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BME Signatures at Baseline and During Treatment Enable Risk Stratifications of Patients With Multiple Myeloma
Bone marrow microenvironment (BME) signatures at baseline and during treatment may enable risk stratifications of patients with multiple myeloma (MM) and may identify patients at high risk for early relapse, according to findings presented by Simon Steiger, PhD, and colleagues at the 64th American Society of Hematology Annual Meeting and Exposition.
The researchers reviewed their study, “Bone marrow immune signatures in multiple myeloma are linked to tumor heterogeneity and treatment outcome,” in which they characterized 1,225 BME samples over time in an attempt to associate the composition of the BME with MM cytogenic and molecular subgroups, understand how treatment combinations that include isatuximab influence the BME, and link BME alterations to therapy response such as minimal residual disease-negativity (MRD-neg) and progressive disease.
In MM, malignant plasma cells interact with a BME that fosters disease progression and drug resistance. When added to standard-of-care (SOC) regimens, anti-CD38 monoclonal antibodies are shown to increase efficacy, as seen by the MRD-neg rates of >50 after induction therapy in patients with newly diagnosed MM (NDMM) treated with SOC plus isatuximab (Isa) in the GMMG-HD7 trial.
“Links between disease characteristics and the (BME) niche have been shown,” Dr Steiger said. “For example in refractory myeloma, carrying a gain of 1q differentially modulates the bone marrow environment. There are also results that imply that the efficacy of established and novel immunomodulatory drugs rely heavily on this bone marrow niche.
“In our study, we addressed four main questions: First, is the bone marrow composition at diagnosis linked to disease characteristics and risk factors? Second, how does the bone marrow composition change during treatment? Third, can we stratify patients based on their bone marrow composition? And finally, is there a link of the stratification to treatment outcome?”
Patients with NDMM were treated either with lenalidomide/bortezomib/dexamethasone (RVd) alone or in a combination regimen with Isa (Isa-RVd, NCT03617731). The researchers combined high-dimensional flow cytometry and single-cell RNA sequencing along with an additional capture of surface markers to characterize cellular and molecular changes in BME at baseline (n = 469), at the end of patients’ induction therapy (n = 391), and following autologous stem cell transplantation (ASCT) (n = 365). MRD-neg was defined using standard protocols via flow and next-generation sequencing.
Paired flow cytometry samples and sequencing data were integrated using a variational autoencoder to construct a BME reference atlas, which allowed the researchers to map the cell state-specific transcriptional signatures from single cell RNA sequencing onto the flow cytometry data.
A comprehensive BME dataset for MM was generated made up of more than 120 million single cells, enabling the definition of at least six subgroups at baseline as well as treatment-specific changes to the BME. With 469 patients in the cohort, researchers were able to gauge combinatorial genetic aberrations that were associated with complex patterns of compositional changes. Changes in the BME that were associated with mutations in MM driver genes were also discovered.
The use of Isa-RVd resulted in a significant impact on the BME composition after ASCT, suggesting that Isa has an effect on the regeneration of the BME posttransplant. The researchers also linked MRD status after induction therapy and relapse risk to BME composition. MRD-neg after induction therapy was associated with a specific BME composition at baseline that was characterized by a significant depletion of CD8+ T cells in patients with Isa-RVd treatment (n = 239), but not in those who received RVd-alone (n = 229).
According to Steiger and colleagues, monitoring of BME over time may support clinical decision making, since a compromised CD8+ memory compartment in patients may factor into the efficacy of novel immunotherapies.
“We found that multiple myeloma heterogeneity is reflected and can also be linked to the heterogeneity of the bone marrow,” Dr Steiger said. “In addition, having longitudinal data, we showed the effects of RVd and isatuximab on various cell types and the regeneration of the bone marrow environment after the stem cell transplant.
“Finally, the heterogeneity of the bone marrow at diagnosis could be used to stratify patients into subgroups based on immune signatures. And this stratification based on the bone marrow ecotype showed significant differences in MRD-negativity if linked to isatuximab treatment, pointing towards the potential clinical relevance of stratification based on the immune environment at diagnosis for immunotherapies.”
Steiger S, Lutz R, Prokoph N, et al. Bone marrow immune signatures in multiple myeloma are linked to tumor heterogeneity and treatment outcome. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022. Abstract 860.
