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In search of the optimal proteosome inhibitor. How, when and for whom?
Monika Engelhardt,1 Sara Bringhen,2 Philippe Moreau,3 Ralph Wäsch1 and Johannes Waldschmidt1
1University of Freiburg, Hematology & Oncology, Faculty of Freiburg, Freiburg, Germany
2Myeloma Unit, Division of Hematology, University of Turino, Azienda Ospedaliero-Universitaria Citta della Salute e della Scienza di Torino, Torino, Italy and 3University Hospital of Nantes, Nantes, France
E-mail: MONIKA ENGELHARDT - monika.engelhardt@uniklinik-freiburg.de doi:10.3324/haematol.2021.278838
Editorials
The article by Yong and colleagues published in this issue of Haematologica presents results from MUKfive, a randomized phase II study in which carfilzomib or bortezomib was used in combination with cyclophosphamide and dexamethasone (KCd vs. VCd, respectively) as second-line treatment in patients with relapsed or refractory multiple myeloma (RRMM).1 The authors utilized a parallel group trial design with a 2:1 ran- domization, fixed duration of therapy and involved 300 patients. In the second part, 141 patients were random- ized 1:1 to carfilzomib maintenance versus observation. Very good partial response or better was observed in 40.2% of patients in the KCd arm and in 31.9% of those treated with VCd. This translated into a median progres- sion-free survival (PFS) of 11.7 versus 10.2 months for KCd and VCd, respectively, with a trend favoring KCd over VCd in patients with high-risk cytogenetics, defined by the presence of del(17p), gain(1q), t(4;14), t(14;16), or t(14;20). Moreover, the PFS in the carfilzomib mainte- nance and observation arms was 11.9 versus 5.6 months, respectively.1
Side-by-side comparisons of bortezomib and carfil- zomib doublets (ENDEAVOR)2 and triplets (CLARION, ENDURANCE)3,4 have been reported. However, a direct comparison of VCd versus KCd is unprecedented, given that both represent important regimens in worldwide practice.5-7 Since daratumumab and immunomodulatory drugs are increasingly being used earlier, proteasome inhibitor-based therapies may also be needed as potent subsequent protocols. Cost efficacy is another concern,8 and VCd and KCd may be particularly advantageous in this regard.5-7
Our UK colleagues should therefore be congratulated on having performed a head-to-head comparison of carfil- zomib versus bortezomib in RRMM patients, given that ENDEAVOR, CLARION and ENDURANCE had seeming- ly generated conflicting results: ENDEAVOR had shown improved response, PFS and overall survival (OS) with carfilzomib and dexamethasone (Kd) versus bortezomib plus dexamethasone (Vd) in patients with RRMM (the dose of carfilzomib in ENDEAVOR was 56 mg/m2 com- pared to 36 mg/m2 in MUKfive, and Vd was reused in some patients),2 whereas in newly diagnosed MM (NDMM), the CLARION trial with carfilzomib, melpha- lan and prednisone (KMP) versus bortezomib, melphalan and prednisone (VMP) and the ENDURANCE trial with carfilzomib, lenalidomide and dexamethasone (KRd) ver- sus bortezomib, lenalidomide and dexamethasone (VRd), showed similar responses, PFS and OS (carfilzomib: 36 mg/m2).3,4 This suggests that the optimal choice of protea- some inhibitor, combination, dose, duration and therapy
tolerance requires more than the latter three studies and cautions us that cross-trial comparisons are deceptive, unless treatment groups are randomly compared in one study.
The MUKfive trial randomized patients to KCd or VCd, since both are effective and economically less challenging than triplets that contain two novel agents. Moreover, although therapy in RRMM is now given until progres- sion, the role of carfilzomib maintenance in RRMM remains fairly unexplored. The results add to our knowl- edge, because both regimens are well-used, i.e., VCd for NDMM and RRMM as a very effective and well-tolerated regimen.5,8 So is KCd – apart from KRd, Kd and the recent- ly introduced carfilzomib-daratumumab-dexamethasone (KDd) regimen.6,7 Unfortunately VCd has not been licensed for NDMM or RRMM; an omission that has often been criticized. Therefore, the MUKfive study is timely and of interest, with a view to answering the questions for which patients, after what prior therapy and with what other backbone agents should carfilzomib or bortezomib be used?
Table 1 summarizes the information regarding selected carfilzomib- and bortezomib-containing doublets, triplets and quadruplets in RRMM/NDMM, and in transplant-eli- gible and –ineligible patients. Although MUKfive failed to show significantly different median PFS and OS between recipients of KCd or VCd, treatment was restricted to 24 weeks, with six 28-day cycles of KCd and eight 21-day cycles of VCd. Carfilzomib doses were 36 mg/m2, where- as in ENDEAVOR, Kd and Vd were given until progression and the doses of carfilzomib were higher (56 mg/m2).2 As a consequence of the 24-week treatment time limit in both the KCd and VCd arms in MUKfive, treatment inten- sity was 36 (6x6) for carfilzomib versus 32 (4x8) for borte- zomib doses (approximately similar), but 18 (3x6) versus 24 (3x8) for the cyclophosphamide-dexamethasone doses (lower in the KCd arm than in the VCd arm). This speaks for the UK trialists in designing equally long relapse sched- ules (6 months) and titrating novel agents to their possibly best efficacy and tolerance (carfilzomib 20/27/36 mg/m2, inducing fewer side effects than 56 or 70 mg/m2),6,7,9 but most likely accounting for their lesser ability to show a superiority of this regimen over VCd.
Another potential hypothesis to explain the time to pro- gression benefit in the CLARION study (KMP: 27.5 versus VMP: 23.5 months), but lack of PFS benefit with a higher percentage of deaths in the carfilzomib group was that KMP was less well tolerated, possibly because of more experience with management strategies for bortezomib- based combinations (Table 1). Moreover, the rate of polyneuropathy in the VMP arm was lower than anticipat-
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