Carfilzomib with immunomodulatory drugs for the treatment of newly diagnosed multiple myeloma

Abstract

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.

Consolidation with carfilzomib, lenalidomide, and dexamethasone (KRd) following ASCT results in high rates of minimal residual disease negativity and improves bone metabolism, in the absence of bisphosphonates, among newly diagnosed patients with multiple myeloma

“…This prospective study showed that four cycles of KRd consolidation significantly improved depth of response and resulted in a high rate of MRD negativity, along with a positive effect on bone metabolism. Although our study was not designed as a phase 2 trial and the statistical power may be suboptimal, the results are consistent with other studies evaluating the activity of KRd in the newly diagnosed setting 5 . The seminal studies by Jakubowiak et al 6 and Korde et al 7 provided a strong rationale for evaluating this combination in the frontline setting.…”

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

“…Combination therapy with carfilzomib and immunomodulatory drugs for NDMM was also evaluated in multiple clinical trials. This treatment regimen was shown to be efficacious with a favorable safety profile in NDMM [119]. The major adverse event of bortezomib, peripheral neuropathy, was found to be less severe in patients receiving carfilzomib treatment [118].…”

The HECT E3 Ligase E6AP/UBE3A as a Therapeutic Target in Cancer and Neurological Disorders

“…With the development of novel substrate profiling technologies such as Orthogonal Ubiquitin Transfer [ 153 ], more information about previously undefined E6AP substrates is expected soon. While proteasome inhibitors are widely used in clinic [ 154 , 155 , 156 , 157 ], small molecules targeting E3 ligases are still in developmental or preclinical phases. Novel screening technologies will further build the avenue to therapeutic discoveries, such as activity-based probes, high-throughput crystallography, and sophisticated uses of mass spectrometry.…”