For patients with multiple myeloma, a cancer of plasma cells in the bone marrow, treatment usually consists of an autologous stem cell transplant (ASCT) followed by maintenance therapy with lenalidomide. Lenalidomide is an immunomodulatory drug that enhances T-cell and natural killer (NK)-cell activity and degrades myeloma-cell survival factors, with the goal of eliminating residual tumor cells. Although this treatment is initially effective, most patients eventually relapse. A new study published in Blood by Simone Minnie and colleagues in the Geoff Hill lab at Fred Hutch has uncovered a mechanism that may contribute to relapse, along with a potential combination strategy to combat the phenomenon.
To investigate how relapse emerges, the researchers profiled immune populations in multiple myeloma patients before ASCT and at 3 months post-transplant, comparing those whose disease remained controlled with those who relapsed. In patients who relapsed, they identified a significantly expanded population of immunosuppressive macrophages characterized by expression of cell-surface proteins CD64, CD163, CD169, PD-L1, CSF-1R and CD155.
To understand the role of these macrophages, the team turned to an intricate mouse model of myeloma, ASCT and relapse. Mice were first injected with Vk12653 myeloma cells (Vk*MYC, a model where MYC is inserted into a promoter active specifically in plasma cells) and underwent ASCT two weeks later. ASCT consisted of naive bone marrow and a T cell infusion from donor mice also injected with myeloma cells; this mimics an autologous transplant where T cells have prior exposure to the myeloma antigens. A specific T cell dose was chosen that was permissive of relapse. Bone marrow was then assessed 6 weeks after transplant.
In their mouse model, the researchers found the emergence of a similar immunosuppressive macrophage population expressing PD-L1 and CSF-1R. To test the disease relevance of these macrophages, antibodies that block CSF-1R were administered after ASCT to deplete them, as CSF-1R is a critical growth signal for these macrophages. Neither the CSF-1R blocking antibody alone, nor lenalidomide alone, made a meaningful difference to disease progression. But when the two were combined, disease progression slowed and survival improved significantly.
To dive further in, the researchers performed single-cell RNA sequencing of immune populations in the mouse model. This revealed that lenalidomide expanded a population of NK-like CD8 T cells, potent cancer-killing immune cells, but paradoxically also expanded immunosuppressive macrophages that counteract these T cells. Cell-cell communication analysis revealed that Csf1r+ macrophages exhibited strong interaction potential with the inhibitory receptor Klrd1/Klrc1(CD94/NKG2A) on NK-like T-cells. Removing the immunosuppressive macrophages by CSF-1R blockade allowed these T cells to do their job unimpeded.
The translational implications are immediate and profound. Lead author Simone Minnie shares, “This study provides compelling preclinical rationale for combining CSF1-R inhibition with standard-of-care maintenance therapy to improve patient responses to autologous stem cell transplantation for myeloma.” A CSF-1R blocking antibody called axatilimab was recently approved by the FDA for a different condition, chronic graft-versus-host disease. Since lenalidomide maintenance after ASCT is already standard care for myeloma patients, adding a CSF-1R antibody to that regimen represents an actionable next step that could improve the length of time patients stay in remission. This strategy will be tested in a clinical trial led by Fred Hutch’s Dr. Andrew Portuguese with support from the pharmaceutical company Incyte.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. Geoffrey Hill contributed to this research.
The spotlighted research was funded by National Institutes of Health and Syndax Pharmaceuticals.
Minnie SA, Ho K, Boiko JR, Adams RC, Ensbey KS, Nemychenkov NS, Legg SRW, Schmidt CR, Comstock ML, Lyons JM, Sekiguchi T, Koyama M, Spencer A, Green DJ, Hill GR. 2026. CSF-1R inhibition and lenalidomide synergize to promote myeloma control after autologous stem cell transplantation. Blood. https://doi.org/10.1182/blood.2025030207.
Science Spotlight writer Kelly Mitchell is a postdoctoral fellow in the Paddison Lab at Fred Hutch Cancer Center. She utilizes live cell reporters and CRISPR screening to study how glioblastoma cancer cells resist chemotherapy and radiation treatment. She obtained her PhD in cellular biology from Albert Einstein College of Medicine.