The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of multiple myeloma

Shah, Nina; Aiello, Jack; Avigan, David; Berdeja, Jesús G.; Borrello, Ivan; Chari, Ajai; Cohen, Adam D.; Ganapathi, Karthik A.; Gray, Lissa; Green, Damian; Krishnan, Amrita; Lin, Yi; Manasanch, Elisabet E.; Munshi, Nikhil C.; Nooka, Ajay K.; Rapoport, Aaron P.; Smith, Eric L.; Vij, Ravi; Dhodapkar, Madhav V.

doi:10.1136/jitc-2020-000734

Cited by 31 publications

(27 citation statements)

References 206 publications

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“…Although most patients with multiple myeloma respond well to initial chemotherapy combinations, the disease almost always relapses and eventually becomes resistant to therapy. BsAbs have shown particular efficacy in B cell malignancies, with some of the most promising clinical trials in development for multiple myeloma with agents targeting the antigen BCMA, encoded by the TNFRSF17 gene (2). There are multiple BCMA/ CD3 BsAbs or BiTEs in phase I clinical trials in heavily pretreated patients with multiple myeloma.…”

mentioning

confidence: 99%

Tumor Burden Limits Bispecific Antibody Efficacy through T-cell Exhaustion Averted by Concurrent Cytotoxic Therapy

Meermeier

Welsh

Sharik

et al. 2021

Blood Cancer Discovery

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Although chemotherapeutic agents and molecular medicine are pillars of successful treatment of cancer, the recent clinical development of immunotherapies shows compelling promise in the treatment of many tumor types. In hematologic malignancies, immunotherapies centered upon cytolytic T lymphocytes as drugs, such as chimeric antigen receptor (CAR)-T cells and bispecific T-cell engagers (BiTE) or antibodies (BsAb), are central among these advances. BiTEs and BsAbs are "offthe-shelf" drug therapies that circumvent the need for timeconsuming and expensive ex vivo manipulation of patient cells. These agents often consist of monoclonal antibodies or singlechain variable fragments in the case of BiTEs, engineered with one binding site directed toward a tumor-specific antigen and another against the T-lymphocyte activating receptor CD3epsilon. BsAbs redirect T cells to kill tumors by bringing them into physical contact and activating secretion of cytotoxic molecules (1). Due to their novel mode of action, BsAb therapeutics may provide an effective option for all patients, including those with cytogenetically high-risk or heavily pretreated disease that renders them more resistant to standard-of-care therapy.

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confidence: 99%

Tumor Burden Limits Bispecific Antibody Efficacy through T-cell Exhaustion Averted by Concurrent Cytotoxic Therapy

Meermeier

Welsh

Sharik

et al. 2021

Blood Cancer Discovery

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“…Since there is no specific treatment for patients with SMM, high-risk patients are treated with agents approved for symptomatic MM. In MM, several immunotherapies have been approved against CD38 ( 31 ), signaling lymphocytic activation molecule F7 (SLAMF7) and B cell maturation antigen (BCMA) ( 32 , 33 ). In this study, we found several inhibitory immune checkpoints (TIGIT, CD96, BTLA, LAG3, KLRC1) upregulated in high-risk SMM patients, some of them being currently tested in clinical trials for patients with relapsed refractory MM, such as dual blockade of TIGIT and LAG-3 (NCT04150965).…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Analysis of the Bone Marrow Microenvironment Reveals Distinct Immunotypes in Smoldering Multiple Myeloma Associated to Progression to Symptomatic Disease

et al. 2021

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BackgroundWe previously reported algorithms based on clinical parameters and plasma cell characteristics to identify patients with smoldering multiple myeloma (SMM) with higher risk of progressing who could benefit from early treatment. In this work, we analyzed differences in the immune bone marrow (BM) microenvironment in SMM to better understand the role of immune surveillance in disease progression and to identify immune biomarkers associated to higher risk of progression.MethodsGene expression analysis of BM cells from 28 patients with SMM, 22 patients with monoclonal gammopathy of undetermined significance (MGUS) and 22 patients with symptomatic MM was performed by using Nanostring Technology.ResultsBM cells in SMM compared to both MGUS and symptomatic MM showed upregulation of genes encoding for key molecules in cytotoxicity. However, some of these cytotoxic molecules positively correlated with inhibitory immune checkpoints, which may impair the effector function of BM cytotoxic cells. Analysis of 28 patients with SMM revealed 4 distinct clusters based on immune composition and activation markers. Patients in cluster 2 showed a significant increase in expression of cytotoxic molecules but also inhibitory immune checkpoints compared to cluster 3, suggesting the presence of cytotoxic cells with an exhausted phenotype. Accordingly, patients in cluster 3 had a significantly longer progression free survival. Finally, individual gene expression analysis showed that higher expression of TNF superfamily members (TNF, TNFAIP3, TNFRSF14) was associated with shorter progression free survival.ConclusionsOur results suggest that exhausted cytotoxic cells are associated to high-risk patients with SMM. Biomarkers overexpressed in patients with this immune gene profile in combination with clinical parameters and PC characterization may be useful to identify SMM patients with higher risk of progression.

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“…A small case series of nine patients showed a promising response rate in patients treated with an isatuximab-based regimen after prior daratumumab therapy [ 128 ]. There is currently no consensus recommendation about the retreatment with daratumumab [ 129 ]. Sequencing of antibodies is another challenging issue.…”

Section: Conclusion—beyond the Moab Therapymentioning

confidence: 99%

Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma

Radocha

Donk

Weisel

2021

Cancers

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Multiple myeloma is the second most common hematologic malignancy. Current treatment strategies are mainly based on immunomodulatory drugs, proteasome inhibitors or combination of both. Novel agents added to these backbone treatments represent a promising strategy in treatment of newly diagnosed as well as relapsed and refractory multiple myeloma patients. In this respect, the incorporation of monoclonal antibodies into standard-of-care regimens markedly improved prognosis of myeloma patients during the last years. More specifically, monoclonal anti-CD38 antibodies, daratumumab and isatuximab, have been implemented into treatment strategies from first-line treatment to refractory disease. In addition, the monoclonal anti-SLAM-F7 antibody elotuzumab in combination with immunomodulatory drugs has improved the clinical outcomes of patients with relapsed/refractory disease. Belantamab mafodotin is the first approved antibody drug conjugate directed against B cell maturation antigen and is currently used as a monotherapy for patients with advanced disease. This review focuses on clinical efficacy and safety of monoclonal antibodies as well as antibody drug conjugates in multiple myeloma.

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The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of multiple myeloma

Cited by 31 publications

References 206 publications

Tumor Burden Limits Bispecific Antibody Efficacy through T-cell Exhaustion Averted by Concurrent Cytotoxic Therapy

Tumor Burden Limits Bispecific Antibody Efficacy through T-cell Exhaustion Averted by Concurrent Cytotoxic Therapy

Gene Expression Analysis of the Bone Marrow Microenvironment Reveals Distinct Immunotypes in Smoldering Multiple Myeloma Associated to Progression to Symptomatic Disease

Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma

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