Weekly carfilzomib regimen evaluated in transplant-ineligible multiple myeloma

Evidence before this study

When this trial was designed, lenalidomide–dexamethasone was considered a standard of care for the first-line treatment of patients with newly diagnosed multiple myeloma. Although carfilzomib–lenalidomide–dexamethasone is currently a standard regimen for the treatment of patients with relapsed refractory multiple myeloma, its role as a first-line treatment remains controversial. We searched PubMed for articles published from Nov 14, 2009, to Nov 14, 2019, using the search terms “multiple myeloma” AND “newly diagnosed” AND “transplant ineligible” AND “carfilzomib” with no language restrictions. The search identified 12 articles published during this timeframe. Of those, four described clinical trials involving the use of carfilzomib-based combinations, although none included lenalidomide. In the phase 3 CLARION study, patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation were randomly allocated to receive carfilzomib or bortezomib in combination with melphalan and prednisone. Patients treated with the carfilzomib-based combination did not achieve a statistical improvement in terms of progression-free survival, as compared with those treated with the bortezomib-based combination. Furthermore, higher rates of cardiac failure were observed in patients treated with carfilzomib, raising concerns about its use in this patient population. The phase 1 IFM 2012-03 study evaluated weekly carfilzomib in combination with melphalan and prednisone and showed that the maximum tolerated dose of weekly carfilzomib was 70 mg/m in patients with newly diagnosed multiple myeloma (56 mg/m in patients aged 75 years or older), with a favourable efficacy and safety profile. The phase 2 IST-CAR-506 study assessed the safety and efficacy of carfilzomib in combination with cyclophosphamide and dexamethasone, and showed a high complete response rate and a good safety profile. In the phase 1/2 IST-CAR-561 study, weekly carfilzomib was evaluated in combination with cyclophosphamide and dexamethasone, showing efficacy with a manageable safety profile, providing a viable option for patients with newly diagnosed multiple myeloma aged 65 years or older or those who were ineligible for transplantation.

Added value of this study

In the EMN20 trial, we evaluated the role of weekly carfilzomib at the dose of 56 mg/m plus lenalidomide–dexamethasone versus lenalidomide–dexamethasone in patients with newly diagnosed multiple myeloma who were transplantation ineligible. To reduce the risk of cardiovascular events, we implemented a frailty-adapted strategy, enrolling only fit and intermediate-fit patients and performed cardiovascular monitoring of patients. Our findings showed that the addition of weekly carfilzomib to lenalidomide–dexamethasone was both effective and had a manageable safety profile in this population. As compared with lenalidomide–dexamethasone, treatment with carfilzomib–lenalidomide–dexamethasone significantly improved the rates of measurable residual disease (MRD) negativity and progression-free survival, with predictable and manageable toxicities.

Implication of all the available evidence

Although only a third of the target sample size of patients has been enrolled, limiting the power of the study, to our knowledge, this is the first randomised phase 3 trial in which a regimen containing weekly carfilzomib showed a significant improvement in terms of both MRD negativity and progression-free survival in fit or intermediate-fit patients with newly diagnosed multiple myeloma who were transplantation ineligible. The generally manageable toxicity profile observed in our study can be attributed to several factors: the exclusion of frail patients, the dosing schedule of weekly carfilzomib, the precise monitoring for early signs of cardiac dysfunction, and the MRD-guided discontinuation of carfilzomib. These findings support the use of carfilzomib–lenalidomide–dexamethasone (with weekly carfilzomib at 56 mg/m) as a potential backbone treatment regimen for this patient population. The addition of monoclonal antibodies to this regimen might become an appealing option in future trials.

Source: The Lancet Haematology