GMMG-CONCEPT trial: Isa-KRd for the treatment of high-risk newly diagnosed MM

Patients with newly diagnosed high-risk multiple myeloma have poor survival outcomes and few prospective trials aiming to determine the optimal treatment strategy. Measurable residual disease (MRD) negativity is the strongest predictor of survival; therefore, is crucial for this patient population.

Leypoldt et al.¹ recently published results from the phase II GMMG-CONCEPT trial (NCT03104842) in Journal of Clinical Oncology investigating transplant-eligible (TE) and transplant-non-eligible (TNE) patients with newly diagnosed high-risk multiple myeloma treated with isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd), followed by triplet maintenance. We summarize the key points below.

Study design¹

• Non-randomized multicenter phase II study
• Study arm A included TE patients who received six cycles of Isa-KRd induction, followed by high-dose therapy and autologous stem cell transplant
• Study arm B included TNE patients, and received identical induction, consolidation, maintenance, and two extra cycles of Isa-KRd
• The primary endpoint was the proportion of patients reaching MRD negativity (<10⁻⁵)

Key findings¹

• N = 153
  • TE patients = 127
  • TNE patients = 26
• Overall, 73% of TE patients completed consolidation and started maintenance therapy vs 58% of TNE patients.
• The overall response rate was comparable between TE and TNE patients (Figure 1).

CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; TE, transplant-eligible; TNE, transplant-non-eligible; VGPR, very good PR.
*Adapted from Leypoldt, et al.¹

• Post-consolidation, 67.7% of TE patients experienced MRD negativity (p = 0.004) vs 54.2% of TNE patients (p =0.012).
• Sustained MRD negativity rates at ≥6 months and ≥12 months were higher for TE patients vs TNE patients (Figure 2).

MRD, measurable residual disease; TE, transplant-eligible; TNE, transplant-non-eligible.
*Adapted from Leypoldt, et al.¹

• Median progression-free survival and median overall survival were not reached in either study arm.

Safety¹

• Treatment was tolerable, with a manageable safety profile
  • The safety profile was comparable between TE and TNE patients and was consistent with previous reports
• In total, 92.6% of patients experienced ≥1 adverse event

Key learnings
An extensive quadruplet approach resulted in high rates of sustained MRD negativity and progression free survival duration in a difficult-to-treat patient population. T-cell engaging strategies in frontline treatment to replace melphalan or use of bispecific antibodies during maintenance could further optimize treatment and result in unprecedented rates of MRD negativity