Chr t(4;14)

P1, N=125, Recruiting, K36 Therapeutics, Inc. | N=60 --> 125 | Trial completion date: Oct 2025 --> Jun 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

Nevertheless, when co-segregation was eliminated, the detrimental effect of +1q or del(1p) was no longer observed. In conclusion, this study confirms the prognostic significance of high-risk cytogenetic abnormalities in MM and highlights the importance of considering co-occurrence for accurate prognosis assessment.

P2, N=61, Active, not recruiting, Omar Nadeem, MD | Recruiting --> Active, not recruiting | Trial completion date: Mar 2029 --> Dec 2030 | Trial primary completion date: Mar 2026 --> Dec 2026

P1, N=20, Completed, Noah Merin | Active, not recruiting --> Completed | N=30 --> 20 | Trial completion date: Nov 2031 --> Nov 2024

P1/2, N=70, Active, not recruiting, Wake Forest University Health Sciences | Trial completion date: Oct 2024 --> Nov 2032 | Trial primary completion date: Oct 2024 --> Apr 2029

P2, N=52, Active, not recruiting, Academic and Community Cancer Research United | Recruiting --> Active, not recruiting

Additionally, TRIM44 counters the TRIM21-mediated suppression of the antioxidant response, enhancing MM cell survival under oxidative stress. Collectively, our discoveries highlight TRIM44's significant role in MM progression and resistance to therapy, suggesting its potential value as a therapeutic target.

Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting.

P2, N=55, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2025 --> Jun 2028

Accordingly, AK2 suppression increased sensitivity of MM cells to proteasome inhibition. These findings delineate a novel mechanism in which aberrant transfer of carbon to the epigenome creates a metabolic vulnerability, with direct therapeutic implications for t(4;14) MM.

P2, N=29, Active, not recruiting, Emory University | Trial completion date: Aug 2024 --> Mar 2026 | Trial primary completion date: Jul 2024 --> Mar 2025

We continue to evaluate the clinical significance of SKY92 in combination with MRD testing as a superior prognostic repertoire of testing. These methods will improve risk stratification, and in future aid with risk-adapted therapy approaches.

P1/2, N=20, Active, not recruiting, Ciusss de L'Est de l'Île de Montréal | Trial primary completion date: Sep 2021 --> Oct 2023

Collectively, the findings offer valuable molecular insights for biomarker validation and potential drug development in t(4;14) MM diagnosis and treatment, with ivermectin emerging as a potential therapeutic alternative.

The literature lacks consensus regarding survival outcomes among patients with different NSD2 breakpoints. Our data align with previous findings indicating that patients with the MB4-2 breakpoint type tend to exhibit unfavorable overall survival.

Major deregulations are found in the lymphoid compartment as well, with skewing towards immune tolerant Th17 and Treg and inhibition of CD8+ cytotoxic and CD4+ activated effector T cells. In summary, this review will provide an overview of the complex cross-talk between MM plasma cells and immune cells in the microenvironment and the molecular mechanisms promoting progression from precursor states to full-blown myeloma.

Activation of this pathway is targetable using Ibrutinib and partially mitigated bortezomib resistance in an REIIBP xenograft model. Mechanistically, REIIBP upregulated TLR7 through eIF3E, and this relied on eIF3E RNA-binding function instead of its canonical protein synthesis activity, as demonstrated by direct binding to the 3'UTR of TLR7 mRNA. Altogether, we provided a rationale that coexistence of different NSD2 isoforms induced diversified oncogenic programs that should be considered in the strategies for t(4;14)-targeted therapy.

At the functional level, we showed that among the 13 genes, p53-regulated BAX expression correlated to, and directly impacted, the MCL1 BH3 mimetic S63845 sensitivity of myeloma cells by decreasing MCL1-BAX complexes...Nevertheless, scRNAseq analysis showed that myeloma cells surviving to the combination had lower p53 score, showing that myeloma cells with higher p53 score were more sensitive to BH3 mimetics. Taken together, we established a functional p53 score that identifies myeloma cells with biallelic TP53 invalidation, demonstrated that p53-regulated BAX is critical for optimal cell response to BH3 mimetics, and showed that MCL1 and BCL2 BH3 mimetics combination may be of interest for patients with biallelic TP53 invalidation, for whom there is still an unmet medical need.

The GFCH present here the overview of genomics alterations identified in MM and related PCs diseases associated with their prognostic factor, when available, and recommendations from an expert group for identification and characterization of those alterations. This work is the update of previous 2016 recommendations.

P3, N=1087, Active, not recruiting, ECOG-ACRIN Cancer Research Group | Trial primary completion date: Nov 2023 --> Nov 2025

A novel NGS targeted panel was designed and successfully validated, whose main novelty resides in the possibility to call CNAs from off-target reads, that can be used to define MM pts’ genomic risk factors, possibly required in the daily clinical practice. Thanks to AIRC IG2018-22059, AILBolognaODV.

CD34+ stem cells (SC) mobilization was performed with cyclophosphamide (2-4 g/smq) and G-CSF in 26 patients (74%) after a median time of 28 days (range: 13-50 221 Posters days) from the end of induction; 3 (11%) patients were mobilized only with G-CSF. Plerixafor on demand was administered in 13 pts (50%) failing to achieve the desired collection target...Hematological toxicity was the most common adverse event (50%; G≥3 anemia, neutropenia, thrombocytopenia occurred in 8%, 17% and 8% respectively), followed by infections (33%) and PNP (25%). In our real-life experience, D-VTD regimen was proven effective and well tolerated in TE-NDMM patients.

Key exclusion criteria included prior ixazomib exposure, refractoriness to anti-CD38 therapy, and refractoriness to bortezomib or carfilzomib therapy at last exposure. Treatment with DVd followed by DId with a PI iCT from bortezomib to ixazomib is a feasible approach for continuous PI and anti-CD38 therapy, leading to durable responses in RRMM pts, among whom nearly all (97%) were lenalidomide refractory. Immune correlates revealed distinct patterns of T-cell and NK-cell phenotypes when profiled serially in responding and non-responding pts. Additional correlative analyses are ongoing.

34 pts (81%) underwent SC collection, all with plerixafor (median yield 8.91x106 CD34+/kg). Extended frontline Dara-KRd for NDMM without ASCT induced high rates of sCR and/or MRD(-) within 8 cycles, meeting the primary endpoint. The rate and depth of MRD(-) improved beyond C8. This ASCT-free approach led to lower PFS for pts with 2+ HRCA, as also seen with ASCT, but excellent PFS in those with standard-risk disease and 1 HRCA.

ConclusionsIn the largest scRNA-seq study on CTCs to date, we demonstrate the utility of CTC-based molecular profiling for prognostication of patients with early-stage disease and provide novel insights into PC circulatory potential. Additional analyses are ongoing to gain further insight into intra-patient CTC heterogeneity and define high-risk disease CTC signatures that emerge throughout the MM disease continuum.

Briefly, pts with RRMM who have received ≥3 prior lines of therapy were enrolled & received a single infusion of CART-ddBCMA following lymphodepletion chemotherapy (fludarabine: 30 mg/m2/d & cyclophosphamide: 300 mg/m2/d daily for 3 days). Adverse events with CART-ddBCMA, including CRS & ICANS, were manageable & no off-tumor tissue-targeted toxicity, delayed neurotoxicity, or Parkinsonian-like events were observed in the entire cohort at the time of data-cut. Ongoing efficacy results are encouraging, with 100% ORR, including 35 (92%) response of VGPR or better & 29 (76%) with CR/sCR. More importantly, clinical responses were durable with an overall estimated 18-mo PFS rate of 67% with comparable clinical responses seen in 'high-risk' patients known to have poor prognosis.

This Phase 1 study will evaluate a potential treatment for RRMM utilizing KTX-1001, which is a novel, first-in-class, potent, oral small-molecule MMSET inhibitor. The study is open and actively enrolling patients at centers in the United States, Spain, France, and Canada.

Lenalidomide has shown to delay progression in patients with high-risk smoldering multiple myeloma (HR-SMM) and curative intent trials with carfilzomib-based therapy and stem cell transplantation have been recently reported in HR-SMM leading to deep responses but with concern for treatment-related toxicities...Treatment with D-RVD is 2 years (24 cycles) with daratumumab subcutaneous (SQ) per standard dose and schedule, bortezomib 1.3mg/m2 SQ on days 1, 8, 15 for cycles 1-6 then biweekly until completion of cycle 24, lenalidomide 25mg on days 1-21 for cycles 1-6 followed by 15mg d1-21 from cycles 7-24 with weekly low dose dexamethasone... D-RVD in HR-SMM demonstrates significant activity, including a 100% ORR and high rates of MRD-negative disease, preventing progression to overt myeloma.

Several studies have shown reduced efficacy of both FDA approved BCMA targeted chimeric antigen receptor T cell therapies (CAR-T) for myeloma, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), when administered after BCMA targeted bi-specific antibodies...Tocilizumab was administered to 4 (18%) pts... This single center study in patients with heavily pretreated and prior BCMA-TT demonstrated favorable ORR (63%) and CR (36%) rates, comparable to pts in the MajesTEC-1 trial, without prior BCMA-TT exposure. No new safety signals were identified. Results on progression free survival (PFS) and overall survival (OS) will be reported with continued follow up and will be presented in the meeting.

In conclusion, CTCs are detectable in about 33% of pts with asymptomatic monoclonal gammopathies, both in MGUS (in 17%) and more frequently in SMM (in 42%) pts. Their presence is associated with a trend towards increased risk of progression to symptomatic disease for SMM, but needs longer follow up to identify the role of CTCs in MGUS and the additive information over available risk stratification tools, which could provide an non-invasive, easy-to-follow longitudinally biomarker.

Systematic chromosomal re-arrangement and accessibility driven by differential epigenetic deposition of histone regulatory marks, differentiates t(4; 14) from non-t(4; 14) MM biology. These analyses suggest that given the nature of the translocation, and additionally the location of the chr4 breakpoint, result in major 3D chromosomal structural rearrangement, mediating biological programs that may explain the differences between successful and poor interventional therapies for this subset of MM disease.

Seven patients (30.4%) were previously treated with belantamab...Post-CAR T ferritin max correlated with the baseline b2m (p<0.001) and tocilizumab dose number (p=0.009) but none correlated with peak CAR T expansion (p=0.315)... In our single-center study of comparative analysis of commercial BCMA targeting CAR T-cell treatments, peak CAR T-cell expansion showed a positive correlation with +1 and +3 month post-CAR-T clinical responses. Despite the delayed peak expansion with ciltacel, the expansion was more robust with a higher level of circulating CAR T-cells. Baseline ALC or fludarabine dose reduction did not have an impact on overall CAR T expansion in combined cohort.

MRD by NGS in the PB was less sensitive compared to the same assessment in the BM by 1-2 logs; however, PB MRD status following 4 cycles of induction therapy was strongly prognostic given its association with PFS. PB MRD status early in treatment may represent a leading indicator of early response and/or a marker of high-risk disease features, and validation of these findings may help to eventually guide intensification of therapy.

We provide evidence for an important contribution of mutations within E and SE regions to the etiology of MM. This may involve either direct selection of mutations within the GC or by the re-entry of a memory B-cell carrying a pattern of mutations it acquired in a pre-MM phase, which then acquires a MM-specific driver. FIGURE: Distribution of mutations across MM genomes.

In the ongoing phase 1/2 CC-220-MM-001 study, iberdomide plus dexamethasone had a favorable safety profile and demonstrated clinically meaningful activity in triple-class refractory multiple myeloma (MM) patients, including those refractory to lenalidomide and pomalidomide (IMiDs®)...All patients received a PI/IMiD-containing induction regimen which also included daratumumab in 41% of patients...Iberdomide represents a novel effective post-ASCT maintenance strategy with a favorable safety profile and superior response improvement at 6 months than what has been observed with lenalidomide maintenance (26% at 6 months in the EMN02 study). Additional follow-up is needed to define the recommended maintenance dose that will be used in the randomized phase 3 EXCALIBER maintenance study, which will evaluate iberdomide vs. lenalidomide maintenance post-ASCT.

P2, N=40, Completed, Maisonneuve-Rosemont Hospital | Active, not recruiting --> Completed

P2, N=52, Recruiting, Academic and Community Cancer Research United | Trial primary completion date: Dec 2023 --> Sep 2024

P2; Trial primary completion date: Aug 2023 --> Jul 2024

Using DNA-encoded libraries, we have identified small molecule ligands that selectively and potently bind to the PWWP1 domain of NSD2, inhibit NSD2 binding to H3K36me2-bearing nucleosomes, but do not inhibit the methyltransferase activity. The ligands were subsequently converted to selective VHL1-recruiting NSD2 degraders and by using one of the most efficacious degraders in cell lines, we show that its leads to NSD2 degradation, decrease in K3K36me2 levels and inhibition of cell proliferation.

85.7% had isatuximab in combination with carfilzomib-dexamethasone and 14.3% pomalidomide-dexamethasone...Patients had a mean of 2.8(±1,19) previous chemotherapy lines(100% on lines including bortezomib and lenalidomide)... Median PFS was not reached in our study, which prevents us from comparing the results with the pivotal trial due to the immature data. Further studies with a larger sample size and longer follow-up period are needed to confirm these real-life results. It shows a good safety and tolerability profile in our patients.

Here we present first real world data demonstrating Ven to be an effective MM treatment option in heavily pretreated MM patients.