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

Russell, Brian M; Avigan, David

doi:10.1007/s12185-023-03579-x

Cited by 5 publications

(5 citation statements)

References 85 publications

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“…Despite the disappointing efficacy, patients achieving a response had a prolonged duration of response. Understanding the predictors of such responses would be key in optimizing patient selection for immune checkpoint therapy ( 96 , 97 ). Please see Table 3 for key trials in multiple myeloma.…”

Section: Immune Checkpoint Blockade In Multiple Myelomamentioning

confidence: 99%

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Immune checkpoint blockade in hematological malignancies: current state and future potential

Pophali,

Varela,

Rosenblatt

2024

Front. Oncol.

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Malignant cells are known to evade immune surveillance by engaging immune checkpoints which are negative regulators of the immune system. By restoring the T-lymphocyte mediated anti-tumor effect, immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid tumors but have met rather modest success in hematological malignancies. Currently, the only FDA approved indications for ICI therapy are in classic hodgkin lymphoma and primary mediastinal B cell lymphoma. Multiple clinical trials have assessed ICI therapy alone and in combination with standard of care treatments in other lymphomas, plasma cell neoplasms and myeloid neoplasms but were noted to have limited efficacy. These trials mostly focused on PD-1/PDL-1 and CTLA-4 inhibitors. Recently, there has been an effort to target other T-lymphocyte checkpoints like LAG-3, TIM-3, TIGIT along with improving strategies of PD-1/PDL-1 and CTLA-4 inhibition. Drugs targeting the macrophage checkpoint, CD47, are also being tested. Long term safety and efficacy data from these ongoing studies are eagerly awaited. In this comprehensive review, we discuss the mechanism of immune checkpoint inhibitors, the key takeaways from the reported results of completed and ongoing studies of these therapies in the context of hematological malignancies.

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Section: Immune Checkpoint Blockade In Multiple Myelomamentioning

confidence: 99%

“…Understanding the predictors of such responses would be key in optimizing patient selection for immune checkpoint therapy (96,97). Please see Table 3 for key trials in multiple myeloma.…”

Section: Immune Checkpoint Blockade In Multiple Myelomamentioning

confidence: 99%

Immune checkpoint blockade in hematological malignancies: current state and future potential

Pophali,

Varela,

Rosenblatt

2024

Front. Oncol.

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“…In contrast, immunotherapy-based approaches have been employed in standard regimens and have led to significant improvements in patient disease remission ( 3 ). The dysregulation of the immune system in multiple myeloma (MM) and its targeting by immunotherapies has been a key reason for immunotherapy success ( 4 ). In particular, Chimeric Antigen Receptor T cells (CAR-T cells) have recently come to the fore due to their efficacy against several hematological malignancies including MM, leukemia and B-cell malignancies ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

Designing combination therapies for cancer treatment: application of a mathematical framework combining CAR T-cell immunotherapy and targeted radionuclide therapy

Adhikarla,

Awuah,

Caserta

et al. 2024

Front. Immunol.

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IntroductionCancer combination treatments involving immunotherapies with targeted radiation therapy are at the forefront of treating cancers. However, dosing and scheduling of these therapies pose a challenge. Mathematical models provide a unique way of optimizing these therapies. MethodsUsing a preclinical model of multiple myeloma as an example, we demonstrate the capability of a mathematical model to combine these therapies to achieve maximum response, defined as delay in tumor growth. Data from mice studies with targeted radionuclide therapy (TRT) and chimeric antigen receptor (CAR)-T cell monotherapies and combinations with different intervals between them was used to calibrate mathematical model parameters. The dependence of progression-free survival (PFS), overall survival (OS), and the time to minimum tumor burden on dosing and scheduling was evaluated. Different dosing and scheduling schemes were evaluated to maximize the PFS and optimize timings of TRT and CAR-T cell therapies. ResultsTherapy intervals that were too close or too far apart are shown to be detrimental to the therapeutic efficacy, as TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing while the therapies being too far apart result in tumor regrowth, negatively impacting tumor control and survival. We show that splitting a dose of TRT or CAR-T cells when administered in combination is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy. DiscussionMathematical models are crucial tools for optimizing the delivery of cancer combination therapy regimens with application along the lines of achieving cure, maximizing survival or minimizing toxicity.

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“…Multiple myeloma (MM) is characterized by the clonal proliferation of plasma cells (PCs) in the bone marrow (BM), leading to the production of monoclonal immunoglobulins [ 3 ]. The disease not only compromises the normal immune response but also impairs the production of functional immunoglobulins, rendering patients susceptible to infections [ 4 ]. The presence of monoclonal proteins and the suppression of polyclonal immunoglobulins, particularly IgG and IgA subclasses, contribute to immune dysfunction and increase the risk of severe infections, including sepsis [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of clinical outcomes, infectious complications and microbiological data in newly diagnosed multiple myeloma patients: a retrospective observational study of 92 subjects

Desantis,

Borrelli,

Panebianco

et al. 2024

Clin Exp Med

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Patients with multiple myeloma (MM) have an increased risk of sepsis due to underlying disease- and treatment-related immunosuppression. However, data on sepsis incidence, causative pathogens, and impact on outcomes in newly diagnosed MM (NDMM) are limited. We conducted a retrospective observational study of 92 NDMM patients who developed sepsis between 2022 and 2023 at a tertiary care center in Italy. Patient characteristics, sepsis criteria [Quick Sequential Organ Failure Assessment, Systemic Inflammatory Response Syndrome (SIRS)], microbiology results, and associations with progression-free survival (PFS) were analyzed. In this cohort of 92 critically-ill patients, pathogenic organisms were identified via microbiological culture in 74 cases. However, among the remaining 18 culture-negative patients, 9 exhibited a SIRS score of 2 and another 9 had a SIRS score of 4, suggestive of a clinical presentation consistent with sepsis despite negative cultures. Common comorbidities included renal failure (60%), anemia (71%), and bone disease (83%). Gram-negative (28%) and Gram-positive (23%) bacteria were frequent causative organisms, along with fungi (20%). Cox Univariate analyses for PFS showed statically significant HR in patients with albumin ≥ 3.5 vs < 3.5 (HR = 5.04, p < 0.001), Karnofsky performance status ≥ 80 vs < 80 (HR = 2.01, p = 0.002), and early-stage vs late-stage disease by International Staging System (HR = 4.76 and HR = 12.52, both p < 0.001) and Revised International Staging System (R-ISS III vs R-ISS I, HR = 7.38, p < 0.001). Sepsis is common in NDMM and associated with poor outcomes. Risk stratification incorporating sepsis severity, comorbidities, and disease stage may help guide preventive strategies and optimize MM management.

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

Cited by 5 publications

References 85 publications

Immune checkpoint blockade in hematological malignancies: current state and future potential

Immune checkpoint blockade in hematological malignancies: current state and future potential

Designing combination therapies for cancer treatment: application of a mathematical framework combining CAR T-cell immunotherapy and targeted radionuclide therapy

Comprehensive analysis of clinical outcomes, infectious complications and microbiological data in newly diagnosed multiple myeloma patients: a retrospective observational study of 92 subjects

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