End of the LYRA study: DARA + VCd induction therapy followed by DARA maintenance

Daratumumab or DARA is a human IgG kappa monoclonal antibody and is approved as monotherapy or in combination with standard of care regimens to treat newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma (RRMM).

In vitro studies suggest that cyclophosphamide may enhance the DARA mediated macrophage anti-myeloma activity.¹ The single-arm phase II LYRA study was designed to evaluate DARA in combination with cyclophosphamide plus bortezomib and dexamethasone (CyBorD or VCd) in patients with NDMM/RRMM. The primary analysis of LYRA (NCT02951819) was previously reported and can be accessed on our hub.

At the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Rifkin, et al. presented the final, end of study analysis for efficacy and safety occurring after all patients completed one year of maintenance therapy with DARA and were followed for 36 months after the start of induction therapy.²

Study design

Details of patient enrolment and study design have been published previously on the Multiple Myeloma hub.

Briefly, patients with NDMM/RRMM with one prior line of therapy received 4–8 induction cycles of DARA+ VCd. The primary endpoint was rate of very good partial response following 4 cycles of induction therapy. Those who were eligible could receive high-dose therapy and autologous stem cell transplant. All patients received up to 12 months of DARA maintenance therapy.

Key outcomes

By the end of the study, the complete response rate was better among patients with NDMM who underwent transplantation than those who did not (Table 1).

Table 1. Efficacy analysis*

With a median follow-up of 35.7 months for newly diagnosed patients, approximately 70% were progression-free after three years, regardless of whether they underwent a transplant. For patients at relapse, after a median follow-up of 35.3 months, the median PFS was 21.7 months. Median overall survival was 94.9, 84.3, and 50 months for patients with NDMM with transplant, without transplant, and with RRMM, respectively.

Treatment-emergent adverse events (TEAE)

Most events were Grade 2/3, with nausea, fatigue, cough, diarrhoea, and back pain were most common in NDMM and RRMM groups (Table 2).

Serious TEAE were reported in 32.6% and 35.7 % of patients with NDMM and RRMM, respectively.

• Treatment discontinuation occurred in seven patients with NDMM.
• TEAE leading to death occurred in both NDMM and RRMM groups (one in each subgroup).
• Cardiac TEAE occurred in 16.3% of patients with NDMM, with 4.7% events classed as Grade 3.
• Infusion-related reactions (IRRs) occurred in 55.8% and 57.1% of patients with NDMM and RRMM, respectively. Overall, 25% experienced ≥1IRR (Grade ½) during the first maintenance cycle among NDMM who resumed DARA treatment after transplant. Grade 3/4 IRRs were also reported (n = 2) in patients with NDMM.
• No patients with RRMM experienced IRRs during maintenance therapy.

Table 2. Treatment-emergent adverse events*

Conclusion

Deep and durable responses were observed in patients with NDMM and RRMM when treated with DARA + VCd induction followed by monthly DARA maintenance therapy. The estimated three-year progression-free survival rate was approximately 70% in newly diagnosed patients regardless of transplant status. No new safety concerns were observed with longer follow up.

The significance of this study is limited by the presence of only one study arm, small sample size (n = 87) and only 14 patients in RRMM along with shorter follow-up duration (~35 months). This combination is now supported by the NCCN guidelines, which suggest its use in certain circumstances for patients with NDMM and RRMM.