Page 12 - 2021_10-Haematologica-web

Editorials
Table 1. Selected carfilzomib- and bortezomib-containing phase I-III clinical trials in relapsed and newly diagnosed multiple myeloma.
Study 1stauthor N of pts Treatment Median ORR Median PFS Median OS Notable findings
name (Ref) arms age (range)
Relapsed or refractory multiple myeloma
MUKfive YongKL 300 KCd:VCd; 68(32-85) 84%: 11.7:10.2m 30.9:28.1m NP≥3or≥2wpain:
Endeavor
Endeavor, Arrow, Champion-1
(1)
Dimopoulos MA
(2)
Moreau P (9)
(201:99) + 141 (69:72)
929 (464:465)
363 (217:146)
K : No maint. in 2.LT
Kd : Vd
Kd56 (BIW) : Kd70 (QW)
65 (30-89)
68.1%
77% : 63%
(HR 0.95; 80%CI: 0.77- 1.18)
18.7 : 9.4 m (HR 0.53 (0.44-0.65)
14.5 : 12.1 m
22.3 : 22.1 m (HR 0.906; 0.746-1.101)
(HR 1.1; 90%CI: 0.68-1.8)
47.6 : 40 m (HR 0.791 (0.648-0.964)
=
= ; n.r. (HR 1.08 0.82-1.43)
1.5% vs. 19.8%
≥3 cardiac events + hypertention: only
w KCd (3.6% each) K-maintenance: median longer PFS 11.9 vs. 5.6 m
NP: Vd > Kd, cardiac events: Kd>Vd more grade 3 AE: Kd>Vd, discontinuation + related deaths: =
≥G3 AEs 85.3%:67.6%
CR: 25.9 : 23.1%
MRD negativity: 15.7%:15.5% Acute RF: 13.9 : 6.2%,
CF: 10.8% : 4.3%, ≥G2 PNP 2.5% : 35.1%
Mean: 64:65 72.4 : 69.9%
Newly diagnosed multiple myeloma; non-transplant eligible
Clarion
Endurance wKCd
KCd QW:BIW
Facon T 955: (478:477) (3)
KMP : VMP
72 (42-91)
65 (57-71) 72 (69-74) 72 (68-75)
54 (32-67) <65y
61 (33-75)
84.3% : 78.8% (OR: 1.412; 1.01-1.973)
Kumar SK 1087 (545:542) (4)
(HR 1.04 (0.83-1.31) 2y PFS: 53.2%
Median
PFS SR/HR: nr/27.8m 3y PFS: 52/43%
Median PFS 35.3 m
Median PFS KRd_ASCT: nr, KRD12 57m, KCd_ASCT: 53 m
Median PFS:
nr : 36.2 m (HR 0.63 (0.51-0.76)
treatment-related death:2:<1%
≥G3 tox.: neutropenia (22%), cardiopulmonary (9%)
Hematological and CF
Well tolerable, outpt.treatment
Benefit KR vs.
R maint., MRD>
w KRd vs. KCd, known AEs
Most common
AE: hematologic +
low incidence of cardiac events
KRd : VRd Weekly KCd 45,56,70
9x KCd (70mg/m2 QW + 36mg/m2 BIW)
87%:84% 34.6:34.4m n.r. ≥G3PNP<1%:8%;
Bringhen S (6)
Mina R (7)
63 94
85%
88% (SR/HR: 86/92%)
post VCD: 85.4%, post Tx: 95.5%
MRD before maint:62:56:43%
>VGPR KRdc :82.3% Rdc/Tdc: 58.9%
2y OS: 81%
Median OS: nr 3y OS: 78/73%
Median OS: nr
3y OS: 90% w KRd_ASCT+KRd12 : 83%
n.r.
Newly diagnosed multiple myeloma; transplant-eligible
DSMM XI Forte
Einsele H (5)
Gay F (11)
414 474
1056
VCd + Tx
KRd+Tx:KRd12: KCd+Tx
KRdcvs.Rdc/Tdc
MyelomaXI+ JacksonGH (10)
Ref: reference; ORR: overall response rate; PFS: progression-free survival; OS: overall survival; KCd: carfilzomib, cyclophsophamide, dexamethasone;VCd: bortezomib, cyclophosphamide, dex- amethasone; K: carfilzomib; maint.: maintenance; 2.LT: second-line treatment; HR: hazard ratio; CI: confidence interval; m: months; NP: neuropathy; NP: neuropathy; w: with; QW: once per week; BIW: biweekly treatment; Kd: carfilzomib-dexamethasone, Vd: bortezomib-dexamethasone, AE: adverse event; KMP: carfilzomib-melphalan, prednisone, VMP: bortezomib-melphalan, pred- nisone; OR: odds ratio; MRD: minimal residual disease; RF: renal failure; CF: cardiac failure; G: grade; PNP: polyneuropathy; KRd: carfilzomib, lenalidomide, dexamethasone,VRd: bortezomib, lenalidomide,dexamethasone,SR/HR:standard-risk/high-risk;Tx:transplantation;ASCT:autologous stem cell transplantation;KR:carfilzomib,lenalomide;R maint:lenalidomide maintenance; VGPR: very good partial response; KRdc: carfilzomib-lenalidomide, dexamethasone, cyclophsophamide; Rdc/Tdc: lenalidomide-dexamethasone-cyclophosphamide/thalidomide-dexametha- sone-cyclophosphamide.
ed, supporting proposed bortezomib-dose reductions. In line, dose intensity was lower in the bortezomib group than in the carfilzomib group, which suggests that physicians were more familiar with dose modifications for bortezomib than for carfilzomib. Due to the higher toxicity of KMP versus VMP, melphalan was possibly also a less ideal drug to combine with carfilzomib, a notion similarly discussed by supporters of cyclophos- phamide instead of melphalan.3
The ENDURANCE study with 12 cycles of VRd at 3- week intervals versus nine cycles of KRd (36 mg/m2) at 4- week intervals4 was – with equally designed treatment duration and carfilzomib doses – in line with that of MUKfive, albeit in NDMM versus RRMM patients and
for much longer versus shorter triplet-exposure, respec- tively (Table 1). Exclusion criteria for ENDURANCE were high-risk MM patients,4 postulated to profit better from antibody-based quadruplets. Although the rate of very good partial response or better in ENDURANCE was significantly higher with KRd than with VRd, this did not translate into better 3-year PFS and OS. The absence of improvement was considered to reflect the impact of treatment-related toxicity of KRd, which led to treatment delays and dose modifications, compromis- ing the overall efficacy. The ENDURANCE trialists dis- cussed whether carfilzomib had a better efficacy in high- risk MM,4 a notion that the MUKfive study addressed, including 54.5% high-risk patients and observing a trend
2540
haematologica | 2021; 106(10)