Page 176 - 2021_10-Haematologica-web

K.L. Yong et al.
and neutropenia. Notably, the carfilzomib dose of 36 mg/m2 in the current study was associated with a relative- ly low incidence of cardiovascular adverse events (3.6%) and grade ≥3 hypertension (3.6%) when compared with the higher dose of 56 mg/m2 in the ENDEAVOR trial (6.5% and 9.0%, respectively).4,9 Relatively high rates of infectious serious adverse events in both arms indicate that antibiotic prophylaxis may be considered for relapsed patients treated with proteasome inhibitor triplets, at least for the first few cycles.
The broadly equivalent outcomes of carfilzomib and bortezomib when used in fixed duration protocols, as demonstrated in this study, are in line with the results of the CLARION and ENDURANCE studies, indicating that the PFS and OS benefits seen with carfilzomib in ENDEAVOR were related to the greater tolerability of this proteasome inhibitor, facilitating extended therapy. Another contributing factor to the differing results between our study and ENDEAVOR may be the smaller percentage of our cohort who were exposed to borte- zomib and who were, thus, less likely to be resistant. Here we extend our observations to show that maintenance with single-agent carfilzomib is effective in prolonging PFS. Taken as a whole, our observations and the results of previous studies suggest that optimal clinical benefit from carfilzomib can be achieved using well-tolerated extended protocols. This notion is further supported by the more recent studies of carfilzomib in combination with the CD38 antibodies, daratumumab and isatuximab, in which outcomes of patients treated at first relapse may indeed be impressive.6,22 With increasing use of carfilzomib leading to improved management of the drug’s toxicity profile, and considering promising results with weekly dosing,23 durable disease control may be achievable with this pro- teasome inhibitor, especially in the setting of relapsed dis- ease.
Certain features of our cohort of patients may have influenced the comparative tolerability of KCd and VCd. Even with a fixed duration of treatment of 6 months, there were fewer discontinuations with KCd than with VCd, and a substantial proportion of patients in the VCd arm discontinued due to their own choice or a clinician’s deci- sion. While we do not have details of these decisions, it is noteworthy that over half of patients in this study had previously received a thalidomide regimen, hence several may have been especially sensitive to or intolerant of a sal- vage regimen containing yet another neurotoxic drug, thus accounting for the high rates of discontinuation in the VCd arm.
We demonstrate that carfilzomib maintenance is effica- cious regardless of genetic risk, and in renally impaired and older patients. Our findings on the activity and toler- ability of carfilzomib maintenance in the RRMM setting add to those from two phase I/II studies in newly diag- nosed patients ≥65 years old, or ineligible for transplanta- tion, who received single-agent carfilzomib maintenance (until progression) after nine cycles of KCd.12,13 In those studies, responses deepened during the maintenance phase, and the 3-year OS rate of around 70% in the two trials indicates that extended treatment with carfilzomib can produce promising results when used early in the treatment pathway. In our study in RRMM patients, carfil- zomib maintenance was well tolerated, and the incidence and severity of known toxicities were similar to those in previous studies. Maintenance was associated with a
higher rate of MRD negativity at 6, but not at 12 months, perhaps linked to the reduction from four to two doses per cycle of carfilzomib. Thus, patients in MUKfive trial who received KCd followed by carfilzomib maintenance had a combined median PFS of 18.1 months, which was slightly shorter than the median of 22.2 months for patients treat- ed at second line in ENDEAVOR. In the A.R.R.O.W. study,24 a dose of 70 mg/m2 was administered weekly until progression to patients treated at third line, with the medi- an treatment duration being 38 weeks (range, 0.1-84.1), suggesting that it may be possible to deliver a weekly maintenance schedule for an extended period.
Our results indicate potentially superior activity of KCd over VCd, in terms of ≥VGPR rate in patients with adverse genetic risk, and ORR in those relapsing early (<12 months) from first-line therapy. The superior major response rate for participants with adverse risk in the KCd arm cannot be explained by higher discontinuation rates in the VCd arm, as the major response rates were similar in the two arms for standard-risk patients among whom the difference in discontinuation rates was more pro- nounced (56.7% for VCd compared to 7.3% for KCd). We also observed that patients with del(17p) and adverse IgH translocations may have benefited especially from KCd in terms of VGPR (Online Supplementary Figure S4B). Despite a higher VGPR rate in adverse-risk patients in the carfil- zomib arm, we did not observe a difference in MRD-neg- ative response, nor a PFS benefit. This is likely because the short duration of triplet therapy (6 cycles), and limited carfilzomib maintenance may be insufficient for optimal disease response in these relapsed patients. We note with interest that the KCd regimen, when used in newly diag- nosed patients ineligible for ASCT, followed by carfil- zomib maintenance until progression, was recently reported to overcome the inferior prognosis of high-risk patients. However, these frontline studies used nine cycles of KCd followed by carfilzomib maintenance with four doses per cycle until progression, altogether a more inten- sive regimen than in the MUKfive study.25 There is, there- fore, increasing evidence that carfilzomib has good activi- ty in adverse-risk disease, although regimen intensity may be vital. In this context, it is interesting to consider the recent ENDURANCE study,11 in which carfilzomib was compared with bortezomib in NDMM patients when given in combination with lenalidomide and dexametha- sone. In this trial, high-risk patients, apart from those with t(4;14), were excluded.
One attraction of the KCd regimen is its relatively mod- est cost, hence its use in studies for RRMM and NDMM patients. In the Nordic CARFI phase II study, patients were treated at first relapse with four cycles of KCd fol- lowed by ASCT conditioned with high-dose melphalan plus two doses of carfilzomib.26 KCd has been used to treat non-transplant-eligible, newly diagnosed patients, with the carfilzomib given bi-weekly or weekly,12,27 for up to nine cycles of induction, followed by carfilzomib main- tenance. The regimen was reported to have been tolerated well in the older patient group, as we also found.
In summary, the results from the MUKfive study demonstrate the non-inferiority of carfilzomib over borte- zomib in combination with cyclophosphamide and dex- amethasone in the early relapse setting, and the efficacy of carfilzomib maintenance. Our data are also consistent with the high activity of carfilzomib in adverse-risk disease, both in terms of a higher VGPR rate, when compared with
2704
haematologica | 2021; 106(10)