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      The role of carfilzomib in relapsed/refractory multiple myeloma

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      Author(s):
      Publication date (Electronic):
      Journal: Therapeutic Advances in Hematology
      Publisher: SAGE Publications
      Keywords: carfilzomib, multiple myeloma

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          Abstract

          Carfilzomib is the second proteasome inhibitor approved for relapsed multiple myeloma. Since its approval in 2012, carfilzomib has been an active and versatile drug, based on its efficacy as a single agent; superiority as a doublet with dexamethasone compared with bortezomib and dexamethasone; and as a partner in diverse three drug combinations such as with lenalidomide or daratumumab. While it has an established place in relapsed disease, clinicians should be aware of its cardiovascular and renal adverse event profile, which is manageable, in order to optimize outcomes. This review will provide a perspective on the current and future role of carfilzomib in relapsed/refractory multiple myeloma.

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          Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.

          A. Stewart, S Vincent Rajkumar, Meletios A. Dimopoulos … (2015)
          Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma.
          Article 0 comments Cited 226 times – based on 0 reviews     Review now
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            Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy

            Ujjawal H Gandhi, Robert Cornell, Arjun Lakshman … (2019)
            The introduction of CD38-targeting monoclonal antibodies (CD38 MoABs), daratumumab and isatuximab, has significantly impacted the management of patients with multiple myeloma (MM). Outcomes of patients with MM refractory to CD38 MoABs have not been described. We analyzed outcomes of 275 MM patients at 14 academic centers with disease refractory to CD38 MoABs. Median interval between MM diagnosis and refractoriness to CD38 MoAB (T 0 ) was 50.1 months. The median overall survival (OS) from T 0 for the entire cohort was 8.6 [95% C.I. 7.5–9.9] months, ranging from 11.2 months for patients not simultaneously refractory to an immunomodulatory (IMiD) agent and a proteasome inhibitor (PI) to 5.6 months for “penta-refractory” patients (refractory to CD38 MoAB, 2 PIs and 2 IMiDs). At least one subsequent treatment regimen was employed after T 0 in 249 (90%) patients. Overall response rate to first regimen after T 0 was 31% with median progression-free survival (PFS) and OS of 3.4 and 9.3 months, respectively. PFS was best achieved with combinations of carfilzomib and alkylator (median 5.7 months), and daratumumab and IMiD (median 4.5 months). Patients with MM refractory to CD38 MoAB have poor prognosis and this study provides benchmark for new therapies to be tested in this population.
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              Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma.

              Deborah Kuhn, Qing Chen, Peter M. Voorhees … (2007)
              The proteasome has emerged as an important target for cancer therapy with the approval of bortezomib, a first-in-class, reversible proteasome inhibitor, for relapsed/refractory multiple myeloma (MM). However, many patients have disease that does not respond to bortezomib, whereas others develop resistance, suggesting the need for other inhibitors with enhanced activity. We therefore evaluated a novel, irreversible, epoxomicin-related proteasome inhibitor, carfilzomib. In models of MM, this agent potently bound and specifically inhibited the chymotrypsin-like proteasome and immunoproteasome activities, resulting in accumulation of ubiquitinated substrates. Carfilzomib induced a dose- and time-dependent inhibition of proliferation, ultimately leading to apoptosis. Programmed cell death was associated with activation of c-Jun-N-terminal kinase, mitochondrial membrane depolarization, release of cytochrome c, and activation of both intrinsic and extrinsic caspase pathways. This agent also inhibited proliferation and activated apoptosis in patient-derived MM cells and neoplastic cells from patients with other hematologic malignancies. Importantly, carfilzomib showed increased efficacy compared with bortezomib and was active against bortezomib-resistant MM cell lines and samples from patients with clinical bortezomib resistance. Carfilzomib also overcame resistance to other conventional agents and acted synergistically with dexamethasone to enhance cell death. Taken together, these data provide a rationale for the clinical evaluation of carfilzomib in MM.
              Article 0 comments Cited 175 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Andrew J. Yee:
                ORCID: https://orcid.org/0000-0003-3623-7491
                Journal
                Journal ID (nlm-ta): Ther Adv Hematol
                Journal ID (iso-abbrev): Ther Adv Hematol
                Journal ID (publisher-id): TAH
                Journal ID (hwp): sptah
                Title: Therapeutic Advances in Hematology
                Publisher: SAGE Publications (Sage UK: London, England )
                ISSN (Print): 2040-6207
                ISSN (Electronic): 2040-6215
                Publication date (Electronic): 8 June 2021
                Publication date Collection: 2021
                Volume: 12
                Electronic Location Identifier: 20406207211019612
                Affiliations
                [1-20406207211019612]Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit St, Boston, MA 02114, USA
                Author notes
                Author information
                https://orcid.org/0000-0003-3623-7491
                Article
                Publisher ID: 10.1177_20406207211019612
                DOI: 10.1177/20406207211019612
                PMC ID: 8191071
                PubMed ID: 34163580
                SO-VID: 9626a1c4-4248-4591-929a-1e0cf4e2f7cf
                Copyright © © The Author(s), 2021
                License:

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Date received : 1 February 2021
                Date accepted : 4 May 2021
                Categories
                Subject: Review
                Custom metadata
                cover-date January-December 2021
                typesetter ts1

                ScienceOpen disciplines: Hematology
                Keywords: carfilzomib,multiple myeloma
                Data availability:
                ScienceOpen disciplines: Hematology
                Keywords: carfilzomib, multiple myeloma

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