Dara-KRd and tandem ASCT for patients with high-risk NDMM: Results of the IFM-2018-04 trial

Patients with newly diagnosed multiple myeloma (NDMM) who are eligible for transplant and have high-risk cytogenetics traditionally have a poor prognosis.¹ To improve this, different treatment combinations have been trialed with some success, such as carfilzomib, lenalidomide, and dexamethasone (KRd) in the FORTE trial and adding daratumumab (dara) to frontline therapy as in the CASSIOPEIA and GRIFFIN trials. In addition, tandem stem cell transplants have improved the outcome of these high-risk patients with NDMM.¹

In the IFM-2018-04 trial, the quadruplet of dara-KRd with tandem transplant was assessed in patients with NDMM eligible for transplant; Touzeau¹ presented the results of this trial at the European Hematology Association (EHA) 2022 Congress, which we are pleased to summarize here.

Study design

The dosing schedule and study design for the IFM2018-04 phase II trial (NCT03606577) are shown in Figure 1.

Inclusion criteria:

• Age, <66 years
• Patients with NDMM who are eligible for transplant
• High-risk fluorescence in situ hybridization: t(4;14), 17p del, and t(14;16)
• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2

Endpoints:

• Primary:
  • Feasibility: >70% of patients completed second transplant
• Secondary:
  • Safety, overall response rate, progression-free survival (PFS), overall survival (OS) and stem cell collection

ASCT, autologous stem cell transplant; cyclo G-CSF, cyclophosphamide and granulocyte-colony stimulating factor; d, dexamethasone; dara, daratumumab; IV, intravenous; K, carfilzomib; Mel, melphalan; R, lenalidomide.
*Adapted from Touzeau.^1
†Dara 16 mg/kg IV every 8 weeks + R 10 mg 21/28 days.

Results

Patient characteristics

The median age of patients included in this trial was 57 years (range, 38−65 years) and the majority (94%) had an ECOG PS of 0−1. High-risk cytogenetics were present in all patients, with the most common being a t(4;14) translocation. In total, 68% of patients had two cytogenetic abnormalities (Table 1).

Table 1. Patient baseline characteristics and treatment disposition*

ASCT, autologous stem cell transplantation; ECOG PS, Eastern Cooperative Oncology Group performance status; R-ISS, revised International Staging System. *Adapted from Touzeau.1
Characteristic, % (unless otherwise stated)	Total (N = 50)
ISS score
Stage 1	42
Stage 2	34
Stage 3	24
R-ISS score
Stage 2	76
Stage 3	24
High-risk cytogenetics	100
17p depletion	40
t(4;14)	52
t(14;16)	20
1q gain	50
Two high-risk cytogenetic abnormalities	68
Treatment disposition
Ongoing	72
Consolidation	22
ASCT #2, n	1
Maintenance	48
Discontinued	28
Progressive disease, n	2
Adverse event, n	4
Withdrawal, n	2
Stem cell collection failure, n	6

Safety

Treatment-emergent adverse events (TEAEs) are shown in Figure 2. No new safety signals were observed in this trial for dara-KRd + tandem transplant. The most common hematologic TEAE was neutropenia, with infection and gastrointestinal disorders being the most frequently observed non‑hematologic TEAEs.

There were two cases of patients with AEs leading to discontinuation (one case of COVID-19 infection and one case of tumor lysis syndrome). Grade III/IV infections occurred in three patients:

• COVID-19 (n = 1)
• Cytomegalovirus infection (n = 1)
• Pseudomonas aeruginosa bacteriemia (n = 1)

GI, gastrointestinal; TEAE, treatment-emergent adverse events.
*Adapted from Touzeau.¹

Stem cell collection

During the first round of stem cell collection, failure occurred in six patients. In the patients in which collection was successful, the median CD34⁺ cell count was 6.1 × 10⁶/kg (range, 0−16 × 10⁶/kg).

As a result of this failure, the protocol was amended to collect stem cells after Cycle 3. Following this change, stem cell collection was successful in 21 patients and the median CD34⁺ cell collection achieved was 8.3 × 10⁶/kg (range, 4.7−26 × 10⁶/kg).

Response

Measurable residual disease (MRD) was measured by next-generation sequencing with a threshold of 10⁻⁵. MRD negativity rate was 62%. The response to treatment is shown in Figure 3. Complete response/stringent complete response rate was 31% and the very good partial response or better rate was 91%.

CR, complete response; ORR, overall response rate; PR, partial response; sCR, stringent CR; VGPR, very good partial response.
*Adapted from Touzeau.¹

Median follow-up was 19.4 months and the survival outcomes for patients with NDMM are shown in Table 2. At all timepoints, median PFS and OS were >90%.

Table 2. Survival outcomes at 12 months and 18 months*

OS, overall survival; PFS, progression-free survival. *Adapted from Touzeau.1
Outcome, % (range)	N = 50
PFS
12 months	96 (90−100)
18 months	92 (84−100)
OS
12 months	96 (90−100)
18 months	96 (90−100)

Conclusion

The results of the IFM-2018-04 trial in high-risk transplant-eligible patients with NDMM show that the quadruplet of dara-KRd + tandem transplant resulted in PFS and OS rates >90% at 18 months. An MRD-negativity rate of 62% was achieved with dara-KRd + tandem transplant, which was the same as the MRD-negative rate of 62% achieved in the FORTE trial with KRd and single transplant. These results are consistent with those achieved in the GMMG concept trial of isatuximab + KRd in high‑risk patients. To confirm both the efficacy and feasibility of this treatment combination and sequencing, a longer follow-up is required.