Immunologic approaches for the treatment of multiple myeloma

Rasche, Leo; Weinhold, Niels; Morgan, Gareth J.; Rhee, Frits van; Davies, Faith E.

doi:10.1016/j.ctrv.2017.03.010

Cited by 31 publications

(25 citation statements)

References 145 publications

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“…However, these are likely to be used in combination with other classes of drugs to maximise response and minimise the emergence of resistance. Novel classes of drugs include Venetoclax (BCL‐2 inhibitor), chimeric antigen receptor (CAR)‐T cells, anti‐BMCA, MCL inhibitor and Nuclear Export inhibitor . These treatments may not modulate ER stress directly but have promising efficacy in PI‐resistant MM patients.…”

Section: Future Treatments For Proteasome Inhibitor‐resistant MM Patimentioning

confidence: 99%

“…Novel classes of drugs include Venetoclax (BCL-2 inhibitor), chimeric antigen receptor (CAR)-T cells, anti-BMCA, MCL inhibitor and Nuclear Export inhibitor. 84 These treatments may not modulate ER stress directly but have promising efficacy in PI-resistant MM patients. Genomics of individual patients may inform actionable targets that contribute to resistance and progressive disease.…”

Section: Future Treatments For Proteasome Inhibitor-resistant MM Patimentioning

confidence: 99%

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Endoplasmic reticulum stress in the development of multiple myeloma and drug resistance

et al. 2018

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Multiple myeloma (MM) is a haematological malignancy of mature antibody‐secreting plasma cells. Currently, MM is incurable, but advances in drug treatments have increased patient lifespan. One of the characteristics of MM is the excessive production of monoclonal immunoglobulin (also referred to as paraprotein). This high level of protein production induces endoplasmic reticulum (ER) stress, and proteasomal degradation of the paraprotein is required to avoid ER stress‐induced cell death. Consequently, proteasomal inhibitors such as bortezomib have been particularly effective therapies. Unfortunately development of resistance to bortezomib is common. In this review, we address how control of endoplasmic reticulum stress is important in the development of MM and how the unfolded protein response and its associated stress response pathways are involved in the development of bortezomib resistance.

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Section: Future Treatments For Proteasome Inhibitor‐resistant MM Patimentioning

confidence: 99%

Section: Future Treatments For Proteasome Inhibitor-resistant MM Patimentioning

confidence: 99%

Endoplasmic reticulum stress in the development of multiple myeloma and drug resistance

et al. 2018

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“…Immune dysfunction is a hallmark of MM, and immunosuppression increases as the disease progresses (Kumar & Anderson, 2016;Rasche et al, 2017;Tamura, 2018). Therefore, therapies that stimulate the immune system can benefit patients, both early in their disease course and after relapse (Kumar & Anderson, 2016;Guillerey et al, 2016).…”

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confidence: 99%

Pomalidomide plus low‐dose dexamethasone in relapsed refractory multiple myeloma after lenalidomide treatment failure

et al. 2019

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Summary Patients with relapsed/refractory multiple myeloma (RRMM) for whom the benefits of lenalidomide have been exhausted in early treatment lines need effective therapies. In cohort A of the phase 2 MM‐014 trial, we examined the safety and efficacy of pomalidomide plus low‐dose dexamethasone immediately after lenalidomide‐based treatment failure in patients with RRMM and two prior lines of therapy. Pomalidomide 4 mg was given on days 1 to 21 of 28‐day cycles. Dexamethasone 40 mg (20 mg for patients aged >75 years) was given on days 1, 8, 15 and 22 of 28‐day cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression‐free survival (PFS), overall survival (OS) and safety. The intention‐to‐treat population comprised 56 patients; all received prior lenalidomide (87·5% lenalidomide refractory) and 39 (69·6%) received prior bortezomib. ORR was 32·1% (28·2% in the prior‐bortezomib subgroup). Median PFS was 12·2 months (7·9 months in the prior‐bortezomib subgroup). Median OS was 41·7 months (38·6 months in the prior‐bortezomib subgroup). The most common grade 3/4 treatment‐emergent adverse events were anaemia (25·0%), pneumonia (14·3%) and fatigue (14·3%). These findings support earlier sequencing of pomalidomide‐based therapy in lenalidomide‐pretreated patients with RRMM, including those who have become refractory to lenalidomide. Trial registration: http://www.ClinicalTrials.gov identifier NCT01946477.

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“…One example is the B cell maturation antigen (BCMA) directed CAR T cell therapy which is showing promising activity in multiple myeloma (34).…”

Section: Current Applications In Human Oncologymentioning

confidence: 99%

CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies

Mochel

Ekker

Johannes

et al. 2019

AAPS J

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The advent of the genome editing era brings forth the promise of adoptive cell transfer using engineered chimeric antigen receptor (CAR) T cells for targeted cancer therapy. CAR T cell immunotherapy is probably one of the most encouraging developments for the treatment of hematological malignancies. In 2017, two CAR T cell therapies were approved by the US Food and Drug Administration: one for the treatment of pediatric acute lymphoblastic leukemia (ALL) and the other for adult patients with advanced lymphomas. However, despite significant progress in the area, CAR T cell therapy is still in its early days and faces significant challenges, including the complexity and costs associated with the technology. B cell lymphoma is the most common hematopoietic cancer in dogs, with an incidence approaching 0.1% and a total of 20-100 cases per 100,000 individuals. It is a widely accepted naturally occurring model for human non-Hodgkin's lymphoma. Current treatment is with combination chemotherapy protocols, which prolong life for less than a year in canines and are associated with severe dose-limiting side effects, such as gastrointestinal and bone marrow toxicity. To date, one canine study generated CAR T cells by transfection of mRNA for CAR domain expression. While this was shown to provide a transient anti-tumor activity, results were modest, indicating that stable, genomic integration of CAR modules is required in order to achieve lasting therapeutic benefit. This commentary summarizes the current state of knowledge on CAR T cell immunotherapy in human medicine and its potential applications in animal health, while discussing the potential of the canine model as a translational system for immuno-oncology research.

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Immunologic approaches for the treatment of multiple myeloma

Cited by 31 publications

References 145 publications

Endoplasmic reticulum stress in the development of multiple myeloma and drug resistance

Endoplasmic reticulum stress in the development of multiple myeloma and drug resistance

Pomalidomide plus low‐dose dexamethasone in relapsed refractory multiple myeloma after lenalidomide treatment failure

CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies

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