Bone Marrow Immune Signatures in Multiple Myeloma Are Linked to Tumor Heterogeneity and Treatment Outcome

Steiger, Simon; Lutz, Raphael; Prokoph, Nina; Palit, Subarna; Tirier, Stephan M.; Reichert, Philipp; Baumann, Anja; Hefner, Nadine; Schumacher, Sabrina; Vonficht, Dominik; Grünschläger, Florian; Poos, Alexandra M; John, Lukas; Haghverdi, Laleh; Mallm, Jan‐Philipp; Elias, K.; Friedrich, Mirco; Kriegsmann, Katharina; Awwad, Mohamed H.S.; Jauch, Anna; Bertsch, Uta; Tichy, Diana; Müller‐Tidow, Carsten; Schroers, Roland; Salwender, Hans; Besemer, Britta; Fenk, Roland; Weisel, Katja; Goldschmidt, Hartmut; Huhn, Stefanie; Hundemer, Michael; Rippe, Karsten; Haas, Simon; Weinhold, Niels; Raab, Marc S.

doi:10.1182/blood-2022-168685

Cited by 4 publications

(6 citation statements)

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“…125,126 Analysis of BM microenvironment samples from GMMG-HD7 trial patients by flow cytometry and single-cell RNA sequencing also revealed that patients with 1q21+ and t(4;14) had significantly increased numbers of monocytes. 127 Hyperdiploid patients with 1q+ also showed significant depletion of B-cell lineage cell types. 127 Some recent reports have analyzed outcomes in patients with 1q21+ receiving different anti-CD38 therapies, with the results showing possible differences in outcomes among the different regimens evaluated.…”

Section: Clinical Trial Findings For Cd38 Antibodies In Patients With MMmentioning

confidence: 99%

“…127 Hyperdiploid patients with 1q+ also showed significant depletion of B-cell lineage cell types. 127 Some recent reports have analyzed outcomes in patients with 1q21+ receiving different anti-CD38 therapies, with the results showing possible differences in outcomes among the different regimens evaluated. [128][129][130] In the MAIA trial investigating daratumumab plus lenalidomide and dexamethasone (Dara-Rd) in transplant-ineligible NDMM patients, subgroup analysis of PFS in patients with 1q21+ and more than 1 other high-risk chromosomal abnormality showed an HR of 1.03 (95% CI: 0.42-2.48).…”

Section: Clinical Trial Findings For Cd38 Antibodies In Patients With MMmentioning

confidence: 99%

“…Copy number gain of 1q21 is one of the most common chromosomal abnormalities in MM, with its incidence increasing with disease progression 125,126 . Analysis of BM microenvironment samples from GMMG‐HD7 trial patients by flow cytometry and single‐cell RNA sequencing also revealed that patients with 1q21+ and t (4;14) had significantly increased numbers of monocytes 127 . Hyperdiploid patients with 1q+ also showed significant depletion of B‐cell lineage cell types 127 .…”

Section: Therapeutic Applications Of Anti‐cd38 Targeting Antibodiesmentioning

confidence: 99%

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Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma

Bisht,

Fukao,

Chiron

et al. 2023

Cancer Medicine

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BackgroundCD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved—daratumumab and isatuximab. CD38 is an ectoenzyme that degrades NAD and its precursors and is involved in the production of adenosine and other metabolites.AimAmong the various mechanisms by which CD38 antibodies can induce MM cell death is immunomodulation, including multiple pathways for CD38‐mediated T‐cell activation. Patients who respond to anti‐CD38 targeting treatment experience more marked changes in T‐cell expansion, activity, and clonality than nonresponders.ImplicationsResistance mechanisms that undermine the immunomodulatory effects of CD38‐targeting therapies can be tumor intrinsic, such as the downregulation of CD38 surface expression and expression of complement inhibitor proteins, and immune microenvironment‐related, such as changes to the natural killer (NK) cell numbers and function in the bone marrow niche. There are numerous strategies to overcome this resistance, which include identifying and targeting other therapeutic targets involved in, for example, adenosine production, the activation of NK cells or monocytes through immunomodulatory drugs and their combination with elotuzumab, or with bispecific T‐cell engagers.

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Section: Clinical Trial Findings For Cd38 Antibodies In Patients With MMmentioning

confidence: 99%

Section: Clinical Trial Findings For Cd38 Antibodies In Patients With MMmentioning

confidence: 99%

Section: Therapeutic Applications Of Anti‐cd38 Targeting Antibodiesmentioning

confidence: 99%

See 1 more Smart Citation

Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma

Bisht,

Fukao,

Chiron

et al. 2023

Cancer Medicine

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“…Host status or bone marrow microenvironment is another key factor impacting patient prognosis, especially in the context of immunotherapies. 13,14 Mass myeloma cells occupying the bone marrow reshape the marrow microenvironment, promoting immunosuppression. 15 Current prognostic models of MM do not incorporate such host-associated predictors like monocyte counts 16 and thrombocytopenia.…”

Section: Introductionmentioning

confidence: 99%

Development and validation of an individualized and weighted Myeloma Prognostic Score System (MPSS) in patients with newly diagnosed multiple myeloma

Mao,

Yan,

Mery

et al. 2024

American J Hematol

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Current standard predictive models of disease risk do not adequately account for the heterogeneity of survival outcomes in patients with new‐diagnosed multiple myeloma (NDMM). In this retrospective, multicohort study, we collected clinical and genetic data from 1792 NDMM patients and identified the prognostic impact of all features. Using the top‐ranked predictive features, a weighted Myeloma Prognostic Score System (MPSS) risk model was formulated and validated to predict overall survival (OS). In the training cohort, elevated lactate dehydrogenase level (LDH), International Staging System (ISS) Stage III, thrombocytopenia, and cumulative high‐risk cytogenetic aberration (HRA) numbers were found to have independent prognostic significance. Each risk factor was defined as its weighted value respectively according to their hazard ratio for OS (thrombocytopenia 2, elevated LDH 1, ISS III 2, one HRA 1, and ≥2 HRA 2, points). Patients were further stratified into four risk groups: MPSS I (22.5%, 0 points), II (17.6%, 1 points), III (38.6%, 2–3 points), and IV (21.3%, 4–7 points). MPSS risk stratification showed optimal discrimination, as well as calibration, of four risk groups with median OS of 91.0, 69.8, 45.0, and 28.0 months, for patients in MPSS I to IV groups (p < .001), respectively. Importantly, the MPSS model retained its prognostic value in the internal validation cohort and an independent external validation cohort, and exhibited significant risk distribution compared with conventional prognostic models (R‐ISS, R2‐ISS, and MASS). Utilization of the MPSS model in clinical practice could improve risk estimation in NDMM patients, thus prompting individualized treatment strategies.

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“…In addition to impacting disease progression and infection risk, an increasing number of studies have demonstrated that the immune signature in MM is a strong predictor of response to therapy and outcome [ 41 ]. In a study of 58 patients undergoing autologous stem cell transplants, phenotypic characterization of the T cell compartment at day 60 and 100 post-transplant strongly correlated with subsequent outcomes, even prior to the emergence of disease relapse.…”

Section: Introductionmentioning

confidence: 99%

Immune dysregulation in multiple myeloma: the current and future role of cell-based immunotherapy

Russell

Avigan

2023

Int J Hematol

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Immune dysregulation is a hallmark of clinically active multiple myeloma (MM). Interactions between malignant clonal cells and immune cells within the bone marrow microenvironment are associated with the formation of a milieu favorable to tumor progression. IL-10, TGF-β and other immunoregulatory pathways are upregulated, promoting angiogenesis, tumor cell survival and inhibition of the native immune response. Transcriptomic evaluation of the bone marrow microenvironment reveals polarization of the T cell repertoire towards exhaustion and predominance of accessory cells with immunosuppressive qualities. These changes facilitate the immune escape of tumor cells and functional deficiencies that manifest as an increased risk of infection and a reduction in response to vaccinations. Immunotherapy with Chimeric Antigen Receptor (CAR) T cells and other cellular-based approaches have transformed outcomes for patients with advanced MM. Characterization of the immune milieu and identification of biomarkers predictive of treatment response are essential to increasing durability and allowing for the incorporation of novel strategies such as cancer vaccines. This paper will review the current use of cancer vaccines and CAR T cell therapy in MM as well as potential opportunities to expand and improve the application of these platforms.

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Bone Marrow Immune Signatures in Multiple Myeloma Are Linked to Tumor Heterogeneity and Treatment Outcome

Cited by 4 publications

References 0 publications

Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma

Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma

Development and validation of an individualized and weighted Myeloma Prognostic Score System (MPSS) in patients with newly diagnosed multiple myeloma

Immune dysregulation in multiple myeloma: the current and future role of cell-based immunotherapy

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