Initial Safety and Efficacy of Daratumumab (DARA) in Combination with Bortezomib, Lenalidomide, and Dexamethasone in the Treatment of Transplant-Eligible Newly Diagnosed Multiple Myeloma (TE-NDMM) Patients with Standard Risk Who Refused to Accept ASCT As First Line in China

Background: Despite the advent of numerously new drugs, multiple myeloma (MM) remains an incurable plasma cell malignancy. Autologous hematopoietic stem cell transplantation (ASCT) remains an important first line treatment for MM. In China, rate of utility of ASCT in front line was as low as 10%. There are many transplant-eligible (TE) patients who refuse ASCT for a variety of subjective and objective reasons,. Bortezomib, lenalidomide and dexamethasone (VRd) combination has been reported to demonstrate high efficacy in these patients (SWOG S0777), And recently, daratumumab combinations, such as D-VRd (GRIFFIN) and D-VTd (CASSIOPEIA), have shown good results in TE-NDMM patients who received ASCT as initial therapy. The observed benefits of these combination therapies have led us to explore the potential efficacy of D-VRd in standard risk TE-NDMM patients without ASCT. In addition, there were no studies assessing minimal residual disease (MRD) data after treatment with the D-VRd regimen in TE-NDMM patients who are unwilling to undergo ASCT in Chinese population , thus we chose MRD as the primary endpoint. This is the first open-label, single arm study to evaluate the efficacy and safety of D-VRd in TE-NDMM in standard risk without ASCT in China (NCT 05088330).

Methods: This is a single-center prospective ongoing clinical study, planning to recruit 76 patients. NDMM patients as documented per IMWG criteria who were evaluated as transplant-eligible, but voluntary not to accept ASCT were enrolled. And t(4;14) or Del(17p) or t(14;16) or R-ISS stage III patients were excluded from this study. D-VRd regimen includes ‘daratumumab’ 16 mg/kg I.V. every week for 2 cycles, 16 mg/kg I.V. every 3 weeks for 6 more cycles, and then 16 mg/kg I.V. for 13 more cycles (Total: 21 cycles); ‘lenalidomide’: 25 mg, P.O., Days 1-14/1-8 cycles; ‘Bortezomib’: 1.3 mg/m2, SC, Days 1, 4, 8, 11/1-8 cycles; dexamethasone: 20 mg, P.O., Days 1, 2, 4, 5, 8, 9, 11, 12/1-8 cycles. The primary endpoint of this study was to evaluate the negativity of NGS MRD at 10-5 after 8 cycles of D-VRd. The secondary objectives of this study were to determine the ORR, sCR, ≥CR ≥VGPR, AE, TTR and DOR of treatment. Patients were recommended to have stem cells collection after 4 cycles of D-VRd treatment.

Result: As of 30 June 2023, 24 patients including 6 safety-run-in patients were enrolled. The median (range) age of these 24 patients was 65 (50-74) years. 54.2% (13/24) were male. 62.5% of patients had a 1q gain. 16.7% (4/24) of patients had renal insufficiency with 30mL/min <CCR <60mL/min (Table 1).

The median follow-up time was 3 (1-11) months, 8 patients completed 4 cycles and 2 patients completed 2 cycles. Among the 17 patients who had response evaluation, the ORR was 94.1%, 87.5% (7/8) of patients had VGPR or better after 4 cycles (Figure 1). All patients (6/6) above VGPR and CR had NGS MRD negativity. Both 2 patients who have completed the 8 cycles treatment achieved CR and MRD negativity. All patients had bone pain relief. The main treatment-related adverse events were hematological toxicity, which occurred in 22 patients including neutropenia (n=14, Grade 1-2 for 10 patients and Grade 3-4 for 4 patients), lymphopenia (n=13, Grade 1-2 for 10 patients and Grade 3-4 for 3 patients) and thrombocytopenia (n=19, Grade 1-2 for 15 patients and Grade 3-4 for 4 patients). One patient had to discontinue lenalidomide due to serious adverse event (SAE) of pulmonary embolism. Other toxicities to date include pneumonia (n=3, Grade 1 for 2 patients and Grade 2 for 1 patient), ALT/AST increase (n=10, all Grade 1), and rash (n=3). The infusion related reactions were reported in 25% of patients (n=6, Grade 1 for 4 patients and Grade 2 for 2 patients).

Conclusion: In the safety-run-in phase, D-VRd induction therapy was well tolerated in the Chinese population in 6 patients. This preliminary study of D-VRd demonstrated excellent efficacy with rapid response even in a population with high 1q gain. The most common adverse events were hematological toxicities that were manageable after 2 cycles. The updated results will be presented in the following phase.