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Editorials
for a better outcome with KCd than with VCd.1
All the trials reported in Table 1 have therefore con- tributed to teaching us how current treatment practice may need to evolve: The results of MUKfive suggest that six 28-day KCd cycles versus eight 21-day VCd cycles in second-line treatment with carfilzomib doses of 20/36 mg/m2 induce comparable survival rates and that addi- tion of carfilzomib is particularly advantageous in high- risk MM patients, those who have received prior borte- zomib treatment, those who are refractory to or intoler- ant of bortezomib and when MM physicians have expe- rience with carfilzomib.1,6,7 ENDEAVOR and other trials with even higher carfilzomib doses, given at 70 mg/m2 weekly rather than biweekly, demonstrate that the effi- cacy of carfilzomib is dose-dependent, but that the inci- dence of cardiac events must be kept low.2,6,7,9,10 The role of continuous versus fixed-duration therapy is also important, explaining differences in outcome among dif- ferent trials. Since continuous treatment may affect qual- ity of life, MUKfive’s fixed duration rather than continu- ous treatment was probably designed with this in mind, but might have been planned differently today in the
light of other experiences (Table 1).
Current carfilzomib studies in transplant-eligible
NDMM patients, such as Forte (NCT02203643) and Myeloma XI+ (ISRCTN49407852), show impressive minimal residual disease negativity rates with KRd-aut- logous stem cell transplantation (ASCT) versus KRd12 versus KCd-ASCT (62%, 56% and 43%, respectively).11 The phase III Myeloma XI+ trial is assessing KRd with cyclophosphamide (KRdc) as compared to Rdc/Tdc (lenalidomide-dexamethasone-cyclophosphamide/ thalidomide-dexamethasone-cyclophosphamide) in 1,056 transplant-eligible NDMM patients with impres- sive rates of very good partial response or better of 82% and 59%, respectively.10 Whether this will translate into better survival and excellent therapy endurance remains to be seen. The future of MM therapies seems bright and exciting, further advances are still to come and the UK study group continues to contribute to this. While longer follow-up for these studies is awaited, the results from the MUKfive trial represent an important milestone in improving our understanding and expanding the clinical use of proteasome inhibitors for the treatment of MM.
Disclosures
No conflicts of interest to disclose.
Contributions
ME wrote the editorial, SB, PM, RW and JW provided dis- cussion, input and recommendations both on the MUKfive paper and this editorial, and also generated thoughts on future studies that should evolve, plus those that are displayed in Table 1 as a review of the literature.
References
1. Yong K, Hinsley S, Auner HW, et al. Carfilzomib or bortezomib in combination with cyclophosphamide and dexamethasone fol- lowed by carfilzomib maintenance for patients with multiple myeloma after one prior therapy: results from a multicenter, phase II, randomized, controlled trial (MUKfive). Haematologica. 2021;106(10):2694-2706.
2. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(10):1327-1337.
3. Facon T, Lee JH, Moreau P, et al. Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood. 2019;133(18):1953-1963.
4. 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(10):1317-1330.
5. Einsele H, Engelhardt M, Tapprich C, et al. Phase II study of borte- zomib, cyclophosphamide and dexamethasone as induction thera- py in multiple myeloma: DSMM XI trial. Br J Haematol. 2017;179(4):586-597.
6. Bringhen S, D’Agostino M, De Paoli L, et al. Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma. Leukemia. 2018;32(4): 979-985.
7.Mina R, Bonello F, Petrucci MT, et al. Carfilzomib, cyclophos- phamide and dexamethasone for newly diagnosed, high-risk myeloma patients not eligible for transplant: a pooled analysis of two studies. Haematologica. 2021;106(4):1079-1085.
8. Kumar SK, Ma E, Engebretson AE, et al. Treatment outcomes, health-care resource utilization and costs of bortezomib and dex- amethasone, with cyclophosphamide or lenalidomide, in newly diagnosed multiple myeloma. Leukemia. 2016;30(4):995-998.
9.Moreau P, Stewart KA, Dimopoulos M, et al. Once-weekly (70 mg/m2) vs twice-weekly (56 mg/m2) dosing of carfilzomib in patients with relapsed or refractory multiple myeloma: a post hoc analysis of the ENDEAVOR, A.R.R.O.W., and CHAMPION-1 trials. Cancer Med. 2020;9(9):2989-2996.
10.Jackson GH, Pawlyn C, Cairns DA, et al. Carfilzomib, lenalido- mide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label ran- domised controlled trial. PLoS Med. 2021;18(1):e1003454.
11. Gay F, Musto P, Rota Scalabrini D, et al. Survival analysis of newly diagnosed transplant-eligible multiple myeloma patients in the ran- domized Forte trial. Blood. 2020;136(Suppl 1):35-37.
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