Cell Atlas Identifies Immune Signatures Associated With Myeloma Outcomes

Researchers have unveiled a comprehensive single-cell Immune Atlas of multiple myeloma (MM), offering unprecedented insights into the bone marrow microenvironment (BMME) and its role in disease progression, according to a landmark study published in Nature Cancer.¹ By profiling over 1.3 million single cells from 337 newly diagnosed participants, the study has identified critical immune signatures that significantly improve the ability to predict patient outcomes and could help to guide personalized therapeutic strategies.

“We did see that there was information that was prognostic and related to how the patients do long-term with therapy,” said George Mulligan, PhD, Chief Scientific Officer at the Multiple Myeloma Research Foundation, in an interview with Targeted Oncology. “We also were able to show that this prognostic information is distinct from what we know about the tumor, which clearly contributes to prognosis. One can combine these 2 and have more information than one would separately.”

Bridging the Prognostic Gap

Although cytogenetic abnormalities have been implemented into risk stratification in MM, they often fail to identify high-risk (HR) patients who experience early relapse. The Immune Atlas addresses this gap by identifying "latent, tumor-extrinsic factors" within the BMME.

A key finding is the identification of distinct immune profiles associated with rapid progressors (RPs)—patients who relapse within 18 months of diagnosis. These RPs exhibit a "proinflammatory immune senescence-associated secretory phenotype." Specifically, their T cell compartment shows an accumulation of terminally differentiated, late-activated cytotoxic CD8+ effector T cells and a depletion of naive T cells. This state of immunosenescence is strongly associated with poor progression-free survival (PFS) and overall survival (OS).

Cytogenetics and Immune Heterogeneity

The findings highlight how specific tumor genotypes dictate unique immune landscapes. In those with 17p13 deletion, T cells showed a distinct enrichment of a type 1 interferon (IFN-I) signature across risk groups. Although acute IFN-I is typically antitumor, chronic activation in the context of TP53 loss may allow tumors to persist while impairing T cell function. IFN-I downregulation was associated with 1q21 gain whereas enrichment of IFN-I populations was strongly associated with a complete loss of TP53; analysis of CD138+ bulk RNA-seq data confirmed reduced IFN-I activity in the former group and increased in the latter.

Participants with MAF translocations such as t(14;16), t(8;14), and t(14;20) uniquely displayed dysregulation in B cells, with a depletion of mature B cells and enrichment of immature B cell states.

Predicting Treatment Response

The study also provides a biological rationale for why some patients respond poorly to standard frontline therapies. The senescent T cell populations (CD8_Teff_HLA) prevalent in RPs lack costimulatory receptors such as CD27 and CD28. Because the efficacy of immunomodulatory drugs (IMiDs) often depends on the CD28+ pathway, these patients’ BMME may be inherently less responsive to standard IMiD-based triplets.

“The immune system is important even with these treatments that don't use immune agents,” said Mulligan.” “It seems like that function contributes to outcomes with all therapies, not just when we're reaching in and activating the immune system.”

The integration of these immune signatures with clinical data and cytogenetics dramatically improved predictive power. Although clinical variables alone achieved an area under the curve (AUC) of 0.70 for predicting PFS, an integrative model including the "best 11" immune subclusters reached an AUC of 0.81 in the discovery cohort and 0.94 in an independent validation cohort. This model also predicted OS with an AUC of 0.73.

Future Clinical Implications

The Immune Atlas represents a significant step toward informed strategies for use of immunotherapies. For patients with 17p13 deletions and chronic IFN-I signaling, the authors suggest that checkpoint inhibitors targeting exhaustion markers such as PD-1 and LAG3 might restore T-cell function. Conversely, for patients with 1q21 gain who lack IFN-I activity, agents such as bortezomib (Velcade) that acutely activate the IFN-I response have synergistic interaction with immunotherapy to improve antitumor response.

Furthermore, for patients identified as RPs by their immune profile, the researchers suggest moving highly targeted therapies such as bispecific antibodies or chimeric antigen receptor (CAR)-T cells to the first-line setting because immunotherapy could worsen the T cell imbalance.

High-risk cytogenetic features already provide valuable guidance on risk stratification, but an immune signature from BMME data could serve as a more personalized approach that can guide treatment selection and predict outcomes based on a patient’s individual immune microenvironment.

“We expect this to emerge as another cornerstone to how we understand myeloma, and we hope that there are a whole series of findings that emerge from this from multiple creative groups across the globe,” said Mulligan.

_REFERENCE

_{1. Pilcher WC, Yao L, Gonzalez-Kozlova E, et al. A single-cell atlas characterizes dysregulation of the bone marrow immune microenvironment associated with outcomes in multiple myeloma. Nat Cancer. 2026;7(1). doi:10.1038/s43018-025-01072-4}