(UPDATE) Carfilzomib (Kyprolis)
Updated: Friday, May 28, 2021
Selecting a therapeutic path for relapsed or refractory myeloma has become increasingly complex in recent years. Patients with relapsed or refractory disease often have limited treatment options and a poor prognosis. With increasing use of the second-generation immunomodulatory agent (IMiD) lenalidomide in the front-line setting as induction and maintenance/continuous therapy in both transplantation-eligible and -ineligible patient populations, there is a growing need for effective and tolerable lenalidomide-free regimens for patients who no longer respond to lenalidomide treatment.
Triplets Versus Doublets as Salvage Therapy
In general, triplets are preferred over doublets as salvage therapies. Although several triplets building upon the lenalidomide/dexamethasone backbone have been approved for patients with relapsed and/or refractory multiple myeloma, trials evaluating such combinations have largely excluded patients who were refractory to lenalidomide. The usefulness of these regimens, therefore, in the vast majority of patients whose disease is progressing on lenalidomide therapy is questionable. As expanding options have emerged, experts tend to prefer triplets incorporating drugs from two different “non-IMiD” classes, if available, as the first salvage regimen in lenalidomide-refractory patients.
Carfilzomib is an epoxyketone that selectively and irreversibly inhibits proteasomes. The ASPIRE trial,1 which compared the efficacy of carfilzomib in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma, failed to show a significant progression-free survival advantage with the addition of carfilzomib. All patients enrolled in the ASPIRE trial had been previously exposed to lenalidomide.
Since the JNCCN 360 Spotlight on Carfilzomib was originally published (see Carfilzomib Spotlight for tips on the clinical use of carfilzomib, including administration and prevention/management of adverse effects), emerging research has indicated that triplet regimens of carfilzomib with dexamethasone and a CD38-directed antibody appear to be an effective treatment option for relapsed or refractory multiple myeloma, including lenalidomide-refractory disease.2-4
EQUULEUS and CANDOR Trials
On August 20, 2020, the U.S. Food and Drug Administration (FDA) approved the use of carfilzomib, daratumumab, and dexamethasone for the treatment of relapsed or refractory multiple myeloma. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma also added daratumumab, carfilzomib, and dexamethasone with category 1 designation under preferred regimens.5 This addition is supported by the encouraging results of two clinical trials: EQUULEUS and CANDOR.6
The EQUULEUS (MMY001) trial is a nonrandomized, multiarm phase b study evaluating the anti-CD38 monoclonal antibody daratumumab in combination with a variety of backbone regimens. One arm of the EQUULEUS trial studied 85 patients with relapsed or refractory multiple myeloma who were not previously exposed to carfilzomib- and daratumumab.3 In this arm, patients received weekly carfilzomib (initial dose of 20 mg/m2 on day 1 cycle 1, increased to 70 mg/m2 on day 8 and 15, cycle 1 onward), dexamethasone, and daratumumab, with the option of first-dose infusion as single (n = 10) or split over 2 days (n = 75). Of note, 95% of the patients were lenalidomide-exposed, and 60% were lenalidomide-refractory. The overall response rate was 84%, and the 18-month progression-free survival rate was 66%.
A subgroup analysis of the EQUULEUS trial revealed comparable results in lenalidomide-refractory patients: the overall response rate was 79%, and the 18-month progression-free survival rate was 56%,3,7 suggesting that the three-drug combination was effective in both the lenalidomide-exposed and lenalidomide-refractory populations.
The results of the phase III CANDOR trial further bolstered those of the EQUULEUS study, although the dose of carfilzomib used in the CANDOR trial was different (20 mg/m2; days 1 and 2 during cycle 1 followed by 56 mg/m2 twice weekly, 3 of 4 weeks).2 A total of 466 patients with relapsed or refractory multiple myeloma were randomly assigned to receive the carfilzomib, dexamethasone, and daratumumab triplet (n = 312) or carfilzomib and dexamethasone (n = 154). The triplet therapy significantly prolonged progression-free survival and reduced the risk of disease progression or death by 37% compared with carfilzomib and dexamethasone. The 18-month progression-free survival rates were 62% in the triplet group and 43% in the carfilzomib/dexamethasone group. Additionally, patients treated with triplet therapy achieved improved overall and deeper responses compared with doublet therapy, with a nearly 10-fold higher minimal residual disease–negative complete response rate at 12 months.
Notably, most patients (90%) in the CANDOR study were previously treated with bortezomib-containing regimens, and more than two-thirds of the cohort was exposed to an IMiD, mirroring the treatment landscape for typical patients with multiple myeloma. Consistent with outcomes in the overall population, the risk of disease progression or death was reduced with triplet therapy compared with doublet therapy across the prespecified subgroups with previous lenalidomide exposure and, perhaps more importantly, among those exhibiting refractoriness to lenalidomide (53% decrease in the risk of disease progression or death). Cardiotoxicity and severe infections were the most common adverse events for which carfilzomib and daratumumab were discontinued, respectively.
Triplet Therapy With Isatuximab-irfc
The IKEMA study evaluated the efficacy of another triplet regimen that included a different CD38-directed antibody, isatuximab-irfc, with carfilzomib (at doses used in the CANDOR study) and dexamethasone until disease progression or unacceptable toxicity in the treatment of relapsed or refractory multiple myeloma.4 The phase III study randomly assigned patients to receive carfilzomib, isatuximab-irfc, and dexamethasone (n = 179) or carfilzomib plus dexamethasone (n = 123). After a median follow-up of 20.7 months, the median progression-free survival was not reached with the triplet therapy versus 19.15 months with carfilzomib plus dexamethasone, with a hazard ratio of 0.531 (one-sided P = .0007).
These interim results indicate that the addition of isatuximab-irfc to carfilzomib and dexamethasone significantly improves progression-free survival and provides a clinically meaningful improvement in the depth of response. On March 31, 2021, based on data from the IKEMA study, the FDA approved carfilzomib, isatuximab-irfc, and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.
Once-Weekly Versus Twice-Weekly Dosing
When carfilzomib was first added to the potential treatment paradigm for multiple myeloma, the inconvenience of the twice-weekly dosing schedule was considered a disadvantage. This changed in October 2018, when the FDA approved once-weekly dosing based on the results of the phase III A.R.R.O.W. trial.8,9
This study directly compared two carfilzomib/dexamethasone doublets in patients with relapsed or refractory multiple myeloma: carfilzomib at 27 mg/m2 intravenously twice weekly versus 70 mg/m2 intravenously once-weekly—a higher cumulative dose despite less frequent administration. The investigators revealed significantly higher median progression-free survival in the once-weekly group compared with the twice-weekly group (11.2 vs 7.6 months, P = .0029).8,9 These findings were confirmed in study subgroups, which looked at factors such as age, renal function, number of prior therapies, and bortezomib-refractory status.10
Dosing schedule was also evaluated in a cross-sectional comparison of the CANDOR and EQUULEUS trials.11 After the first dose of carfilzomib at 20 mg/m2 in both studies, patients in the CANDOR trial received a twice-weekly dose at 56 mg/m2; those in the EQUULEUS trial received a once-weekly dose at 70 mg/m2.2,3 In the comparison of dose strategies, once-weekly dosing of carfilzomib appeared to be as efficacious and safe as the twice-weekly dosing, but the once-weekly dosing offers a more convenient schedule that in turn may improve adherence, potentially leading to better outcomes in the real world setting. The FDA’s approval of carfilzomib, daratumumab, and dexamethasone has included both once-weekly and twice-weekly dosing regimens.
Ongoing Research in Newly Diagnosed Multiple Myeloma
A carfilzomib-containing regimen remains a treatment option (not listed under preferred regimens) for patients with newly diagnosed multiple myeloma.5 The ENDURANCE trial—a phase III trial published in 2020 that included patients with newly diagnosed multiple myeloma who were ineligible for, or did not intend to have, immediate autologous stem cell transplantation—concluded that a regimen of carfilzomib, lenalidomide, and dexamethasone did not improve progression-free survival compared with a bortezomib, lenalidomide, and dexamethasone regimen.12 The carfilzomib triplet regimen also was associated with increased toxicity compared with bortezomib. Therefore, the bortezomib triplet regimen remains the standard of care for induction therapy in patients with standard-risk and translocation (4;14) newly diagnosed multiple myeloma.
- Stewart AK, Rajkumar V, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015;372:142–152.
- Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet 2020;396:186–197.
- Chari A, Martinez-Lopez J, Mateos MV, et al. Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood 2019;134:421–431.
- Moreau P, Dimopoulos MA, Mikhael J et al. Isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA): Interim analysis of a phase 3, randomized, open-label study. 2020 ASH Annual Meeting & Exposition. Abstract 2316.
- Kumar SK, Callander NS, Adekola K, et al. NCCN Clinical Practice Guidelines. Multiple Myeloma. Version 7.2021: Multiple Myeloma. April 26, 2021. Available at https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed April 28, 2021.
- U.S. Food and Drug Administration. FDA approves carfilzomib and daratumumab with dexamethasone for multiple myeloma. August 20, 2020. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-carfilzomib-and-daratumumab-dexamethasone-multiple-myeloma. Accessed April 26, 2021.
- Chari A, Martinez-Lopez J, Mateos MV, et al. Daratumumab in combination with carfilzomib and dexamethasone in lenalidomide-refractory patients with relapsed multiple myeloma: subgroup analysis of MMY1001. 2018 ASCO Annual Meeting. Abstract 8002.
- FDA Approves Once-Weekly Carfilzomib in Combination With Dexamethasone for Relapsed or Refractory Multiple Myeloma. The ASCO Post, October 1, 2018. Available at https://ascopost.com/News/59319. Accessed April 22, 2021.
- Moreau P, Mateos MV, Berenson JR, et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol 2018;19:953–964.
- Dimopoulos MA, Niesvizky R, Weisel K, et al. Once- versus twice-weekly carfilzomib in relapsed and refractory multiple myeloma by select patient characteristics: phase 3 A.R.R.O.W. study subgroup analysis. Blood Cancer J 2020;10:1–13.
- Leleu X, Beksac M, Chou T, et al. Efficacy and safety of weekly carfilzomib (70 mg/m2), dexamethasone, and daratumumab (KdD70) is comparable to twice-weekly KdD56 while being a more convenient dosing option: a cross-study comparison of the CAND and EQUULEUS studies. Leuk Lymph 2021;62:358–367.
- Kumar SK, Jacobus SJ, Cohen AD, et al. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol 2020;21:1317–1330.