Background: Isatuximab and daratumumab target the CD38 transmembrane glycoprotein on MM cells. IKd and DKd regimens have shown reductions of HR=0.53 (95%CI 0.32-0.89) and HR=0.63 (95%CI 0.46-0.85) resp. in progression or death risk compared to Kd in RRMM. In the absence of a direct IKd vs DKd trial, we performed an indirect treatment comparison on progression free survival (PFS) to enable cost-effectiveness analyses. Methods: A 3-state (pre-progression, progression, death) partitioned survival model was specified. NMA-adjusted transition probabilities were estimated from fitted exponential functions (time horizon of 6 and 12 m; cycle length 28 days). Inputs included the Wholesale Acquisition Cost of IKd, DKd, and premedications; cost of medication administration; and cost of adverse event management. Utility inputs for pre-progression (0.65) and progression (0.61) were per literature. Costs and utilities were discounted at 3.5%/y. A payer perspective was adopted. Life years (LY), quality adjusted LY (QALY), and incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) were estimated in base case (BCA) and probabilistic sensitivity analyses (PSA). Cost-effectiveness acceptability curves (CEAC) were generated. Results: As detailed in the Table, 6m of IKd treatment was associated with incremental gains of 0.01 (PSA 0.01) LYs but no gains in QALYs at cost savings of $24,188 ($23,762), yielding a dominant ICER of $ -2,418,800 ($-2,376,200) per LYg (ICUR not estimable). Further, 12m of IKd treatment was associated with incremental gains of 0.04 (PSA 0.04) LYs (or 0.48m) and 0.02 (0.03) QALYs at incremental cost of $1,585 ($2,239), yielding ICER of $39,625 ($55,975) per LYg and ICUR of $79,250 ($74,633) per QALYg. Per CEAC, IKd is the dominated strategy in the 6m model and had probability of 50% of being cost-effective at WTP of $100,000 in the 12m model. Conclusions: Clinically, compared to DKd, IKd is associated with slight incremental gains in LYs of 0.12m over 6m and 0.48m over 1y. The 6m clinical gain comes with cost savings of approximately $24,000 or about 15% of IKd therapy, while the 12m gain requires a minimal cost commitment of around $2,000 or 0.6% of DKd treatment. These findings imply a clinico-economic benefit of isatuximab compared to daratumumab containing regimens in RRMM.