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The Carthadex study (#NTR2422), published in Haematologica by Ruth Wester, Erasmus MC Cancer Institute, Rotterdam, NL, and colleagues, investigated the use of carfilzomib, thalidomide and dexamethasone (KTD) in patients with newly diagnosed multiple myeloma (NDMM) who were eligible for transplant. This study used KTD as induction and consolidation in a dose escalation cohort of 111 patients, with results reported at a median follow-up of 58.7 months.1
Achieving a deep response to induction therapy and high-dose melphalan (HDM) with autologous stem cell transplant (ASCT) has been shown to increase progression-free survival (PFS) and overall survival (OS) rates in NDMM. The choice of induction and consolidation therapy is therefore important, with physicians needing to identify a highly effective and safe treatment plan that patients will adhere to.1
Results from the initial cohorts of the Carthadex trial, reported in 2015, demonstrate a very good partial response (VGPR) or better of 89% and a complete response (CR) rate of 63%, after consolidation. The 3-year PFS was 72% and the authors concluded that the KTD combination was well-tolerated, as well as clinically active.2
Subsequently, this dose-escalation study, included the three original carfilzomib doses (27, 36 and 45 mg/m2) but also included a higher dose (56 mg/m2) based on the hypothesis that a higher dose could lead to a better response. No consensus exists on the optimum dose of carfilzomib, this trial sought to answer this question.1
Treatment consisted of four cycles of induction therapy (28-day cycles) followed by HDM/ASCT and four cycles of consolidation therapy.
Table 1 shows the response rates of the total cohort based on the stage of treatment. Table 2 displays the ≥ VGPR rates by carfilzomib dose.
Table 1: Response rates by stage of treatment
ASCT, autologous stem cell transplant; CR, complete response; HDM, high-dose-melphalan; PR, partial response; VGPR, very good partial response | ||||||
Stage of treatment |
≥CR |
n |
≥VGPR |
n |
Overall response (≥PR) |
n |
---|---|---|---|---|---|---|
Post-induction |
18% |
20 |
65% |
72 |
93% |
103 |
Post-HDM/ASCT |
31% |
34 |
77% |
86 |
94% |
104 |
Post-consolidation |
63% |
70 |
86% |
96 |
94% |
104 |
Table 2: ≥ VGPR rates by stage of treatment and dose of carfilzomib
ASCT, autologous stem cell transplant; HDM, high-dose-melphalan | ||||
|
27 mg/m2 (%) |
36 mg/m2 (%) |
45 mg/m2 (%) |
56 mg/m2 (%) |
---|---|---|---|---|
N |
50 |
20 |
21 |
20 |
Post-induction |
27 (54) |
16 (80) |
13 (62) |
16 (80) |
Post-HDM/ASCT |
32 (64) |
17 (85) |
19 (90) |
18 (90) |
Post-consolidation |
40 (80) |
18 (90) |
20 (95) |
18 (90) |
Traditional triplets containing bortezomib are associated with higher rates of polyneuropathy (PN). This study explored the use of carfilzomib, a second generation proteasome inhibitor, as an alternative. In total, 52 patients (47%) experienced PN with 20% being grade 2 or higher. However, these were manageable and not associated with carfilzomib dose. There was one grade 3 event of PN at 27 mg/m2.
In total, 83 patients completed the whole treatment pathway (75%). Nine patients discontinued treatment after induction therapy, six of which were due to AEs. Four did not receive HDM/ASCT. With regards to consolidation therapy, four patients discontinued prior to starting, and a further nine discontinued during consolidation.
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