Marizomib for central nervous system‐multiple myeloma

Badros, Ashraf; Singh, Zeba N.; Dhakal, Binod; Kwok, Young; MacLaren, Ann; Richardson, Paul G.; Trikha, Mohit; Hari, Parameswaran

doi:10.1111/bjh.14498

Cited by 54 publications

(32 citation statements)

References 9 publications

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“…Encouraging phase I/II clinical trial results in relapsed/refractory MM patients led to completion of a phase I study evaluating marizomib, pomalidomide and dexamethasone in heavily pre‐treated patients with relapsed/refractory disease (Richardson et al , ; Spencer et al , ). With an ORR of 53% and clinical benefit rate of 64%, this new proteasome inhibitor will probably be examined in more advanced clinical trials in the near future, not only for its ability to re‐sensitise patients to proteasome inhibition but for its activity in MM involving the central nervous system (Badros et al , ). Oprozomib is structurally similar to carfilzomib with the advantage of being orally administered and has demonstrated pre‐clinical efficacy in bortezomib‐resistant MM cells (Chauhan et al , ).…”

Section: Later‐generation Proteasome Inhibitorsmentioning

confidence: 99%

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: Later‐generation Proteasome Inhibitorsmentioning

confidence: 99%

Resistance to proteasome inhibitors and other targeted therapies in myeloma

et al. 2018

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“…Recently, higher doses of MRZ infused for a shorter duration (0·8 mg/m 2 , 10 min IV infusion) have been administered under compassionate use in a limited number of MM patients with CNS relapse (CNS‐MM). This dosing schedule, which is identical to the schedule being evaluated in glioma, appears to be well tolerated in CNS‐MM patients and is showing promising signs of clinical benefit (Badros et al , ).…”

Section: Discussionmentioning

confidence: 99%

A phase 1 clinical trial evaluating marizomib, pomalidomide and low‐dose dexamethasone in relapsed and refractory multiple myeloma (NPI‐0052‐107): final study results

et al. 2017

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SummaryMarizomib (MRZ) is an irreversible, pan-subunit proteasome inhibitor (PI) in clinical development for relapsed/refractory multiple myeloma (RRMM) and glioma. This study analysed MRZ, pomalidomide (POM) and low-dose dexamethasone (Lo-DEX) [PMD] in RRMM to evaluate safety and determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Intravenous MRZ (0Á3-0Á5 mg/m 2 ) was administered over 2 h on days 1, 4, 8, 11; POM (3-4 mg) on days 1-21; and Lo-DEX (5 or 10 mg) on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22 and 23 of every 28-day cycle. Thirty-eight patients were enrolled that had received a median of 4 (range 1-10) prior lines of therapy; all patients received prior lenalidomide and bortezomib. No dose-limiting toxicities (DLTs) were observed and 0Á5 mg/m 2 MRZ was determined to be the RP2D. The most common treatment-related ≥Grade 3 adverse events were: neutropenia (11/38 patients: 29%), pneumonia (4/38 patients 11%), anaemia (4/38 patients; 11%) and thrombocytopenia (4/38 patients; 11%). The overall response rate and clinical benefit rate was 53% (19/36) and 64% (23/36), respectively. In conclusion, PMD was well tolerated and demonstrated promising activity in heavily pre-treated, high-risk RRMM patients.

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“…Marizomib irreversibly inhibits the three proteolytic sites of the 20S proteasome and pre-clinical studies have shown efficacy in Bortezomib-resistant MM cells [32]. A phase I study evaluating Marizomib, Pomalidomide and Dexamethasone in heavily pre-treated patients with relapsed/refractory MM demonstrated an impressive ORR of 53% and clinical benefit rate of 64% [33][34][35]. This new proteasome inhibitor will likely be examined in more advanced clinical trials in the near future, not only for its ability to re-sensitise patients to proteasome inhibition but for its activity in MM involving the central nervous system.…”

Section: Later-generation Proteasome Inhibitorsmentioning

confidence: 99%

Resistance Mechanisms to Novel Therapies in Myeloma

Wallington-Beddoe¹,

Coghlan²

2019

Update on Multiple Myeloma

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The number of novel therapies for the treatment of multiple myeloma (MM) is rapidly increasing with proteasome inhibitors, immunomodulatory agents and monoclonal antibodies being the most well-known therapeutic classes whilst histone deacetylase inhibitors, selective inhibitors of nuclear export and CART cells amongst others also being actively investigated. However, in parallel with the development and application 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 proteasome inhibitors, and within-class differences in efficacy, toxicity and resistance mechanisms have been observed. Immunomodulatory agents share the common cellular target cereblon and thus resistance patterns relate to cereblon expression and its pathway components. However, the cell surface antigens to which monoclonal antibodies are directed means these agents frequently exhibit unique within-class differences in clinical efficacy and resistance patterns. Despite the progressive biological elucidation of resistance mechanisms to these novel therapies, attempts to specifically exploit these processes lag considerably behind and until such approaches become available, resistance to these therapies will remain a concern.

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Marizomib for central nervous system‐multiple myeloma

Cited by 54 publications

References 9 publications

Resistance to proteasome inhibitors and other targeted therapies in myeloma

Resistance to proteasome inhibitors and other targeted therapies in myeloma

A phase 1 clinical trial evaluating marizomib, pomalidomide and low‐dose dexamethasone in relapsed and refractory multiple myeloma (NPI‐0052‐107): final study results

Resistance Mechanisms to Novel Therapies in Myeloma

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