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At the 2020 annual meeting of the American Society of Clinical Oncology (ASCO), Shaji Kumar presented the interim results from the phase III ENDURANCE trial (NCT01863550). This study compared induction with bortezomib, lenalidomide, and dexamethasone (VRd) with carfilzomib, lenalidomide, and dexamethasone (KRd), in newly diagnosed multiple myeloma (MM) patients.1
The current standard of care for patients with newly diagnosed MM is VRd. This triplet was established following the significantly improved overall survival (OS) obtained with VRd when compared with lenalidomide and dexamethasone (Rd) in the phase III trial SWOG S0777 (NCT00644228).2 Since those results, the efficacy of VRd has been demonstrated in multiple settings, including as backbone and post-induction to autologous stem cell transplantation (auto-SCT).3
Carfilzomib has shown great promise in the relapsed MM setting when used in combination with dexamethasone or Rd, leading to increased progression-free survival (PFS) and deeper responses when compared with arms without carfilzomib.3 The KRd arm in the FORTE trial revealed the promising efficacy of this triplet in the front-line setting too, with a complete response rate of 43%, a very good partial response (VGPR) of ≥ 87% and measurable (minimal) residual disease (MRD) negativity of 54%.3
Until the phase III ENDURANCE trial there had been no direct comparison of KRd to VRd in any MM setting. The results of this pivotal study, as presented by Shaji Kumar at ASCO 2020, are summarized below.1, 4
Table 1. Baseline characteristics of patients in the ENDURANCE phase III trial2
ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; KRd, carfilzomib, lenalidomide, dexamethasone; VRd: bortezomib, lenalidomide, dexamethasone |
||
|
VRd (n = 542) |
KRd (n = 545) |
Median age (range), years ≥ 70 years, % ≥ 65 years, % |
64 (32–88) 30.8 48.7 |
65 (32–86) 32.5 52.8 |
Race, % White Black Other |
84.5 13.0 2.5 |
86.3 11.4 2.3 |
ISS Stage, % I II III |
30.6 43.1 26.3 |
32.5 42.9 24.6 |
ECOG PS, % 0 1 2-3 |
39.1 49.8 11.1 |
44.2 45.7 10.1 |
Cytogenetics, % Normal t(11;14) t(4;14)
|
71.8 20.6 10.4 |
72.3 18.7 8.4 |
Table 2. Survival outcomes results from the ENDURANCE phase III trial2
Auto-SCT, autologous stem cell transplantation; HR, hazard ratio; KRd, carfilzomib, lenalidomide, dexamethasone; NE, not estimated; OS, overall survival; PFS, progression-free survival; VRd: bortezomib, lenalidomide, dexamethasone |
|||
|
VRd |
KRd |
HR (95% CI); p value |
Median PFS, (95% CI) |
34.4 months (30.1–NE) |
34.6 months (28.8–37.8) |
1.04 (0.83–1.31); p = 0.742 |
Median PFS for patients ≥ 70 years, (95% CI) |
37.0 months (29.0–NE) |
28.0 months (24–36) |
— |
Median PFS with censoring at auto-SCT or other therapy (95% CI) |
31.7 months (28.5–44.6) |
32.8 months (27.2–37.5) |
— |
3-year OS from randomization to induction, probability (95% CI) |
0.84 (0.80–0.88) |
0.86 (0.82–0.89) |
— |
Table 3. Response rates from the phase III ENDURANCE trial2
Statistically significant p values are indicated by bold font CR, complete response; KRd, carfilzomib, lenalidomide, dexamethasone; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response; VRd: bortezomib, lenalidomide, dexamethasone |
|||
|
VRd (n = 527) |
KRd (n = 526) |
p value |
≥ CR, % |
14.8 |
18.3 |
0.261 |
CR, % |
10.8 |
12.4 |
— |
VGPR, % |
49.9 |
55.5 |
0.002 |
PR, % |
19.5 |
12.9 |
0.132 |
SD, % |
7.6 |
6.5 |
— |
PD, % |
0.2 |
0.0 |
— |
Unevaluable/insufficient, % |
8.0 |
6.8 |
— |
The results of the ENDURANCE phase III trial showed that KRd does not improve the PFS of patients with newly diagnosed MM when compared with the standard of care VRd. OS and secondary endpoints including MRD negativity rates will be published in a later follow-up.
These results were further discussed by Jesus Berdeja, Director of Myeloma Research at the Sarah Cannon Institute.3 Berdeja summarised the results of ENDURANCE and highlighted some additional interesting points regarding the toxicity profiles and costs of KRd versus VRd. The incidence of peripheral neuropathy was higher with VRd, while the incidence of cardiac, pulmonary, and renal treatment-related events was higher with KRd treatment. Thus, he concluded that patient-specific comorbidities and toxicity profiles should lead the choice between the two triplets on an individual basis.
Moreover, he highlighted that since high-risk patients were excluded from ENDURANCE, there are still unanswered questions regarding the efficacy of KRd in high-risk patients (t(14;20), t(14;16), del17p, high serum lactate dehydrogenase), as there is no true standard of care for these patients.
He concluded that ‘‘Both VRd and KRd remain excellent triplets for the front-line therapy of newly diagnosed multiple myeloma. VRd enthusiasts can now stand proud and cite the ENDURANCE trial to support their decision.’’
You can also listen to Shaji Kumar himself discussing these results in our podcast below.
Should we use KRd or VRd for patients with NDMM?
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