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Carfilzomib (K) in combination with lenalidomide (R) and dexamethasone (d; KRd) has shown very promising efficacy both in the relapsed multiple myeloma (MM) and newly diagnosed MM (NDMM) setting.1
To date, the standard of care for the treatment of patients with NDMM is bortezomib in combination with R and d (VRd).1 This was further supported by the initial results of the phase III ENDURANCE trial (NCT01863550), which was the first head-to-head comparison between VRd and KRd for the NDMM setting.2 The results of this pivotal study were recently presented by Shaji Kumar at the 2020 American Society of Clinical Oncology (ASCO) meeting and are summarized at the Multiple Myeloma Hub, here. Briefly, KRd did not seem to improve progression-free survival (PFS) over the standard of care VRd in patients with NDMM. Overall survival (OS) and secondary endpoints, including measurable residual disease (MRD) negativity rates, are yet to be published.2 Interestingly, the two triplets have distinct toxicity profiles with the incidence of peripheral neuropathy being higher with VRd, while cardiopulmonary and renal events being mostly associated with KRd.3
Recently, the results of a phase II trial (NCT01816971) that investigated the addition of autologous stem cell transplantation (auto-SCT) to KRd for NDMM, has shed more light into the activity of the triplet in this setting. The study was published in Blood by Jagoda Jasielec et al. and is summarized below. Fundamental differences between the study design of this trial and the ENDURANCE trial are discussed below in the ‘Conclusion’ section.
Multicenter, open-label, single-arm, phase II trial for NDMM transplant-eligible patients aged ≥ 18.
Table 1. Patient baseline characteristics1
ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; ISS, International Staging System; ITT, intention-to-treat. *Defined according to the International Myeloma Working Group (IMWG) criteria: t(4;14), del(17p), t(14;16), t(14;20), non-hyperdiploidy and 1q gain. |
|
Baseline characteristic |
ITT population (N = 76) |
Age |
|
Median age (range), years |
59 (40–76) |
≥ 65 years, n (%) |
21 (27.6) |
ECOG PS, n (%) |
|
0–1 |
65 (85.5) |
Unknown |
11 (14.5) |
ISS stage, n (%) |
|
I |
31 (40.8) |
II |
31 (40.8) |
III |
10 (13.2) |
Unknown |
4 (5.3) |
Cytogenetic risk by FISH*, n (%) |
|
High |
27 (35.5) |
Del(17p) |
11 (14.5) |
Ultra-high (≥ 3 abnormalities) |
8 (10.5) |
Standard |
49 (64.5) |
Table 2. Efficacy outcomes with KRd plus auto-SCT for NDMM1
Auto-SCT, autologous stem cell transplantation; CR, complete response; ITT, intention-to-treat population; KRd, carfilzomib, lenalidomide, dexamethasone; mITT, modified ITT; MRD, minimal (measurable) residual disease; neg, negative; sCR, stringent CR; VGPR, very good partial response. |
||||
Responses, % |
After auto-SCT (n = 76) |
After 8 KRd cycles (n = 72) |
After 18 cycles (n = 76) |
Best response after KRd + auto-SCT (ITT; n = 76) |
MRD neg < 10-5 (in mITT) |
— |
52 |
61 |
70 |
sCR |
20 |
60 |
74 |
76 |
≥ CR |
25 |
65 |
75 |
79 |
≥ VGPR |
84 |
90 |
84 |
91 |
Table 3. 5-year survival rates1
ITT, intention-to-treat; MRD, minimal (measurable) residual disease; neg, negative; PFS, progression-free survival; OS, overall survival. |
||
Population |
5-year PFS, % |
5-year OS, % |
ITT population |
72% (95% CI, 60–81) |
84% (95% CI, 71–92) |
MRD neg at < 10-5 |
85% (95% CI, 69–93) |
91% (95% CI, 75–97) |
Standard-risk patients |
81% |
92% |
High-risk patients |
57% |
72% |
The current Editorial Theme of the Multiple Myeloma Hub is focusing on how to identify and treat patients with high-risk MM. Read more information, here.
Table 4. Safety profile of KRd plus auto-SCT in NDMM1
AEs, adverse events; Auto-SCT, autologous stem cell transplantation; KRd, carfilzomib, lenalidomide, dexamethasone; R, lenalidomide. *AEs during auto-SCT and single-agent R maintenance were not evaluated; †Two patients had asymptomatic ejection fraction of 45–50% prior to auto-SCT, and one had a transient ejection fraction decrease to 47%, which was linked to hypertension during KRd maintenance. |
||
KRd + auto-SCT AEs* |
All grade AEs (> 10%; N = 76) |
Grade 3–4 AEs (N = 76) |
Hematological, n (%) |
|
|
Thrombocytopenia |
47 (62) |
11 (14) |
Anemia |
32 (42) |
9 (12) |
Lymphopenia |
32 (42) |
24 (32) |
Neutropenia |
30 (39) |
26 (34) |
Non-hematological, n (%) |
|
|
Infection |
56 (74) |
17 (22) |
Fatigue |
51 (67) |
4 (5) |
Diarrhea |
39 (51) |
7 (9) |
Hyperglycemia |
33 (43) |
6 (8) |
Dyspnea |
30 (39) |
2 (3) |
Rash |
33 (43) |
4 (5) |
Hypophosphatemia |
22 (29) |
11 (14) |
Hypertension |
15 (20) |
4 (5) |
Thromboembolic events |
14 (18) |
5 (7) |
Cardiac events† |
10 (13) |
2 (3) |
The results of this phase II trial indicate that KRd plus auto-SCT lead to a high rate and durable responses, which are further improved following extended KRd maintenance. The reported MRD negativity at < 10-5 rates were also very high (70% in the modified ITT population), and when specifically evaluating high-risk cytogenetic patients.
According to the data, the initial rapid response to KRd required extended treatment with KRd in order to achieve the best responses. These results seem to contradict the phase II FORTE trial, which reported that the addition of auto-SCT to eight cycles of KRd did not alter outcomes for patients with NDMM. Nevertheless, a recent subanalysis of the FORTE trial showed that there is a lower risk for early relapse and a higher rate of sustained MRD with KRd plus auto-SCT, when compared to KRd alone.1
When comparing the study design of the ENDURANCE trial to this phase II study,2 the patient population used in ENDURANCE was mainly of standard cytogenetic risk, mostly transplant ineligible, and KRd was administered for fewer cycles (nine). Thus, the authors stipulate that their results indicate that KRd plus auto-SCT offers a very promising regimen for high-risk NDMM patients, and that there is a need for extended treatment with KRd to achieve more profound and durable responses.
Further prospective trials on specific NDMM subpopulations are needed to further validate these results and clarify the precise role of KRd in the management of NDMM.
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