Daratumumab maintenance therapy in patients with NDMM: Findings from CASSIOPEIA Part 2

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.

Study design (CASSIOPEIA Part 2)

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.

Baseline characteristics

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*

≥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. *Adapted from Moreau.1,2 †Pre-consolidation. ††Pre-induction. ‡Patients with del(17p) or t(11;14). ‖As determined by MRD measured by multiparametric flow cytometry at 10−4 and postconsolidation response per investigator assessment for stratification.
Characteristic	DARA (n = 442)	OBS (n = 444)
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

Patients not randomized to Part 2

• Overall, 199 patients who received VTd induction/consolidation treatment were not randomized to Part 2.
• The most common reasons included adverse events (AEs), disease progression in Part 1, and worse than partial response post-consolidation.
• At a median PFS of 25.4 months and 30.7 months in the D-VTd and VTd arms, respectively, poor outcomes were observed in these patients.

Results

Efficacy

• The primary endpoint of PFS was met at a median follow-up of 35.4 months and was significantly improved in the daratumumab arm compared with the OBS arm. Patients treated with daratumumab maintenance did not attain a median PFS, while patients in the OBS arm had a median PFS of 46.7 months (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.42–0.68; p<0.0001).
• Of note, all prespecified subgroups showed consistent and favorable PFS for daratumumab maintenance, except for patients who received D-VTd as induction or consolidation therapy, for which both maintenance options were not statistically different (HR, 1.05; 95% CI, 0.73–1.51).
• Prolonged time to progression, PFS2, and OS were observed in patients receiving daratumumab maintenance compared with patients in the OBS arm (Table 2). In addition, improved ≥CR rates and MRD negativity were observed in the daratumumab arm (Table 3).

• Comparison of induction/consolidation and maintenance treatment showed a significant interaction with a favorable PFS for VTd/daratumumab vs VTd/OBS (HR, 0.32; 95% CI, 0.23–0.46; p<0.0001). Although, no differences were observed in patients receiving D‑VTd/daratumumab vs D‑VTd/OBS (HR, 1.02; 95% CI, 0.71–1.47; p = 0.9133).
• Patients receiving VTd/daratumumab also showed a significant improvement in ≥CR and MRD negativity rates compared with patients receiving VTd/OBS.
• However, ≥CR and MRD negativity were the highest in the D-VTd/daratumumab arm.

Table 2. TTP, PFS2, and OS in the DARA and OBS arms*

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. *Adapted from Moreau.1,2 †Nominal p value.
Endpoint	DARA (n = 442)	OBS (n = 444)	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)

Table 3. ≥CR and MRD negativity rates*

≥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. *Adapted from Moreau.1,2
Rates, %	DARA (n = 442)	OBS (n = 444)	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)

Updated analysis: First randomization (CASSIOPEIA Part 1)

• At a median follow-up of 44.5 months, median PFS was not reached in the D-VTd arm vs 51.5 months in the VTd arm.
• In addition, D-VTd also reduced the risk of disease progression or death by 42%.

Safety

• The proportion of patients discontinuing treatment due to AEs was low, at 3% (Table 4).
• Among patients receiving VTd induction/consolidation, 47% experienced an infusion-related reaction following the first daratumumab treatment. However, most of these reactions were either Grade 1 or 2.
• Secondary primary malignancies were observed in 6% vs 3% of patients receiving daratumumab and OBS, respectively.

Table 4. AEs observed in the DARA and OBS cohorts*

AE, adverse event; DARA, daratumumab; NA, not applicable; OBS, observation; TEAE, treatment emergent adverse event; VTd, bortezomib, thalidomide, and dexamethasone. *Adapted from Moreau.1,2 †T-cell lymphoma, blastic plasmacytoid dendritic cell neoplasia, myelodysplastic syndrome, and natural killer-cell lymphoblastic lymphoma in the DARA cohort, and acute myeloid leukemia in the OBS cohort. ‡Among patients receiving VTd as induction therapy. §Grade 1 or 2.
AE, %	DARA (n = 440)	OBS (n = 444)
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

Conclusion

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.

Expert Opinion