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Efficacy and toxicity profile of carfilzomib based regimens for treatment of multiple myeloma: A systematic review.

ABSTRACT: Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has side effects like peripheral neuropathy (PNP) with reported incidence of grade ?3 PNP between 2%-23% Schlafer et al., 2017. Carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PNP. CFZ is already approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone. Extensive literature search identified a total of 1839 articles. Twenty-six articles (n?=?5980) met the inclusion criteria, 15 in newly diagnosed multiple myeloma (NDMM) and 11 in RRMM group. CFZ demonstrates comparable or even better efficacy to bortezomib with much favorable AE profile. Deep, rapid and sustainable response using KRd with safer toxicity profile supports extension of KRd therapy to frontline therapy for all risk categories of MM. High incidence of grade ?3 HTN underscores the importance of serial BP monitoring. In RRMM, CFZ has documented efficacy with standard 20-27mg/m2 dose. Further large-scale trials are needed to study benefit-to-risk profile of 20-56 and 20-70?mg/m2 dose of CFZ vs standard 20-27?mg/m2 dose in NDMM and RRMM.

SUBMITTER: Mushtaq A

PROVIDER: S-EPMC5901887 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Efficacy and toxicity profile of carfilzomib based regimens for treatment of multiple myeloma: A systematic review.

Mushtaq Adeela A Kapoor Vikas V Latif Azka A Iftikhar Ahmad A Zahid Umar U McBride Ali A Abraham Ivo I Riaz Irbaz Bin IB Anwer Faiz F

Critical reviews in oncology/hematology 20180302

Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has side effects like peripheral neuropathy (PNP) with reported incidence of grade ≥3 PNP between 2%-23% Schlafer et al., 2017. Carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PNP. CFZ is already approved for treatment of relapsed and refr ...[more]

PMID: 29650268

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Project description:Carfilzomib, a selective proteasome inhibitor (PI), is approved for the treatment of patients with relapsed or refractory multiple myeloma (MM). Combination regimens incorporating a PI and immunomodulatory drug (IMiD) have been associated with deep responses and extended survival in patients with newly diagnosed MM (NDMM). Carfilzomib-based combinations with immunomodulators are being extensively studied in the frontline setting. The objective of this review was to describe efficacy and safety data for carfilzomib-based, PI/immunomodulatory combinations in NDMM. Information sources were articles indexed in PubMed and abstracts from key hematology/oncology congresses published between January 2012 and December 2018. PubMed and congresses were searched for prospective clinical studies assessing the combination of carfilzomib with an IMiD for NDMM treatment. Retrospective and preclinical reports, case reports/series, reviews, and clinical studies not evaluating carfilzomib-immunomodulator combinations in NDMM were excluded based on review of titles and abstracts. A total of nine articles and 72 abstracts were deemed relevant and included in the review. A total of six distinct carfilzomib-based, PI/immunomodulator combination regimens have been evaluated in 12 clinical trials. Overall, treatment with these regimens has resulted in deep responses, including high rates of negativity for minimal residual disease. These deep responses have translated to long progression-free survival and overall survival rates. Efficacy results for these regimens have generally been consistent across subgroups defined by age, transplant eligibility, and cytogenetic risk. The safety profile of carfilzomib in NDMM is consistent with that observed in the relapsed-refractory MM setting. Clinical studies have found that carfilzomib-based combinations with immunomodulators are highly active with a favorable safety profile in NDMM. The carfilzomib, lenalidomide, and dexamethasone (KRd) drug backbone is a promising foundation for treatment strategies aimed at achieving long-term, deep responses (functional cures) in the frontline setting. Several ongoing studies are evaluating KRd, with or without anti-CD38 monoclonal antibodies.

Project description:BackgroundPatients with relapsed/refractory multiple myeloma (RRMM) usually have dismal prognostic outcomes. Venetoclax, a selective inhibitor of antiapoptotic protein B-cell lymphoma-2 (BCL-2), demonstrates antimyeloma activity in plasma cells with t(11;14) or high BCL-2 expression.ObjectivesThis meta-analysis aimed to investigate the efficacy and safety of venetoclax-based therapy in RRMM.DesignThis is a meta-analysis study.Data sources and methodsPubMed, Embase, and Cochrane were searched for studies published up to 20 December 2021. Overall response rate (ORR), rate of very good partial response or better (≧VGPR), and complete response (CR) rate were pooled with the random-effects model. Safety was evaluated by the incidences of grade ≧3 adverse events. Subgroup analysis and meta-regression were performed to identify the causes of heterogeneities. All the analyses were conducted by STATA 15.0 software.ResultsA total of 14 studies with 713 patients were included for analysis. The pooled ORR, rate of ≧VGPR, and CR for all patients were 59% [95% confidence interval (CI) = 45-71%], 38% (95% CI = 26-51%), and 17% (95% CI = 10-26%), respectively. The median progression-free survival (PFS) ranged from 2.0 months to not reached (NR), and the median overall survival (OS) ranged from 12.0 months to NR. Meta-regression showed that patients treated with more drugs combined or less heavily pretreated had higher response rates. Patients with t(11;14) had superior ORR [relative risk (RR) = 1.47, 95% CI = 1.05-2.07], ≧VGPR (RR = 1.71, 95% CI = 1.12-2.60), CR (RR = 1.86, 95% CI = 1.34-2.57), PFS [hazard ratio (HR) = 0.47, 95% CI = 0.30-0.65], and OS (HR = 0.30, 95% CI = 0.08-0.52) compared with patients without t(11;14). Most grade ≧3 adverse events were hematologic, gastrointestinal, and infectious related and were manageable.ConclusionVenetoclax-based therapy is an effective and safe option for RRMM patients, especially those with t(11;14).

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Efficacy and toxicity profile of carfilzomib based regimens for treatment of multiple myeloma: A systematic review.

Publications

Efficacy and toxicity profile of carfilzomib based regimens for treatment of multiple myeloma: A systematic review.

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