Safety and Efficacy of Dara-VTD Induction and Autologous Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma Patients Presenting with Renal Failure - a Tertiary Centre UK Experience on Behalf of the UK-MRA

Introduction - Renal failure (est glomerular filtration rate, eGFR <30ml/min) in newly diagnosed transplant eligible multiple myeloma (NDTEMM) remains high, affecting up to 20% of patients. Management is challenging, with limited data on optimal induction as these patients are often excluded from clinical trials. Following CASSIOPEIA data supporting quadruplet DaraVTD induction and autologous stem cell transplant (ASCT) in NDTEMM (inclusion criteria - eGFR >40ml/min), this strategy has been increasingly used in the renal failure cohort.

Method - We analysed all NDTEMM ASCT referrals to our tertiary centre at King's College Hospital over a 2yr period (Jan22 - Apr24) following approval of DaraVTD induction in the UK. 126 patients commenced DaraVTD and were referred for ASCT by treating centres. Of these, a study cohort of 11 patients presented with renal failure. We excluded patients with pre-existing kidney disease with baseline eGFR<30ml/min and used IMWG renal response criteria to assess outcomes. Treatment comprised Dara 1800mg sc, bortezomib 1.3mg/m² (twice weekly for cycles 1-2 in patients with suspected cast nephropathy) dexamethasone 40mg days 1,8,15,22 and Thalidomide 100mg/d for up to four 28d cycles, followed by Melphalan ASCT, 2 cycles DaraVTD consolidation and disease reassessment prior to Lenalidomide maintenance.

Results - Median age of patients = 61 (range 53-75) and 10/11 patients (91%) had light chain myeloma, with 1 IgA lambda and coexisting renal amyloidosis. All patients were ECOG PS 0-1 with no significant comorbidities. ISS was stage 3 in all patients and 5/11 (45%) had high-risk genomics - 3 TP53 deletions (one co-existing t(14;16)), one t(14;20) and one gain 1q. All patients had presenting eGFR <30ml/min and in 6/11 (55%) this was <15ml/min. A renal biopsy was done in 3 cases - 2 confirmed cast nephropathy and 1 renal amyloid. 4 patients (36%) required hemodialysis.

10 patients (91%) commenced DaraVTD induction with 4 cycles. 1 patient had 2 cycles VCD (bortezomib, cyclophosphamide, dexamethasone) before switching to DaraVTD. All patients had at least a myeloma partial response (PR) post induction, with very good partial response (VGPR) in 6/11 (55%) and complete response (CR) in 2/11 (18%). Renal outcomes were most often a modest response (MR) in 5/11 (45%), renal PR in 1 patient, renal CR in 1 patient and no response (NR) in the remaining 4 patients (36%). Of the 4 patients requiring RRT, 2 became hemodialysis independent after DaraVTD induction, within 2 and 3 months respectively.

4 patients required bridging with 2 x VTD and myeloma and renal responses pre-ASCT were unchanged. All 11 patients proceeded to Melphalan ASCT, with 10/11 having a renal protocol (140mg/m², cell return 48h later) and 1 patient (renal CR) having Melphalan 200mg/m² with cell return 24h later. Median length of stay for ASCT was 19d (range 8-75d). 3 patients (27%) required ICU admission for neutropenic sepsis, higher than our overall ASCT ICU admission rate of 7%. There was 1 death at 75d post ASCT in ICU related to chronic empyema. 1 patient (renal amyloid) developed a new hemodialysis requirement after Melphalan with dialysis independence at day 100.

10/11 (91%) patients had DaraVTD consolidation post ASCT with 8 proceeding to Len maintenance. 2 of these were intolerant of the 5mg dose and discontinued. Day 100 myeloma responses were CR in 10/11 patients (91%) with 8/11 (72%) being MRD negative by immunophenotyping (1 insufficient aspirate, 1 low level MRD+, 1 overt relapse). This compares favourably to day 100 responses of the DaraVTD cohort in CASSIOPEIA.

Day 100 renal responses in our cohort were MR in 5 patients (45%), CR in 2 patients, PR in 1 patient and NR in 3 patients. The surviving 10 patients remain free of significant toxicity at last follow-up (Jul 24).

Conclusion - Outcomes from this high risk group of NDTEMM patients presenting with renal failure show that DaraVTD induction and ASCT can be delivered safely. Despite being a small cohort, myeloma CR rates of over 90% at day 100 with significant MRD negativity and renal responses in over 70% are very encouraging, with no lasting deterioration in renal function or significant toxicity. This was reflected in 2 of the 4 RRT dependent patients achieving hemodialysis independence after induction and no new RRT dependence observed across the entire cohort after treatment. This supports DaraVTD and ASCT as an effective induction strategy in this high risk population.

Benjamin:Allogene Therapeutics, Arovella Therapeutics, Bristol-Myers Squibb, Janssen, Oncopeptides, Secura Bio: Consultancy; Alimera Sciences; Servier: Research Funding. Patten:Abbvie: Honoraria, Other, Research Funding; Astra Zeneca: Honoraria, Research Funding; Beigene: Honoraria, Other, Research Funding; Janssen: Honoraria, Other, Research Funding; Novartis: Research Funding.