General MM

High MRD-negativity rates observed with wKRd-D for patients with newly diagnosed multiple myeloma  

During the 61st American Society of Hematology (ASH) meeting, Orlando, US, Ola Landgren, Memorial Sloan Kettering Cancer Center, New York, US, presented an analysis from a two-arm phase II trial of carfilzomib, lenalidomide and dexamethasone (KRd) in combination with daratumumab (KRd-D) in patients with newly diagnosed multiple myeloma (NDMM, n= 82). One arm was administered carfilzomib weekly (wKRd-D) whilst in the other carfilzomib was administered bi-weekly (bKRd-D). The primary endpoint was to achieve a > 60% (target 80%) minimal residual disease (MRD)-negativity rate with eight cycles of therapy, or less. The results reported by Ola Landgren during the ASH meeting were for 30 patients in the wKRd-D cohort enrolled between October 2018 and August 2019 (NCT03290950) who were evaluable for the primary endpoint.

Dosing schedule, measurement methods and patient characteristics
Dosing schedule
  • Eight cycles of treatment, 28-day cycles:
    • Carfilzomib:
      • wKRd-D arm (n= 41): 20mg/m2 on Day 2 and 56mg/m2 on Days 8 and 15 of Cycle 1 and 56mg/m2 on Days 1, 8 and 15 of Cycles 2-8
      • bKRd-D arm (n= 41): 20/36mg/m2 on Days 1, 2, 8, 9, 15 and 16 of each cycle
    • Lenalidomide: 25mg on Days 1–21 of each cycle
    • Dexamethasone: 40mg weekly for Cycles 1–4 and 20mg weekly for Cycle 5 onwards
    • Daratumumab: 16mg/kg on Days 1, 8, 15 and 22 of Cycles 1–2, Day 1 and 15 of Cycles 3–6 and on Day 1 of Cycles 7–8
  • Following enrollment of the first stage, the bKRd-D arm was closed based on comparable efficacy and safety to wKRd-D but with a lower number of infusions
Stem cell collection
  • Peripheral stem cell collection was recommended after 4–6 cycles of therapy for transplant eligible patients, with KRd-D therapy continuing afterwards to a total of eight cycles
    • Patients eligible for stem cell mobilization and collection received granulocyte-colony stimulating factor (G-CSF) and plerixafor
    • Median yield (n= 28): 8.5 million CD34 cells/kg (range: 2.4–10.7)
Measurement methods

MRD assessment was conducted using parallel bone marrow (BM)-based assays of 10 color single tube flow cytometry and next generation sequencing (NGS) detection of the immunoglobulin heavy chain variable region gene (IGHV). MRD sensitivity was 10-5 as per International Myeloma Working Group (IMWG) guidelines.

Patient characteristics

The median patient age was 57 years (range: 36–70), of whom 61% were female and 49% had high risk cytogenetics.

Efficacy
  • At a median follow-up of 8.6 months, 30 patients were evaluable for primary endpoint of MRD-negativity after eight cycles of therapy or less:
    • MRD-negativity: 77% (23/30)
      • Median time to MRD negativity: 6 cycles
      • No patients who achieved MRD-negative status have progressed
    • MRD-negativity in patients aged 65 or older: 75% (6/8)
  • Responses in all evaluable patients:
    • Complete response (CR) or ≥ very good partial response (VGPR): 97% (34/35)
    • Overall response rate (ORR): 100% (39/39)
  • In the 24 patients that completed all eight treatment cycles:
    • MRD-negativity: 75%
    • CR/VGPR or better: 92%
    • ORR: 100%
  • No MRD-negative patients had progressed at time of sampling
Safety
  • No additional grade ≥ 3 clinical toxicities were observed compared to standard of care (bKRd)
  • No grade ≥ 3 peripheral neuropathy events or deaths were observed
  • Dose reductions occurred in 21 patients, mainly for dexamethasone (n= 12) or lenalidomide (n= 15)
Conclusion

Up to eight cycles of wKRd-D provided a 77% MRD-negativity rate in patients with NDMM who had not received autologous stem cell transplant. Looking forwards, the ADVANCE trial, a large, randomized, multi-center trial, will evaluate wKRd-D compared to standard of care therapies.

References
  1. Landgren O. et al., Weekly Carfilzomib, Lenalidomide, Dexamethasone and Daratumumab (wKRd-D) Combination Therapy Provides Unprecedented MRD Negativity Rates in Newly Diagnosed Multiple Myeloma: A Clinical and Correlative Phase 2 Study; 2019 Dec 9. Oral abstract #862: 61st American Society of Hematology (ASH) annual meeting & exposition, Florida, US.
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