P-343: Safety and Efficacy of Dara-KAD induction followed with tandem ASCT and KP maintenance in Transplant-eligible, Ultra High-risk, Newly Diagnosed Multiple Myeloma and Primary Plasma Cell Leukemia

Introduction: Patients with ultra-high-risk multiple myeloma(UHRMM), including "double-hit"or “triple-hit” MM, and primary plasma cell leukemia (pPCL), have a significantly poor prognosis with current therapeutic strategies. Circulating plasma cell is associated with poor outcome in NDMM. The addition of daratumumab (Dara) to induction improved response rate and PFS in TE-NDMM patients.Double transplant also improved outcome of HR TE NDMM patients.Dara-KRd with tandem transplant is feasible in patients with HR TE-NDMM and resulted in high response rates and PFS, but some patients discontinued the study due to stem cell collection failure(IFM2018-04) . This study will assess the efficacy and safety of the combination of daratumumab, carfilzomib, liposomal doxorubicin, and dexamethasone induction followed with tandem ASCT and maintenance with carfilzomib and pomalidomide in patients with ultra high-risk TE NDMM and pPCL.

Methods: This is a single-arm and prospective study. Key inclusion criteria were: 1.NDMM patients with ultra high-risk disease, as defined by one of the following: 1)"Double hit" or “Triple hit” (≥2 adverse markers: t(4;14), t(14;16), 1q21+, 1p32-, del(17p), BLPC≥ 1% ; 2.Newly-diagnosed pPCL；3. Aged 18 years to 70 years. Treatment strategy includes Dara-KAD induction (4-6 cycles), tandem autologous stem cell transplantation (ASCT), carfilzomib-pomalidomide maintenance. The primary endpoint is PFS. Here, we report efficacy and safety analysis of Dara-KAD induction.

Results: Thirteen patients including 9 ultra-high risk NDMM and 4 pPCLwere included from Feb 2023 to May 2024. Median age was 56 (range 34-68) years old. ISS stage 3 and RISS stage 3 were present in 6 (46.2%) and 4(30.8%) patients. Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n=3, 23.1%), t(4;14) (n=3, 23.1%), t(14;16) (n=0,0.0%),and 1q21+ (n=11, 84.6%) . Eleven(84.6%) patiens had circulating plasma cells. Six patients completed Dara-KAD induction, 4 patients completed stem cell collection, and 2 completed ASCT1. One patients discontinued treatment due to severe adverse event (neutropenic fever, n=1). Mobilization success rate was 100% in 4 patients and all CD34+ were ≥6*10^6/kg. Grade 3-4 treatment related adverse event were neutropenia (38.5%), thrombocytopenia (15.4%) and infection (23.1%).

Rate of any TEAEs leading to definitive discontinuation was 10%, and rate of life-threatening TEAEs was 0%. Among 6/13 evaluable patients post induction, overall response rate of Dara-KAD induction was 100.0%, including 33.3% MRD (NGF, 10-5) negativity, 83.3 % ≥CR, and 100.0% ≥ VGPR.

Conclusions: Dara-KAD as a pre-transplant induction therapy is safe and facilitates profound responses in patients with ultra-high risk TE NDMM and pPCL. The study is in progress,

longer follow-up is needed to evaluate safety and efficacy of the comprehensive treatment approach with Dara-KAD induction, subsequent tandem ASCT, and KP maintenance in this subset of UHR patients.