T-Cell Senescence and Exhaustion Are Associated with Interval Progression of Multiple Myeloma before Autologous Hematopoietic Cell Transplant

Background: The introduction of novel therapies in multiple myeloma (MM) has greatly improved patient outcomes, but the disease remains incurable. Induction therapy followed by autologous hematopoietic stem cell transplant (aHSCT) is widely adopted as the standard-of-care strategy for eligible patients. The current treatment timeline includes a gap between the end of induction and the day of aHSCT to permit correct mobilization and collection of stem cells. During this interval, some patients experience interval progression (IP) of their disease. The association between a complete response (CR) after aHSCT and outcomes has been well studied. However, the association between pre-aHSCT responses and outcomes is less clear. MM patients have abnormal immune cell markers, with increased percentages of exhausted and senescent T lymphocyte markers compared with healthy donors. We hypothesize that IP is associated with a permissive immune microenvironment, likely involving T cell dysfunction.

Methods: We completed a retrospective analysis of 482 patients who underwent aHSCT at The Ohio State University between 2011 and 2016. A 20% increase in the index protein between the end of induction and the day of aHSCT was defined as IP. Of these patients, we had access to peripheral blood (PB) samples for 40 patients (n = 18 patients with IP, n = 22 non-progressors) taken from day -2 of aHSCT and 6 healthy donors. Samples were stained to evaluate the percentage and phenotype of different subsets of CD3⁺, CD4⁺ cells and CD3⁺, CD8⁺ cells, including additional markers LAG3, CD28, CD25, CD57, PD1, CD45RA, and CD62L. Samples were acquired using an AttuneNxT flow cytometry machine and analysis was performed by FlowJo software.

Results: One hundred and fifty-six (32.3%) patients were defined as having IP. Of those, 44.8% changed International Myeloma Working Group response groups between induction therapy and aHSCT, with 11.9% of patients dropping more than one response group. Patients in the IP cohort experienced significantly shorter five-year progression-free survival (36.0% vs 47.1%, P = 0.003) and five-year overall survival (69.6% vs 76.8%, P = 0.029). Patients with IP had significantly greater percentages of CD3⁺, CD8⁺, CD57⁺, CD28^- terminally differentiated-senescent-like T-cells (Median subset cell percentage (MSCP): 33% IP, 20.3% non-progressors, P = 0.05; healthy donors: 22.60%), CD3⁺, CD4⁺, LAG3⁺ exhausted T cells (MSCP: 4.15% IP, 0.245% non-progressors, P = 0.01; healthy donors: 0.4%), and CD3⁺, CD4⁺, PD1⁺ inhibitory exhausted T cells (MSCP: 17.3% IP, 6.8% non-progressors, P = 0.0006; healthy donors: 3.6%). There was no significant difference in effector memory (CD45RA^-, CD62L^-) or central memory (CD45RA^-, CD62L⁺) T cell populations between the IP and the non-progressor groups, but the non-progressor group had significant increased naïve CD3⁺, CD4⁺ T cell population (CD45RA⁺, CD62L⁺), with median of 13.9% in non-progressor patients versus 5.46% in IP patients; P = 0.0449 (healthy donors: 18.40%). These findings suggest that exhausted and senescent T cells are more common in MM patients with IP, potentially leading to a less robust immune response.

Conclusion: In this study, we show that patients who experience pre-aHSCT rapid disease progression have inferior long-term survival post-aHSCT. Efforts to discern identifiers that contribute to IP and hence early relapse are crucial in improving and maintaining long-term disease control. We also demonstrated that patients with IP have features of T cell dysfunction, likely causing a permissive immune microenvironment and reduced anti-tumoral responses. As immunophenotyping becomes more accessible, knowing these differences would allow planning for additional induction therapy cycles prior to proceeding with aHSCT or additional consolidation after aHSCT.

Bumma:Amgen: Consultancy, Speakers Bureau; Sanofi, Genzyme: Other: Ad Board, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Ad Board. Khan:Secura Bio: Consultancy, Research Funding; Janssen: Honoraria; Amgen: Speakers Bureau; Sanofi: Speakers Bureau. Rosko:Genentech: Research Funding; Pfizer: Research Funding; Merck Foundation: Research Funding.