Is Carfilzomib an Appropriate Treatment Option for Patients With Newly Diagnosed Multiple Myeloma?

Treatment regimens for patients with relapsed/refractory multiple myeloma (RRMM) are well established. Over the past 10 years, understanding of the diagnosis and treatment of this cancer of plasma cells, as well as the adverse effects from its treatment, have greatly expanded. Novel agents in the treatment armamentarium for MM now include immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and deacetylase inhibitors, all of which have produced marked improvements in progression-free survival (PFS) and overall survival (OS) for patients. In addition, clinical trials are ongoing in selinexor, venetoclax, iberdomide, and new immunotherapeutics, such as bispecific T-cell engager molecules and chimeric antigen receptor T cells.

Many patients who have MM are older in age, and likely frail with comorbidities, but there are also patients who are fit. Therefore, in order to ensure an ongoing disease response, physicians should consider testing treatment regimens to determine which treatments to give patients, and when. This is all in the name of improving quality of life and reducing MM-induced comorbidity and treatment toxicity, primarily cardiovascular adverse events.

As a second-in-class proteasome inhibitor, carfilzomib (Kyprolis) with dexamethasone or with lenalidomide (Revlimid) and dexamethasone is approved to treat RRMM, thanks to the ENDEAVOR and ASPIRE studies, respectively. Now, triplet and quadruplet therapies with carfilzomib are in clinical trials in the setting of patients with newly diagnosed MM (NDMM).

The updated Carthadex trial data, published recently in Haematologica, aim to confirm the utility of carfilzomib in combination with thalidomide and dexamethasone, and the results are encouraging for use in patients with NDMM. The average patient age was 58 years (range, 29-66), and all were transplant eligible. The dose-escalation study combined carfilzomib doses of 20/27, 20/36, 20/45, and 20/56 mg/m² twice weekly with 200-mg daily thalidomide and 40-mg weekly dexamethasone. There were 4 induction cycles prior to autologous stem cell transplantation (ASCT).

The overall response rate was 93%, and PFS and OS were 58 and 83 months, respectively, at the extended median follow-up of 58.7 months. (The initial follow-up was at the 36-month mark, which showed a 72% PFS and 86% overall response rate. No OS data were available at the time.)

According to the authors, “Since this was an updated study report, with a last cohort of further escalated [carfilzomib], a specific aim of the study had been to compare tolerability and efficacy between the various [carfilzomib] doses.”

Efficacy in regard to complete remission did not improve with doses above 20/36 mg/m². However, in addition to the improved PFS and OS, another positive outcome is the lack of increased rates of cardiovascular adverse events with the dose escalation method. In fact, the adverse event rates were low, at 12% for all grades and just 5% that were at least grade 3.

Several other studies, which Carthadex builds on, provide ample evidence for the use of carfilzomib in patients with NDMM, with similar results. CYKLONE tested a quadruplet regimen of carfilzomib, cyclophosphamide, thalidomide, and dexamethasone. The 2-year PFS and OS were 76% and 96%, respectively. The Myeloma XI trial studied carfilzomib, cyclophosphamide, lenalidomide, and dexamethasone. There was a very good partial response rate of at least 82.3% and a 36-month PFS rate of 64.5%. FORTE is testing carfilzomib with lenalidomide or cyclophosphamide, with or without ASCT. There are 3 trial arms, and their results show 89%, 87%, and 76% very good partial response rates.

At present, although it has proven its merit (efficacy and tolerability) and the evidence is promising, carfilzomib is still not approved for use in patients with NDMM because more research, especially real-world evidence, is needed. The study authors concluded, “The findings from ongoing phase II and multiple phase III studies will help to determine optimum dosing regimens; to establish the position of [carfilzomib] in relapse, first-line, and subsequent therapies; and for consolidation and maintenance approaches.”

Reference

Engelhardt M, Yong K, Bringhen S, Wäsch R. Carfilzomib combination treatment as first-line therapy in multiple myeloma: where do we go from the Carthadex (KTd)-trial update? Haematologica. 2019;104(11):2128-2131. doi: 10.3324/haematol.2019.228684.