Immunomodulatory Drugs in Multiple Myeloma: Mechanisms of Action and Clinical Experience

Holstein, Sarah A.; McCarthy, Philip L.

doi:10.1007/s40265-017-0689-1

Cited by 180 publications

(187 citation statements)

References 196 publications

(189 reference statements)

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“…The immunomodulatory drugs (IMiDs), thalidomide, lenalidomide and pomalidomide have also made a major impact in the management of MM. The anti‐MM effects of IMiDs are related to their binding to the E3 ubiquitin ligase cereblon (CRBN) and subsequent ubiquitination and degradation of two B‐cell transcription factors, Ikaros (IKZF1) and Aiolos (IKZF3) (Holstein & McCarthy, ). A landmark study identified CRBN as a primary target in thalidomide teratogenicity, further demonstrating that thalidomide binds to CRBN, disrupting the function of the E3 ubiquitin ligase complex, ultimately leading to the downregulation of fibroblast growth factor genes and the teratogenetic affects associated with thalidomide (Ito et al , ).…”

Section: Immunomodulatory Agents Used To Treat Myelomamentioning

confidence: 99%

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Resistance to proteasome inhibitors and other targeted therapies in myeloma

et al. 2018

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The number of novel therapies for the treatment of myeloma is rapidly increasing, as are the clinical trials evaluating them in combination with other novel and established therapies. Proteasome inhibitors, immunomodulatory agents and monoclonal antibodies are the most well known and studied classes of novel agents targeting myeloma, with histone deacetylase inhibitors, nuclear export inhibitors and several other approaches also being actively investigated. However, in parallel with the development and clinical use of these novel myeloma therapies is the emergence of novel mechanisms of resistance, many of which remain elusive, particularly for more recently developed agents. Whilst resistance mechanisms have been best studied for proteasome inhibitors, particularly bortezomib, class effects do not universally apply to all class members, and within-class differences in efficacy, toxicity and resistance mechanisms have been observed. Although immunomodulatory agents share the common cellular target cereblon and thus resistance patterns relate to cereblon expression, the unique cell surface antigens to which monoclonal antibodies are directed means these agents frequently exhibit unique within-class differences in clinical efficacy and resistance patterns. This review describes the major classes of novel therapies for myeloma, highlights the major clinical trials within each class and discusses known resistance mechanisms.

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Section: Immunomodulatory Agents Used To Treat Myelomamentioning

confidence: 99%

“…Finally, pomalidomide is a third generation IMiD approved for relapsed/refractory MM patients, exhibiting efficacy in those who have previously been treated with bortezomib and lenalidomide. (Holstein & McCarthy, ). Table details important phase III studies.…”

Section: Immunomodulatory Agents Used To Treat Myelomamentioning

confidence: 99%

Resistance to proteasome inhibitors and other targeted therapies in myeloma

et al. 2018

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“…PIs act through multiple mechanisms to suppress tumor survival pathways and to arrest tumor growth, tumor spread and angiogenesis [14]. IMiDs increase T-cell and natural killer (NK) cell activation, induce apoptosis and inhibit cell adhesion molecules [15].…”

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confidence: 99%

Isatuximab Plus Pomalidomide/Dexamethasone Versus Pomalidomide/Dexamethasone in Relapsed/Refractory Multiple Myeloma: Icaria Phase Iii Study Design

et al. 2017

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Treatment for relapsed/refractory multiple myeloma (RRMM) remains an unmet need. Isatuximab, an anti-CD38 monoclonal antibody has shown efficacy and tolerability as a monotherapy and combination therapy in Phase I/II studies in RRMM. Here, we describe the design of the Phase III ICARIA-MM study (NCT02990338) which will evaluate isatuximab in combination with pomalidomide (Pom) and low-dose dexamethasone (dex) (Pom/dex) versus Pom/dex alone in RRMM. Patients will be randomized in a 1:1 ratio. The primary endpoint is progression-free survival. Response will be determined by an independent response review committee using IMWG criteria (2016) and safety will be assessed throughout. Approximately 300 patients (150 in each arm) are expected to enroll. The first patient was recruited in January 2017 and accrual is ongoing.

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“…Another issue of clinical relevancy concerns CRBN, the ClC-1-binding substrate receptor protein of the CUL4 E3 ligase complex. CRBN is known to be the binding target of thalidomide and lenalidomide (194)(195)(196), both immunomodulatory drugs used for the treatment of multiple myeloma (197,198). Common side effects of thalidomide and lenalidomide treatments include muscle weakness and muscle cramps (197,199), suggesting the presence of drug-induced hyperexcitability in skeletal muscles.…”

Section: Clinical Significancementioning

confidence: 99%

Defective Gating and Proteostasis of Human ClC-1 Chloride Channel: Molecular Pathophysiology of Myotonia Congenita

Jeng¹,

You

et al. 2020

Front. Neurol.

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The voltage-dependent ClC-1 chloride channel, whose open probability increases with membrane potential depolarization, belongs to the superfamily of CLC channels/transporters. ClC-1 is almost exclusively expressed in skeletal muscles and is essential for stabilizing the excitability of muscle membranes. Elucidation of the molecular structures of human ClC-1 and several CLC homologs provides important insight to the gating and ion permeation mechanisms of this chloride channel. Mutations in the human CLCN1 gene, which encodes the ClC-1 channel, are associated with a hereditary skeletal muscle disease, myotonia congenita. Most disease-causing CLCN1 mutations lead to loss-of-function phenotypes in the ClC-1 channel and thus increase membrane excitability in skeletal muscles, consequently manifesting as delayed relaxations following voluntary muscle contractions in myotonic subjects. The inheritance pattern of myotonia congenita can be autosomal dominant (Thomsen type) or recessive (Becker type). To date over 200 myotonia-associated ClC-1 mutations have been identified, which are scattered throughout the entire protein sequence. The dominant inheritance pattern of some myotonia mutations may be explained by a dominant-negative effect on ClC-1 channel gating. For many other myotonia mutations, however, no clear relationship can be established between the inheritance pattern and the location of the mutation in the ClC-1 protein. Emerging evidence indicates that the effects of some mutations may entail impaired ClC-1 protein homeostasis (proteostasis). Proteostasis of membrane proteins comprises of biogenesis at the endoplasmic reticulum (ER), trafficking to the surface membrane, and protein turn-over at the plasma membrane. Maintenance of proteostasis requires the coordination of a wide variety of different molecular chaperones and protein quality control factors. A number of regulatory molecules have recently been shown to contribute to post-translational modifications of ClC-1 and play critical roles in the ER quality control, membrane trafficking, and peripheral quality control of this Jeng et al.ClC-1 Proteostasis and Myotonia chloride channel. Further illumination of the mechanisms of ClC-1 proteostasis network will enhance our understanding of the molecular pathophysiology of myotonia congenita, and may also bring to light novel therapeutic targets for skeletal muscle dysfunction caused by myotonia and other pathological conditions.

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Immunomodulatory Drugs in Multiple Myeloma: Mechanisms of Action and Clinical Experience

Cited by 180 publications

References 196 publications

Resistance to proteasome inhibitors and other targeted therapies in myeloma

Resistance to proteasome inhibitors and other targeted therapies in myeloma

Isatuximab Plus Pomalidomide/Dexamethasone Versus Pomalidomide/Dexamethasone in Relapsed/Refractory Multiple Myeloma: Icaria Phase Iii Study Design

Defective Gating and Proteostasis of Human ClC-1 Chloride Channel: Molecular Pathophysiology of Myotonia Congenita

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