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(n=20 patients), given twice weekly combined with daily thalidomide [200 mg day (d) 1-28] and weekly dexam- ethasone for four KTd induction cycles before autologous stem cell transplantation (ASCT) was performed. These promptly induced responses allowed peripheral blood stem cell (PBSC) mobilization in 92%, and were followed by ASCT in 88% and Cfz-consolidation in 85% of patients. Since this was an updated study report,20 with a last cohort of further escalated Cfz (20/56), a specific aim of the study had been to compare tolerability and efficacy between the various Cfz doses. This objective is clinically highly relevant; however, the small patient numbers allowed only preliminary observations to be made on this. Nevertheless, increasing Cfz doses beyond 20/36 did not seem to improve efficacy in terms of CR rates. Of note, CVAE did not seem to increase with Cfz dose esca- lation and were generally low (12% all grade, 5% grade ≥3), while infection rates, particularly pneumonia, did. The authors comment that their previous experience with this regimen likely contributed to the low incidence of SAE.19
With the usual caveats of conducting cross-trial com- parisons, Table 1 summarizes selected Cfz-combination trials in NDMM, with the Carthadex results shown first.19
As compared to the Carthadex-trial with KTd, the Cyklone trial21 investigated Cfz in quadruplet-combina- tion in 64 transplant-eligible NDMM patients and was similar in its treatment combination: patients were treat- ed with Cfz (d1, 2, 8, 9, 15, and 16), 300 mg/m2 cyclophosphamide (d1, 8, and 15 ), 100 mg thalidomide (d1-28), and 40 mg dexamethasone (d1, 8, 15, and 22) in 28-day cycles. Cfz was dose-escalated at four dose levels to determine the maximum tolerated dose (MTD), which was 20/36 mg/m2. OS was similar as that reported by Wester et al. and Sonneveld et al.,19,20 as were the 2-year PFS (76%) and OS (96%) (Table 1). Similar to the Carthadex trial, the Cyklone-quadruplet led to rapid and deep responses with limited PNP, cardiac or pulmonary toxicity.21 Although due to PNP risks thalidomide is less used in Europe, and particularly in the US, than lenalido- mide or pomalidomide, both Carthadex and Cyklone results illustrate the safety and efficacy of combining novel PI with IMiD, steroids and cyclophosphamide to a quadruplet. The UK Myeloma XI+ study evaluated a sim- ilar quadruplet, but with lenalidomide instead of thalido- mide, KCRd (Cfz 20/36) as induction prior to ASCT, fol- lowed by randomization to lenalidomide maintenance or no further treatment.22 This quadruplet was well tolerat- ed, and response rates and PFS rates were remarkably similar to those in the Carthadex study (Table 1).22
In transplant-eligible patients, the combination of Cfz with lenalidomide (KRd) or cyclophosphamide (KCD), with or without ASCT (KRd-ASCT-KRd vs. KRd12 vs. KCd-ASCT-KCd), is also being assessed in the Forte trial:23 the three Forte trial arms show high and deep very good partial response (VGPR) rates of 89%, 87% and 76%, respectively, with so far well manageable SAE sig- nals, especially low grade 3/4 cardiac AE, thrombosis or discontinuation rates (Table 1).
In transplant-ineligible patients, Moreau et al. showed tolerability and efficacy of Cfz-melphalan-prednisone (KMP) in a phase I/II trial.24 MTD of Cfz was 36 mg/m2,
the combination of KMP was feasible and ORR, PFS and 3-year OS were remarkable with 90%, 21 months, and 80%, respectively. This led to the randomized Clarion study of KMP versus VMP for nine 6-week cycles, the results of which showed that both regimens resulted in similar PFS and response rates, while PNP rates were higher with VMP, and acute renal failure and cardiac fail- ure were higher with KMP (Table 1).25 The reason for the lack of superior results with KMP may be the high level of experience of physicians managing VMP-treatment, the lower tolerability of KMP than VMP in elderly patients, and the much lower than anticipated PNP rate of VMP, so that the study endurance in both groups were similar.
Since cyclophosphamide is better tolerated than mel- phalan and a useful backbone for numerous MM proto- cols, Bringhen et al. assessed the safety and efficacy of Cfz in combination with cyclophosphamide and dexametha- sone (KCd) in NDMM patients ≥65 years, ineligible for ASCT, both in twice- and once-weekly schedules.26–28 In the twice-weekly Cfz-study, 58 patients were enrolled and received KCd for up to nine cycles, followed by maintenance with Cfz until progression or intolerance. Patients received oral cyclophosphamide 300 mg/m2 and dexamethasone 40 mg on d1, 8 and 15; Cfz (20/36) was administered as 30-minute infusions on d1, 2, 8, 9, 15, and 16. In the maintenance phase, patients were treated with 36 mg/m2 Cfz on d1, 2, 15, and 16 every 28 days. After a median of nine cycles of KCd, 71% of patients achieved ≥ VGPR and the 2-year PFS and OS after a medi- an follow up of 18 months were 76% and 87%, respec- tively. The rate of ≥ grade 3 AE was low, and the most common toxicities were neutropenia (20%), anemia (11%), and cardiopulmonary events (7%).26
The once-weekly KCd-combination escalated Cfz ini- tially from 45 to 56 and 70 mg/m2. Patients were treated with Cfz on d1, 8 and 15 of a 28-day cycle. A total of 63 patients were enrolled in the phase I and II of the study; 54 of them received recommended phase II dose 70 mg/m2. At least VGPR was achieved in 36 (66%). The fre- quency of hematologic and non-hematologic AE was similar or lower than that reported in previous studies with twice weekly Cfz.26–28
Several triplet and quadruplet schedules of KRd, KCD, e.g. with both elotuzumab and daratumumab antibodies, are being assessed in phase II/III clinical trials (e.g. the Deutsche Studiengruppe Multiples Myelom, the German- Speaking Multiple Myeloma Group, and others). The results of these studies are eagerly awaited, and prelimi- nary safety and efficacy results have been highly promis- ing.
The Carthadex trial investigating KTd in transplant-eli- gible NDMM is also of interest in the light of the Cassiopeia (VTd-Dara) transplant-eligible NDMM study that was presented at the recent 2019 ASCO and EHA meetings.29 Although Cassiopeia is a randomized phase III trial and Carthadex was not, the responses in both are impressive and remarkably similar. In Carthadex, the sCR after induction and consolidation therapy for the triplet was 30%; in Cassiopeia the sCR for the experimental arm (VTd-Dara: quadruplet) was 28.9% after induction and consolidation. While such comparisons should be made
haematologica | 2019; 104(11)