Insights on Multiple Myeloma Treatment Strategies

Mateos, María Victoria; Ludwig, Heinz; Bazarbachi, Ali; Beksaç, Meral; Bladé, Joan; Boccadoro, Mario; Cavo, Michèle; Delforge, Michel; Dimopoulos, Meletios A.; Façon, Thierry; Geraldes, Catarina; Goldschmidt, Hartmut; Hájek, Roman; Hansson, Markus; Jamroziak, Krzysztof; Leiba, Merav; Masszi, Tamás; Mendeleeva, Larisa; O’Dwyer, Michael; Plesner, Torben; Miguel, Jesús F. San; Straka, Christian; Donk, Niels W.C.J. van de; Yong, Kwee; Zver, Samo; Moreau, Philippe; Sonneveld, Pieter

doi:10.1097/hs9.0000000000000163

Cited by 37 publications

(43 citation statements)

References 95 publications

(212 reference statements)

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“…The treatment of MM patients has improved significantly over the past few years (147). A better understanding of the immuneescape mechanisms contributing to tumor progression, has led to the development of several active and well-tolerated forms of immunotherapy that has significantly improved outcome of MM patients (9, 10).…”

Section: Discussionmentioning

confidence: 99%

Deregulation of Adaptive T Cell Immunity in Multiple Myeloma: Insights Into Mechanisms and Therapeutic Opportunities

et al. 2020

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Immunotherapy has recently emerged as a promising treatment option for multiple myeloma (MM) patients. Profound immune dysfunction and evasion of immune surveillance are known to characterize MM evolution and disease progression. Along with genomic changes observed in malignant plasma cells, the bone marrow (BM) milieu creates a protective environment sustained by the complex interaction of BM stromal cells (BMSCs) and malignant cells that using bidirectional connections and cytokines released stimulate disease progression, drug resistance and enable immune escape. Local immune suppression and T-cell exhaustion are important mediating factors of clinical outcomes and responses to immune-based approaches. Thus, further characterization of the defects present in the immune system of MM patients is essential to develop novel therapies and to repurpose the existing ones. This review seeks to provide insights into the mechanisms that promote tumor escape, cause inadequate T-cell stimulation and impaired cytotoxicity in MM. Furthermore, it highlights current immunotherapies being used to restore adaptive T-cell immune responses in MM and describes strategies created to escape these multiple immune evasion mechanisms.

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Section: Discussionmentioning

confidence: 99%

Deregulation of Adaptive T Cell Immunity in Multiple Myeloma: Insights Into Mechanisms and Therapeutic Opportunities

et al. 2020

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“…IMiDs were rapidly followed by highly successful antibodies such as the SlamF7-specific Elotuzumab and the CD38-specific Daratumumab. These antibodies achieve unprecedented response rates in heavily pretreated patients, especially in combination with IMiDs and proteasome inhibitors [8].…”

Section: Introductionmentioning

confidence: 99%

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Holthof

Mutis

2020

Cancers

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The power of immunotherapy in the battle of Multiple Myeloma (MM) started with allogeneic stem cell transplantation, and was rediscovered with immunomodulatory drugs and extended with the outstanding results achieved with targeted antibodies. Today, next to powerful antibodies Elotuzumab and Daratumumab, several T-cell-based immunotherapeutic approaches, such as bispecific antibodies and chimeric antigen receptor-transduced T-cells (CAR T-cells) are making their successful entry in the immunotherapy arena with highly promising results in clinical trials. Nonetheless, similar to what is observed in chemotherapy, MM appears capable to escape from immunotherapy, especially through tight interactions with the cells of the bone marrow microenvironment (BM-ME). This review will outline our current understanding on how BM-ME protects MM-cells from immunotherapy through immunosuppression and through induction of intrinsic resistance against cytotoxic effector mechanisms of T- and NK-cells.

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“…In recent years, the prognosis of MM has improved markedly with the development of various new agents such as immunomodulatory drugs, PIs, and monoclonal antibodies. However, all cases of MM remain incurable because they acquire drug resistance 1 . The drug‐resistant fraction of myeloma cells is thought to be protected by multiple factors in the bone marrow microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia‐inducible hexokinase‐2 enhances anti‐apoptotic function via activating autophagy in multiple myeloma

et al. 2020

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Multiple myeloma (MM) is an incurable hematopoietic neoplasm derived from plasma cells, and existing in the bone marrow. Recent developments in the field of myeloma onco‐biology have enabled the use of proteasome inhibitors (PIs) as key drugs for MM. PIs can increase cell sensitivity to endoplasmic reticulum stress, leading to apoptosis of myeloma cells. PI cannot kill all myeloma cells, however; one reason of this might be activation of autophagy via hypoxic stress in the bone marrow microenvironment. Hypoxia‐inducible gene(s) that regulate autophagy may be novel therapeutic target(s) for PI‐resistant myeloma cells. Here, a hypoxia‐inducible glycolytic enzyme hexokinase‐2 (HK2) was demonstrated to contribute by autophagy activation to the acquisition of an anti‐apoptotic phenotype in myeloma cells. We found that hypoxic stress led to autophagy activation accompanied by HK2 upregulation in myeloma cells. Under hypoxic conditions, HK2 knockdown inhibited glycolysis and impaired autophagy, inducing apoptosis. The cooperative effects of a PI (bortezomib) against immunodeficient mice inoculated with HK2‐knocked down myeloma cells were examined and significant tumor reduction was observed. An HK2 inhibitor, 3‐bromopyruvate (3‐BrPA), also induced apoptosis under hypoxic rather than normoxic conditions. Further examination of the cooperative effects between 3‐BrPA and bortezomib on myeloma cells revealed a significant increase in apoptotic myeloma cells. These results strongly suggested that HK2 regulates the activation of autophagy in hypoxic myeloma cells. Cooperative treatment using PI against a dominant fraction, and HK2 inhibitor against a minor fraction, adapted to the bone marrow microenvironment, may lead to deeper remission for refractory MM.

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Insights on Multiple Myeloma Treatment Strategies

Cited by 37 publications

References 95 publications

Deregulation of Adaptive T Cell Immunity in Multiple Myeloma: Insights Into Mechanisms and Therapeutic Opportunities

Deregulation of Adaptive T Cell Immunity in Multiple Myeloma: Insights Into Mechanisms and Therapeutic Opportunities

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Hypoxia‐inducible hexokinase‐2 enhances anti‐apoptotic function via activating autophagy in multiple myeloma

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