Background: Approximately 20% of NDMM patients (pts) demonstrate early therapeutic resistance, manifesting as primary refractoriness (1REF) to 1st-line therapy (1L) or early progression (EP) despite optimal induction therapy ± ASCT and lenalidomide maintenance. Most of these pts do not exhibit diagnostic high-risk cytogenetics/FISH, precluding a risk-adapted approach to therapy and underscoring the need for genomic analysis to enhance risk-stratification. Classified as functional high-risk (FHR) disease, these pts have unacceptably short OS, median 16.9 vs 78.2 months (mos) for pts progressing <12 vs >12 mos from 1L (p<0.001) (unpublished, ANZ MRDR landmark analysis). This impact persists even after redefining FHR MM as EP≤18 mos of 1L therapy (post-hoc analysis of the CASTOR trial), highlighting an ongoing unmet need for effective therapies for FHR MM.

Methods: The Australasian Myeloma Research Consortium (AMaRC) IBIS trial (ACTRN12621001037897) combines iberdomide (IB), isatuximab (IS) and dexamethasone (DEX) salvage for 50 FHR pts relapsing ≤18 months of 1L: IB 1.6mg PO D1-21, IS 10mg/kg IV D1,8,15,22 of cycle 1 and 2-weekly thereafter and DEX 40mg D1,8,15,22 (20mg, age>70 years) of each 28-day cycle to PD. Primary objective is to establish ORR and safety at end of cycle (EOC) 12. We present the second pre-specified, interim analysis of this endpoint of 29 evaluable pts defined as having either ≥12 months of follow-up or those who withdrew from study earlier.

To understand the underlying genomics, we performed low-coverage whole genome sequencing (LC-WGS) and targeted amplicon sequencing (TAS) of MM-specific genes from circulating tumour DNA (ctDNA) to quantify tumour fraction (TF), copy number alterations and mutational spectrum. Bioinformatic analysis was conducted using ichorCNA for LC-WGS data to derive TF estimates while TAS analysis is ongoing with a custom QIAseq library kit and validated bioinformatic pipeline.

Results: 51 pts were enrolled prior to 27MAY2025; one pt withdrew prior to receiving study drug. As of 25JUN2025, 29/50 pts are evaluable – 51.7% males, median age 65.4 years (43.1-81.7), 24.1% R-ISS III at diagnosis. Of 50 pts: 28%, 32%, 16%, 12% with 0, 1, 2 or 3 high-risk chromosomal abnormalities respectively; 34% fulfilling IMS2025 high-risk criteria, 54% standard-risk and 12% in whom diagnostic CG/FISH were omitted, 83% received PI-IMID 1L (76% VRd, 3% VRd+chemotherapy, 7% VRd+Selinexor), 10% bortezomib-cyclophosphamide-dexamethasone (VCD), 7% lenalidomide-dexamethasone (Rd), 24% ASCT; 10% 1REF to 1L and 90% relapsed after initial response to 1L, of these 72% had ³PR to 1L. Median time from 1L to IBIS salvage was 6.3 months (1.6 – 19.2).

For the primary endpoint, of the 29 evaluable patients, 20 achieved best response ≥PR, ORR 69.0% (95%CrI 50.3-82.6%). Posterior probability that the true ORR rate >40% is 99.9% and thus protocol-specific proof of concept (POC) criteria continued to be met. In those with ≥PR (N=20), response was rapid, 95% by EOC3. Of 29, 15 remain alive and progression-free, 8 alive with confirmed PD and 6 dead: 5 myeloma-related deaths and 1 due to infection. Preliminary estimates of PFS and OS at 9 months are 51% and 82% respectively.

To date in all pts, the 5 most common adverse events (AEs) were: neutropenia (54%; grd 3-4 52%), insomnia (36%; grd 3-4 8%), infusion-reaction (28%; grd 3-4 2%), upper respiratory tract infection (26%; grd 3-4 4%) and constipation (24%; no grd 3-4). Overall, 2 grd 5 events: lung infection and sepsis, 3 adverse events of special interest: 1 grd 3 infusion-reaction to isatuximab and 2 reports of squamous cell carcinoma.

Preliminary analysis of ctDNA LC-WGS results were available for 49/50 pts (1 pt had an unevaluable sample). A TF was detected in 23/49 pts (46.9%, median=17.3% [5.3-82.8%]), with 18/23 pts exhibiting >10% TF and of which 5/18 showing a TF >50%. Of the 8/29 pts with PD, 6 had a TF (median=76% [59.6- 82.8%]). FISH, cytogenetic, and LC-WGS analyses revealed del(17p) in 30% of pts. LC-WGS identified MYC copy number gains in (12/49) 24% pts.

Conclusion: In this second planned interim analysis, IB-IS-DEX was well-tolerated, achieved early disease control and demonstrated promising efficacy in FHR MM. Preliminary ctDNA genomic analyses highlight a substantial burden of adverse biology, with frequent del(17p), MYC copy number gains, and high cTF among pts with PD. Updates on survival will be presented at the conference.

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2025
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