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How to sequence BCMA-directed therapies in early relapsed/ refractory multiple myeloma
At the ESH 7th Translational Research Conference:
Multiple Myeloma
with Martin Kaiser, Mohamad Mohty, and Rakesh Popat
Saturday, October 5, 2024 | 09:10-10:10 CEST
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The Multiple Myeloma Hub has previously published the findings of CASSIOPEIA Part 1, a phase III randomized controlled trial in patients with newly diagnosed multiple myeloma (NDMM) comparing daratumumab, an anti-CD38 antibody, in combination with bortezomib, thalidomide and dexamethasone (D-VTd) to bortezomib, thalidomide, and dexamethasone (VTd) alone. Based on the results from this study, the U.S. Food and Drug Administration (FDA) approved the combination of D‑VTd for the treatment of patients with NDMM. Philippe Moreau, a member of the Multiple Myeloma Steering Committee, presented findings from CASSIOPEIA Part 2, investigating the efficacy and safety of daratumumab maintenance at the 2021 American Society of Oncology (ASCO) Annual Meeting1 and the European Hematology Association (EHA) 2021 Virtual Congress.2 The key findings are presented here.
CASSIOPEIA is a phase III randomized trial (NCT02541383) in transplant-eligible patients with NDMM. Part 1 of the trial included induction and consolidation phases and a summary can be found here. In Part 2 of the study (maintenance phase), patients completing consolidation and achieving a partial response or better (n = 886) were re-randomized to receive either daratumumab 16 mg/kg every 8 weeks followed by observation (OBS) until progressive disease or OBS alone until progressive disease.
The primary endpoint was progression-free survival (PFS) after the second randomization. Secondary endpoints included rates of complete response or better (≥CR), minimal residual disease (MRD) negativity rates, and overall survival (OS). Updated analyses of PFS from first randomization and subsequent progression after next line of therapy (PFS2) were performed.
Nearly 15% of patients in each arm had high-risk cytogenetics, and >75% of patients in both arms were MRD negative with very good partial response or better. The baseline characteristics were well balanced in both arms (Table 1).
Table 1. Baseline characteristics*
Characteristic |
DARA |
OBS |
---|---|---|
Median age (range), years† |
59 (27–66) |
59 (36–66) |
Male sex, %† |
59 |
57 |
ECOG PS, %† |
|
|
0 |
57 |
59 |
1 |
39 |
39 |
≥2 |
4 |
3 |
ISS staging, %‡ |
|
|
I |
43 |
39 |
II |
41 |
48 |
III |
16 |
13 |
Cytogenetic profile, %‡ |
|
|
Standard risk |
87 |
84 |
High risk§ |
13 |
16 |
Type of induction/consolidation, % |
|
|
D-VTd |
52 |
52 |
VTd |
48 |
48 |
Depth of response, %‖ |
|
|
MRD negative, ≥VGPR |
76 |
76 |
MRD positive, ≥VGPR |
15 |
16 |
MRD positive, PR |
8 |
9 |
≥VGPR, very good partial response or better; D-VTd, daratumumab, bortezomib, thalidomide, and dexamethasone; DARA; daratumumab monotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; MRD, minimal residual disease; OBS, observation; PR, partial response; VTd, bortezomib, thalidomide, and dexamethasone. |
Table 2. TTP, PFS2, and OS in the DARA and OBS arms*
Endpoint |
DARA |
OBS |
p value |
HR (95% CI) |
---|---|---|---|---|
TTP, months |
NR |
46.7 |
<0.0001 |
0.49 (0.38–0.62) |
PFS2, months |
NR |
NR |
0.0298† |
0.62 (0.40–0.96) |
OS, months/events |
NR/29 |
NR/27 |
NA |
1.07 (0.63–1.80) |
CI, confidence interval; DARA, daratumumab; HR, hazard ratio; NA, not applicable; NR, not reached; OBS, observation; OS, overall survival; PFS2, progression free survival after next line of therapy; TTP, time to progression from second randomization. |
Table 3. ≥CR and MRD negativity rates*
Rates, % |
DARA |
OBS |
p value |
OR (95% CI) |
---|---|---|---|---|
≥CR |
||||
DARA vs OBS |
73 |
61 |
<0.0001 |
2.17 (1.54–3.07) |
VTd/DARA vs VTd/OBS |
69 |
49 |
<0.0001 |
3.14 (1.93–5.10) |
D-VTd/DARA vs D-VTd/OBS |
76 |
72 |
0.1624 |
1.43 (0.87–2.37) |
MRD negativity at 10−4 by MFC |
||||
DARA vs OBS |
59 |
47 |
0.0001 |
1.80 (1.33–2.43) |
VTd/DARA vs VTd/OBS |
53 |
36 |
0.0002 |
2.26 (1.47–3.48) |
D-VTd/DARA vs D-VTd/OBS |
64 |
58 |
0.1037 |
1.43 (0.93–2.19) |
≥CR, complete response or better; CI, confidence interval; DARA, daratumumab; D-VTd, daratumumab, bortezomib, thalidomide, and dexamethasone; MFC, multiparameter flow cytometry; MRD, minimal residual disease; OBS, observation; OR, odds ratio; VTd, bortezomib, thalidomide, and dexamethasone. |
Table 4. AEs observed in the DARA and OBS cohorts*
AE, % |
DARA |
OBS |
---|---|---|
Any TEAE |
96 |
89 |
Any serious TEAE |
23 |
19 |
Grade ≥3 TEAE |
30 |
24 |
Treatment discontinuation due to TEAE |
3 |
NA |
Fatal AE |
1 |
0 |
Neutropenia, Grade 2 |
2 |
2 |
Secondary primary malignancy† |
6 |
3 |
Infusion-related reactions |
55‡ |
NA |
Infections§ |
78 |
64 |
AE, adverse event; DARA, daratumumab; NA, not applicable; OBS, observation; TEAE, treatment emergent adverse event; VTd, bortezomib, thalidomide, and dexamethasone. |
The interim analysis from the CASSIOPEIA Part 2 trial demonstrated that daratumumab maintenance therapy every 8 weeks significantly improved outcomes for patients with NDMM receiving VTd induction/consolidation treatment, but no benefit was observed compared with OBS in patients who received D-VTd. On the other hand, the updated results from Part 1 were supportive of daratumumab-containing induction/consolidation regimens. The safety profile was also confirmed by the high dropout rates in the VTd arm compared with the D-VTd arm.
The immature OS and PFS2 observed in patients who received D-VTd induction/consolidation indicate that a longer-term evaluation is needed to determine if daratumumab maintenance will benefit patients exposed to daratumumab. As Moreau highlighted during his presentation, the high rates of MRD negativity in patients coming from the D-VTd arm at the start of the maintenance phase might be one reason why the survival curves from the daratumumab and OBS arms are still very similar.
Ongoing trials, such as GRIFFIN (NCT02874742) and PERSEUS (NCT03710603), may further elucidate maintenance strategies using daratumumab single-agent or as a doublet with lenalidomide.
Which patients could benefit most from post-HSCT maintenance therapy with daratumumab single agent?
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