A comprehensive overview of daratumumab and carfilzomib and the recently approved daratumumab, carfilzomib and dexamethasone regimen in relapsed/refractory multiple myeloma

ABSTRACT

Introduction: Novel, effective regimens are needed in patients with relapsed and refractory myeloma (RRMM) who inevitably relapse after PI and IMID containing treatment.

Areas covered: Pre-clinical data, early clinical and pivotal trials relevant to the development of the two backbone drugs of carfilzomib and daratumumab, and the two important recent trials, EQUULEUS and CANDOR leading to the FDA approval of the combination regimen of daratumumab, carfilzomib, and dexamethasone (DKd) for RRMM are detailed in this review.

Expert opinion: EQUULEUS and CANDOR have established the efficacy of the DKd regimen in the landscape of bortezomib and lenalidomide refractory patients. The split dosing schedule of the first dose of daratumumab was approved by the FDA based on EQUULEUS, significantly improving patient convenience. Subcutaneous daratumumab is being evaluated in this combination to further improve tolerance and convenience. Further studies are needed to evaluate and optimally sequence the many effective and potent drugs available in RRMM.

KEYWORDS:

• CANDOR
• carfilzomib
• daratumumab
• EQUULEUS
• myeloma
• refractory
• relapsed

Article highlights

• Efficacy results from phase 3 studies of novel combination therapies in lenalidomide refractory patients are particularly unsatisfactory.

• The clinical benefit of the daratumumab-carfilzomib combination was initially reported in the phase 1b EQUULEUS trial which showed efficacy in RRMM patients, 60% of whom were lenalidomide refractory.

• The feasibility of split dosing of the first dose of daratumumab was also shown in this study leading to FDA approval of this manoeuver for improved tolerability and reduced infusion time.

• CANDOR is the first phase 3 randomized study that compared DKd to Kd in RRMM and showed significantly longer PFS, deeper responses, and a nearly 10 fold higher MRD negative CR rate in the DKd arm, leading to FDA approval of this regimen.

• Drug discontinuations were primarily due to cardiac toxicity with carfilzomib and to infection risk with daratumumab, therefore, there needs to be a heightened awareness of the potential for these side effects.

• The observed benefit was consistent across clinically relevant prespecified subgroups including the lenalidomide exposed and refractory patients, leading to this regimen becoming an important lenalidomide sparing anti-myeloma option.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

S Jagannath reports fees from Antengene, BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda. HJ Cho received commercial research support from Genentech Roche, Bristol-Myers Squibb, and Takeda outside the submitted work, and is employed by the Multiple Myeloma Research Foundation in a capacity that does not conflict with the submitted work. S Parekh reports consulting fees from Foundation Medicine; Research funding from Celgene, Karyopharm, Amgen, Pfizer. D Madduri reports consulting fees from Janssen, Celgene, Takeda, Legend, GSK, Foundation Medicine, BMS, Kinevant.

J Richter is on the speaker bureau for Janssen, Celgene, Adaptive biotechnologies; receives consulting fees/advisory board for Celgene, Janssen, BMS, Karyopharm, Antengene, Sanofi, X4 pharmaceuticals, oncopeptides, adaptive biotechnologies, Secura bio, Astra Zeneca. A Chari reports consulting fees from Janssen, Celgene, Novartis Pharmaceuticals, Amgen, BMS, Karyopharm, Sanofi Genzyme, Seattle Genetics, Oncopeptides, Takeda, Antengene, Glaxo Smith Kline, Secura Bio; research funding from Janssen, Celgene, Novartis Pharmaceuticals, Amgen, Pharmacyclics, Seattle Genetics, Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was funded.