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

By Oscar Williams

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Mar 5, 2024

Learning objective: After reading this article, learners will be able to cite a new clinical development in newly diagnosed high-risk multiple myeloma.


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).

Figure 1. Response rates of TE and TNE patients treated with Isa-KRd* 

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).

Figure 2. Rates of sustained MRD negativity at ≥6 months and ≥12 months in TE and TNE patients treated with Isa-KRd* 

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

References

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What is the most significant limitation you have identified when using lenalidomide or pomalidomide for the treatment of patients with multiple myeloma?