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
- Eight cycles of treatment, 28-day cycles:
- 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)
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.
The median patient age was 57 years (range: 36–70), of whom 61% were female and 49% had high risk cytogenetics.
- 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)
- MRD-negativity: 77% (23/30)
- 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
- 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)
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.