Immunotherapy in Multiple Myeloma—Time for a Second Major Paradigm Shift

Mohan, Meera; Hari, Parameswaran; Dhakal, Binod

doi:10.1200/op.21.00032

Cited by 15 publications

(17 citation statements)

References 98 publications

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“…The phase III German-speaking Myeloma Multicenter Group (GMMG HD6) trial studied the addition of the anti-SLAMF7 monoclonal antibody (mAb) elotuzumab to lenalidomide, bortezomib and dexamethasone (RVd) in induction, consolidation and maintenance treatment in transplanteligible NDMM. 12 Along the lines of the ELOQUENT-1 13,14 and SWOG 1211 15 studies, the addition of elotuzumab did not result in improved PFS or OS in NDMM. Is this the end of the road for elotuzumab therapy in NDMM?…”

Section: Frontline Therapies In Newly Diagnosed Multiple Myelomamentioning

confidence: 95%

Updates in the Management of Multiple Myeloma from the American Society of Hematology Meeting 2021

Vasudevan¹,

Gundarlapalli²,

Thalambedu³

et al. 2022

Oncology &Amp; Haematology

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Multiple myeloma (MM) remains largely an incurable disease with only a small percentage of patients achieving long-term remission. Here, we highlight some of the major studies on MM presented at the American Society of Hematology meeting in December 2021. Early results of the first ever population-based screening studies for precursor states of MM, iStopMM and PROMISE, were reported. These studies will inform on the risks and benefits of screening in MM and could lead to a paradigm shift towards screening and early therapy. In newly diagnosed MM, there were promising data on quadruple therapy with addition of a monoclonal antibody against the CD38 antigen to the existing backbone of lenalidomide, bortezomib and dexamethasone. T-cell–directed therapy including bispecific antibody and chimeric antigen receptor therapy demonstrated high clinical response, especially in triple-class refractory myeloma. We acknowledge that this review focuses on some exciting studies in both precursor and active MM and is not comprehensive by any means.

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Section: Frontline Therapies In Newly Diagnosed Multiple Myelomamentioning

confidence: 95%

Updates in the Management of Multiple Myeloma from the American Society of Hematology Meeting 2021

Vasudevan¹,

Gundarlapalli²,

Thalambedu³

et al. 2022

Oncology &Amp; Haematology

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“…However, BM-mediated therapeutic resistance promotes tumor escape and immune evasion that represent obstacles to extending patient outcomes. Recently developed myeloma-directed immunotherapies, e.g., monoclonal antibodies, CAR-T cells, antibody-drug conjugates (ADCs), and BiTEs represent the emerging phase of myeloma care [115][116][117][118] . Similar to the mechanisms of resistance observed following the administration of cytotoxic chemotherapy, PIs and IMiDs, novel strategies are needed to prevent or overcome resistance to immunotherapies.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

“…BM-mediated immune exhaustion as well as immune checkpoint proteins on T-and NK cells and their corresponding ligands on MM cells, e.g., PD1/PDL-1, or T cell immunoglobulin and tyrosine-based inhibitory motif (TIGIT) domains, represent additional obstacles [119][120][121] . Innovative platforms will provide the foundation for the next paradigm shift in myeloma to overcome current limitations and improve high-risk and newly diagnosed patient survival [115][116][117] .…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Therapeutics to harness the immune microenvironment in multiple myeloma

Ignatz-Hoover¹,

Driscoll²

2022

Cancer Drug Resist

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Multiple myeloma (MM) remains an incurable, genetically heterogeneous disease characterized by the uncontrolled proliferation of transformed plasma cells nurtured within a permissive bone marrow (BM) microenvironment. Current therapies leverage the unique biology of MM cells and target the immune microenvironment that drives tumor growth and facilitates immune evasion. Proteasome inhibitors and immunomodulatory drugs were initially introduced to complement and have now supplanted cytotoxic chemotherapy as frontline anti-myeloma agents. Recently, monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor T cells were developed to revamp the immune system to overcome immune suppression and improve patient responses. While current MM therapies have markedly extended patient survival, acquired drug resistance inevitably emerges and drives disease progression. The logical progression for the next generation of MM therapies would be to design and validate agents that prevent and/or overcome acquired resistance to immunotherapies. The complex BM microenvironment promotes resistance to both current anti-myeloma agents and emerging immunotherapies. Myeloma cells are intertwined with a complex BM immune microenvironment that contributes to the development of adaptive drug resistance. Here, we describe recently FDA-approved and investigational anti-myeloma agents that directly or indirectly target the BM microenvironment to prevent or overcome drug resistance. Synergistic effects of anti-myeloma agents may foster the development of rationally-designed drug cocktails that prevent BM-mediated resistance to immunotherapies.

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“…Since plasma cells (PCs) are professional antibody-producing factories, myeloma cells are exquisitely sensitive to proteasome inhibitors (PIs) that disrupt protein homeostasis ( 8 – 12 ). Clinical success of the first U.S. Food and Drug Administration (FDA)-approved PI bortezomib launched a meteoric rise in interest of MM by basic scientists, physicians and the pharmaceutical industry ( 5 – 7 , 13 – 15 ). Recently, immunotherapy in the form of antibodies, antibody-drug conjugates and engineered T-cells has been incorporated into first-line and relapse regimens, to improve OS for newly diagnosed and relapsed and/or refractory MM (RRMM) ( 14 – 16 ).…”

Section: Car T-cells As a Strategy To Treat Multiple Myelomamentioning

confidence: 99%

Road testing new CAR design strategies in multiple myeloma

et al. 2022

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A deeper understanding of basic immunology principles and advances in bioengineering have accelerated the mass production of genetically-reprogrammed T-cells as living drugs to treat human diseases. Autologous and allogeneic cytotoxic T-cells have been weaponized to brandish MHC-independent chimeric antigen receptors (CAR) that specifically engage antigenic regions on tumor cells. Two distinct CAR-based therapeutics designed to target BCMA are now FDA-approved based upon robust, sustained responses in heavily-pretreated multiple myeloma (MM) patients enrolled on the KarMMa and CARTITUDE-1 studies. While promising, CAR T-cells present unique challenges such as antigen escape and T-cell exhaustion. Here, we review novel strategies to design CARs that overcome current limitations. Co-stimulatory signaling regions were added to second-generation CARs to promote IL-2 synthesis, activate T-cells and preclude apoptosis. Third-generation CARs are composed of multiple co-stimulatory signaling units, e.g., CD28, OX40, 4-1BB, to reduce exhaustion. Typically, CAR T-cells incorporate a potent constitutive promoter that maximizes long-term CAR expression but extended CAR activation may also promote T-cell exhaustion. Hypoxia-inducible elements can be incorporated to conditionally drive CAR expression and selectively target MM cells within bone marrow. CAR T-cell survival and activity is further realized by blocking intrinsic regulators of T-cell inactivation. T-Cells Redirected for Universal Cytokine Killing (TRUCKs) bind a specific tumor antigen and produce cytokines to recruit endogenous immune cells. Suicide genes have been engineered into CAR T-cells given the potential for long-term on-target, off-tumor effects. Universal allo-CAR T-cells represent an off-the-shelf source, while logic-gated CAR T-cells are designed to recognize tumor-specific features coupled with Boolean-generated binary gates that then dictate cell-fate decisions. Future generations of CARs should further revitalize immune responses, enhance tumor specificity and reimagine strategies to treat myeloma and other cancers.

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Immunotherapy in Multiple Myeloma—Time for a Second Major Paradigm Shift

Cited by 15 publications

References 98 publications

Updates in the Management of Multiple Myeloma from the American Society of Hematology Meeting 2021

Updates in the Management of Multiple Myeloma from the American Society of Hematology Meeting 2021

Therapeutics to harness the immune microenvironment in multiple myeloma

Road testing new CAR design strategies in multiple myeloma

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