASCT. Half of patients fail to mount IgG responses to high-dose non-adjuvanted influenza vaccine, a defect overcome by the lipid nanoparticle (LNP) adjuvanted COVID mRNA vaccine, which elicited responses in all patients, supporting adjuvanted influenza vaccine strategies in MM. Together these findings define how myeloma and its treatment durably reshape immunity from the marrow outward.