Initial results of daratumumab + lenalidomide in frail patients: The IFM 2017-03 trial

The International Myeloma Foundation (IFM) 2017-03 (IFM 2017-03) trial (NCT03993912) is a phase III clinical trial exploring the use of daratumumab and lenalidomide (DR) compared with lenalidomide and dexamethasone (Rd) for the treatment of patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant.¹

The Multiple Myeloma Hub is pleased to summarize the oral presentation given by Manier¹ at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition, which detailed outcome and safety data from the IFM 2017-03 trial. Their research question was: does the benefit of dexamethasone justify potentially higher rates of infection and pneumonia in frail patients?¹

Study design

The IFM 2017-03 trial randomized patients to Rd versus DR in the ratio 1:2. All patients had NDMM, were ≥65 years, and had an IFM frailty score of ≥2 (calculated using age, Eastern Cooperative Oncology Score, and Charlson Comorbidity Index).² The study design can be seen in Figure 1. Treatment in both arms was given until disease progression or unacceptable toxicity, with low dose dexamethasone (20 mg/week) in Arm B.

Figure 1. Study design of the IFM 2017-03 trial* 

C, Cycle; Dara, daratumumab; Dex, dexamethasone; DR, lenalidomide and dexamethasone; IFM, International Myeloma Foundation; Len, lenalidomide; Lo-Dex, low-dose dexamethasone; LT, long-term; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PD, progressive disease; Rd, lenalidomide and low-dose dexamethasone; SC, subcutaneous.
*Adapted from Manier.¹

This pre-planned interim analysis included overall response rate, very good partial response or better (≥VGPR), minimal residual disease (MRD) rate, and the occurrence of ≥Grade 3 adverse events. Longer follow-up is ongoing to evaluate progression-free survival assessed up to 84 months (primary endpoint), as well as time-to-treatment failure, time-to-next treatment, and overall survival, among other secondary outcomes.

Results

In total, 295 patients were recruited, with 199 in the DR arm compared with 94 in the Rd arm. Patient disposition can be seen in Figure 2. In total, 3 patients dropped out prior to treatment. For the analysis presented, data cut off was performed at 12 months, with a higher percentage of Rd patients discontinuing treatment compared with DR patients (Figure 2).

Figure 2. Patient disposition of patients recruited to IFM 2017-03* 

DR, lenalidomide and daratumumab; IFM; International Myeloma Foundation; Rd, lenalidomide and dexamethasone.
*Adapted from Manier.¹

Patient demographics can be seen in Table 1, showing that patients in both groups were well matched for age and frailty.

Table 1. Patient data from the IFM 2017-03 trial*

The analysis presented was from a data cut-off of 12 months:

• Overall response rate was 96% in the DR group compared with 85% in the Rd group (p = 0.001), with a ≥VGPR rate of 64% vs 43%, respectively, that improved over time.

• MRD assessment by next generation sequencing at 10⁻⁵ was performed in patients with ≥VGPR at 12 months and patients with missing MRD data were considered positive. At a 10⁻⁵ sensitivity in an intention-to-treat interim analysis, DR significantly improved rates of MRD negativity compared with Rd (10% vs 3%; p = 0.012).
• Safety data can be seen in Table 2. Treatment discontinuation due to adverse events for DR and Rd were 14% and 16%, respectively, with no statistically significant difference.

Table 2. Grade ≥3 adverse events in the IFM 2017-03 trial*

Higher rates of infection were seen in patients with ≥4 IFM frailty score in both the DR (21%) and Rd (27%) groups, relative to patients with a IFM frailty score of 2–3 (9% and 13%, respectively). Manier comments on a trend towards higher rates of infection in patients with increased frailty in both arms but notes that there were no statistical significance in either.

Conclusion

The IFM 2017-03 trial is a novel phase III clinical trial exploring the possibility of avoiding steroid use for the treatment of frail patients with NDMM. This interim analysis suggests superior rates of ≥VGPR and MRD negativity in patients treated with DR compare with Rd. Safety data for both treatments is comparable to date, with no increased risk of infection or pneumonia with DR despite the significant increase of neutropenia. Further follow-up is ongoing to determine if frail patients with NDMM can be safely treated without steroid-containing regimens.