CRBN mutation

Conclusions These data illustrate that late-line RRMM subjects have appreciable immunosuppression compared to NDMM subjects, with particular dysfunction in the CD4+ helper T-cell compartment, suggesting that the efficacy of immunotherapies in late line myeloma may benefit from combinations with agents that improve CD4+ T-cell function. These data also show enrichment of molecular high-risk segments and CRBN-related genomic aberrations in RRMM subjects in the CC-220-MM-001 study.

This session is dedicated to advancing therapeutic strategies in the field of multiple myeloma and Waldenström's Macroglobulinemia. The session encompasses approaches to enhancing CAR T-cell tumor specificity, single-cell multi-omic analysis to identify novel mediators and therapeutic targets, the investigation of CRBN mutations and their impact on treatment response, the potential exploitation of gut microbiota to boost immunotherapy, and insights into methylation and chromatin accessibility for disease classification and evolution.

We included all pts with ≥2 paired bone marrow samples before and after an IMiD-based treatment (lenalidomide [LEN], thalidomide [T], pomalidomide [POM]) (baseline and relapse samples) and analyzed the patterns of molecular lesions of 42 CRBNPGs (based on Sievers et al. Notably, new/enriched mutations in other genes, beyond CRBNPGs, with known roles as MM drivers cannot be excluded as alternative explanations for these relapses. Additional and more complex, genomic or non-genomic, mechanisms may account for relapse from IMiD-based regimens.

Moreover, HR SKY92 was significantly more common in patients who received high-dose melphalan (48/89, 53.9%) than the remaining patients (9/32, 28.1%) ( P =0.01)...We found CRBN mutation in 3 out of 7 patients with only HR SKY92 but SR FISH. We provide the first prospective evidence that “double-HR” (SKY92 + FISH according to R2-ISS) indicates the highest-risk MM.

P=N/A, N=40, Active, not recruiting, University of Turin, Italy | Trial completion date: Jul 2023 --> Jul 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

Moreover, HR SKY92 was more common in patients who received high-dose melphalan and autologous stem cell transplant (48/89, 53.9%) than the remaining patients (9/32, 28.1%) (P=0.01)... We provide the first prospective evidence that "double-HR" (SKY92 + FISH according to R2-ISS) indicates the highest-risk MM.

P=N/A, N=40, Active, not recruiting, University of Turin, Italy | Recruiting --> Active, not recruiting

We provide the first prospective evidence that "double-HR" (SKY92 + FISH according to R2-ISS) indicates the highest-risk MM.

ARV-471 is an orally bioavailable cereblon (CRBN)-based PROteolysis-TArgeting Chimera (PROTAC®) small molecule that demonstrates superior ER degradation and anti-tumor activity compared to fulvestrant in endocrine sensitive and resistant xenograft models and has shown significant ER degradation and promising clinical benefit in late-line ER-positive breast cancer patients. CRBN knockout in ER+ breast cancer cells did not confer resistance to ARV-471, consistent with ARV-471 possessing ER antagonist activity independent of its degrader activity. Together, these data suggest that acquired resistance to ARV-471 may be associated with alterations within Receptor Tyrosine Kinase/MAPK signaling pathways rather than ER signaling or E3 ligase machinery.

All 5 patients were exposed in previous lines to lenalidomide and pomalidomide. All patients were treated with CC-92480 in combination with dexamethasone...Streptavidin pulldown and immunoprecipitation assays showed decreased binding of thalidomide, DDB1 and CUL4A to R309H-CRBN mutant compared to WT-CRBN... We here defined in primary patient plasma cells the mechanisms of resistance to the novel CELMoD CC-92480 to be driven by biallelic CRBN copy number loss or alteration of its structure, resulting from CRBN mutations or splicing (exon 10) coupled with monoallelic 3p loss. COP9 signalosome subunits gene expression decreased in resistant patients and may also play a critical role in CELMoD sensitivity.

A transcriptional signature was associated with more durable ide-cel responses, which we postulate may outline a distinct suboptimal pretreatment feature in an ide-cel context; further exploration of this preliminary signal is ongoing. **Authors contributed equally to this abstract.

FISH is the preferred approach in pts with BM PCI <10% and for the detection of clones <15% or variant ploidy levels. WGS is superior to FISH regarding the identification of biallelic events and rearrangements with heterogeneous breakpoints and rare partners. But even more, WGS can address various questions in follow up in terms of increase of complexity, target specific therapy, therapy failure and relapse.

The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide and pomalidomide are approved drugs for the treatment of multiple myeloma. After transplantation, MOPC.315.BM.Luc.eGFP cells expressing murine Crbn induced multiple myeloma in mice and treatment with lenalidomide and pomalidomide significantly delayed tumor growth. This straightforward model provides a proof-of-concept for studying the effects of IMiDs in multiple myeloma in mice, which allows for in vivo testing of IMiDs and other CRBN E3 ligase modulators.