Kortüm, K. Martin

Abstract Solitary bone plasmacytoma (SBP) and SBP with minimal marrow involvement (SBPmm) are treated similarly with definitive radiation therapy (RT) followed by observation. However, differences in the natural disease course after RT between the two, are not well described. We performed a multicenter study assessing outcomes after RT in 141 patients with SBP and 102 with SBPmm diagnosed between January 2010 and December 2024. About 92% of patients with SBPmm progressed to multiple myeloma (MM) vs 76% of those with SBP (P = .01). Among patients with SBP, 21% progressed with a second solitary bone lesion vs 4% with SBPmm (P< .01). Patients with longer time to progression (TTP) after initial RT could achieve durable responses with RT to a second solitary plasmacytoma in the absence of other myeloma-defining events (MDE). Multifocal lytic bone lesions were the most common MDE, occurring in 89% and 81% of patients with SBPmm and SBP, respectively. Patients with SBPmm had a median TTP of 15 months (95% confidence interval [CI], 14-21) compared to 43 months (95% CI, 34-55) for those with SBP (P< .0001); 67% with SBPmm progressed within 2 years of diagnosis. Del(17p) and 1q+ (gain or amplification) were associated with shorter TTP to MM in SBPmm, with 2-year progression rates of 100% and 82%, respectively. We report significant differences in risk and modes of progression between SBP and SBPmm. Patients with SBPmm are at particularly high risk for early progression to MM, with most developing bone disease as the MDE. These findings support prospective studies incorporating frontline systemic therapy for SBPmm.

Abstract Gastrointestinal (GI) involvement is a clinically relevant but undercharacterized manifestation of systemic light chain amyloidosis (AL). We aimed to define the clinical spectrum, histologic patterns, and outcomes of symptomatic GI involvement in AL. We retrospectively analyzed 4396 patients with AL from 2010 to 2024, of whom 521 (11.9%) had provider-attributed symptomatic GI involvement; 66% had biopsy-proven GI AL. Symptoms most commonly included early satiety (61%), bowel irregularities (58%), nausea (35%), abdominal pain (28%), and dysphagia (23%). Autonomic neuropathy was frequent (43% clinician attributed; 23% via autonomic reflex testing) and contributed to dysmotility-related symptoms, often without GI biopsy positivity. Among 747 GI biopsies, mucosal infiltration predominated (71%) and was associated with bleeding (22% vs 9%), cachexia, and inferior survival, whereas vascular involvement was associated with lower bleeding risk. Combined involvement of mucosa, submucosa, and vessels conferred the worst prognosis (median overall survival [mOS], 2.4 vs 5.1 vs 7.8 years for 3 vs 2 vs 1 layer); mOS was 6.8 years and was primarily driven by cardiac stage and hematologic response (very good partial response [VGPR] or better: hazard ratio, 0.20; 95% CI 0.13-0.32), with more favorable outcomes in patients with isolated GI involvement. Cachexia and persistent diarrhea were the main drivers of morbidity, need for nutritional support, and GI-related mortality (odds ratio, 2.7 for the combined end point). GI bleeding rarely recurred after achieving VGPR or better. Overall, mucosal involvement, cachexia, and dysmotility define clinically meaningful GI AL and support systematic assessment of autonomic dysfunction as well as evaluation of the need for nutritional support as a GI-specific end point for AL trials.

Abstract Systemic light chain amyloidosis (AL) arises from monoclonal immunoglobulin light chains, but determinants of progression from precursor states remain poorly defined. In a cross-sectional cohort comprising 1950 systemic AL patients diagnosed 2010-2024, 258 (13.2%) patients with a previously diagnosed plasma cell disorder (PCD) were compared to patients with no prior PCD diagnosis. Patients with monoclonal gammopathy of undetermined signficance (MGUS) and smoldering multiple myeloma (SMM) in the former group had lower difference between involved and uninvolved FLCs (dFLC), higher M-protein, and lower rates of t(11;14) at AL diagnosis. Patients developing AL from SMM had a shorter time to AL (median 34.2 versus 61.3 months) and higher dFLC (median 28.9 versus 11.0 mg/dl) compared to those from MGUS. Patients developing AL after known multiple myeloma (MM) or lymphoplasmacytic lymphoma (LPL) commonly lacked deep hematologic response before AL (≤ very good partial response in 78% of MM, 100% of LPL patients). We additionally studied longitudinally followed cohorts of 3,966 MGUS and 426 (SMM) patients with longitudinal FLC measurements and matched follow-up, in which 1.8% of MGUS and 7.2% of SMM patients developed AL. Those patients who developed AL showed markedly higher dFLC at MGUS/SMM diagnosis and more frequent λ restriction and rates of t(11;14). Higher dFLC was associated with progressively earlier AL development; a 10% cumulative risk occurred at 20 months for patients with a dFLC >80 mg/dL but was not reached if dFLC <10 mg/dL at an estimated median follow-up of 86 months. In multivariable analysis, dFLC >6.4 mg/dL (HR 11.3) and λ isotype (HR 3.6) independently predicted AL, whereas heavy chain secretion was associated with lower risk (HR 0.2 for IgG). These findings indicate that AL risk is primarily driven by cumulative light chain exposure, refining our knowledge of AL pathophysiology and providing guidance for follow-up of patients with elevated dFLC.

PURPOSE Venetoclax, an oral BCL-2 inhibitor, has efficacy in t(11;14)-positive relapsed/refractory multiple myeloma (RRMM), which is enhanced by dexamethasone, which promotes BCL-2 dependency. METHODS The randomized, open-label, phase III CANOVA study (ClinicalTrials.gov identifier: NCT03539744 ) enrolled adults with t(11;14)-positive RRMM who had received ≥2 previous lines of therapy. Patients were randomly assigned (1:1) to venetoclax-dexamethasone or pomalidomide-dexamethasone until progression or intolerable toxicity. The primary end point was independent review committee assessed–progression-free survival (PFS) in the intention-to-treat population analyzed by stratified log-rank test (two-sided type I error rate, α = .05), with hazard ratio (HR) and 95% CI estimated by stratified Cox proportional hazard model. Secondary end points included response rates, overall survival (OS), minimal residual disease (MRD) negativity rate (<10 –5 ), and safety. RESULTS Overall, 263 patients were randomly assigned (venetoclax-dexamethasone, n = 133; pomalidomide-dexamethasone, n = 130). Median PFS was 9.9 months (95% CI, 6.9 to 12.6) with venetoclax-dexamethasone versus 5.8 months (95% CI, 3.8 to 9.2) with pomalidomide-dexamethasone (HR, 0.823 [95% CI, 0.596 to 1.136]; P = .24). Overall response and very good partial response or better rates were 62% and 39%, respectively, with venetoclax-dexamethasone versus 35% and 14% with pomalidomide-dexamethasone. MRD negativity rate was 8% with venetoclax-dexamethasone and 0% with pomalidomide-dexamethasone. Median OS was 32.4 months (95% CI, 26.4 to 40.7) with venetoclax-dexamethasone and 26.9 months (95% CI, 20.4 to 38.9) with pomalidomide-dexamethasone (HR, 0.856 [95% CI, 0.612 to 1.197]). Grade ≥3 treatment-emergent adverse event rates were 67% with venetoclax-dexamethasone versus 83% with pomalidomide-dexamethasone. There were 16 (12%) treatment-emergent deaths with venetoclax-dexamethasone versus 8 (6%) with pomalidomide-dexamethasone. CONCLUSION The primary end point of PFS was not met. PFS and OS were numerically longer with venetoclax-dexamethasone versus pomalidomide-dexamethasone in t(11;14)-positive RRMM. Consistent with previous studies, infections were associated with venetoclax-dexamethasone; no new safety signals were observed.

Abstract In this study, we investigated tumor intrinsic mechanisms of resistance to cevostamab, a bispecific T-cell engager targeting Fc receptor-like protein 5 (FCRL5) and CD3 that has shown promising clinical activity and durable responses in advanced MM. Longitudinal bone marrow aspirates from nine MM patients treated with cevostamab were analyzed. All patients had previously been treated with both immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI) and eight patients had received daratumumab prior to cevostamab, which was, on average, the 6th line of treatment (mean treatment duration 220±273 days). Five of nine patients responded with ≥PR. Whole genome and transcriptome sequencing was performed on sorted CD138+ MM cells at baseline, and whole exome and transcriptome sequencing was performed on five and three samples, respectively, following cevostamab discontinuation. Baseline FCRL5 expression levels did not correlate with clinical response. However, in one non-responder patient, FCRL5 expression increased four-fold after 28 days of treatment. Given the location of the FCRL5 gene on chromosome 1q—commonly amplified in advanced MM—we evaluated the presence of Gain(1q) in our study cohort. All patients whose best response was ≤PR (n=6) harbored a Gain(1q), whereas it was absent in those who achieved VGPR and sCR (n=3). Crucially, one of the patients that achieved sCR was initially treated with 60 mg of cevostamab for one year and then escalated to a higher dose cohort (90 mg) in the second year. At progression, a clonal FCRL5E115A missense mutation (allelic frequency = 56%) and a subclonal FCRL5G455Efs*19(allelic frequency = 5%) frameshift deletion mutation were detected, both absent at baseline. The missense mutation was located on the extracellular domain of FCRL5 targeted by cevostamab. To validate the functional impact of FCRL5E115Aand FCRL5G455Efs*19 on the sensitivity to cevostamab in vitro, we generated a FCRL5 knockout (KO) model utilizing CRISPR-Cas9 technology in OPM2 MM cells. In vitro cevostamab cytotoxicity assay with PBMCs and pan T cells from healthy donors at various effector to target (E:T) ratios confirmed a complete loss of cevostamab sensitivity in our FCRL5KO models. cDNA encoding patient-derived FCRL5 alterations (FCRL5E115Aand FCRL5G455Efs*19) as well as FCRL5wtwere cloned into mammalian expression vector and reintroduced into FCRL5KO cells. Cevostamab sensitivity was reinstated by FCRL5wt expression in KO cells. In contrast, FCRL5E115A conferred complete resistance to cevostamab (p&lt;0,001) and FCRL5G455Efs*19 depicted a significant decline in cevostamab sensitivity relative to FCRL5wt expressing models. Additional experiment utilizing direct stochastic optical reconstruction microscopy (dSTORM) are ongoing to monitor the membrane localization of FCRL5 mutants. By integrating genomic, transcriptomic and functional data with clinical outcomes, this work is the first to report on acquired FCRL5 mutations causing resistance to cevostamab. We hypothesize that the prolonged treatment duration may have contributed to the acquisition of the target mutations and note a subsequent durable sCR response to BCMA-targeted immunotherapy in the same patient, suggesting immune-related factors such as T cell exhaustion, were not drivers of cevostamab resistance. Due to the limited sample size, these findings require validation in larger cohorts. Nonetheless, our findings begin to elucidate tumor intrinsic mechanisms associated with cevostamab resistance.

Abstract Accurate prediction of risk of progression from smoldering (SMM) to active multiple myeloma (MM) is paramount to individualized early therapeutic strategies with minimum risk of overtreatment. Current risk stratification models do not account for evolving biomarker trajectories. We assembled the largest cohort to date of 2,270 SMM patients from six international centers with longitudinal clinical and biological data to train and validate the PANGEA 2.0 risk models. Four evolving biomarkers were significantly associated with shorter time-to-progression: M-protein increase ≥0.2g/dL, involved:uninvolved serum free light chain ratio increase ≥20, creatinine increase >25%, and hemoglobin decrease ≥1.5g/dL. PANGEA 2.0 outperforms established models including the 20/2/20 and IMWG models by more accurately predicting progression (C-statistics=0.69–0.84), even without biomarker history (C-statistics=0.69–0.83) or recent bone marrow biopsy. PANGEA 2.0 is an easy-to-use, open-access tool (https://ghobrial.shinyapps.io/pangea_2_calculator) to improve and individualize SMM risk stratification. Validation tools are available to compare PANGEA 2.0 to established models (https://ghobrial.shinyapps.io/pangea_validation).

Background Emerging evidence has demonstrated rare subacute to late neurological toxicities (NTs) after BCMA CAR T-cell therapy (CAR-T) in multiple myeloma (MM). These adverse events can be categorized as: 1) Parkinsonism (PD), 2) cranial nerve (CN) palsies, and 3) peripheral neuropathies/Guillan Barré syndrome (GBS). These toxicities can cause significant morbidity, but given their relative rarity in clinical trials, there is limited data regarding evaluation and treatment. To our knowledge, this is the largest and only global registry of delayed NTs after BCMA CAR-T. Methods We retrospectively established a registry of NTs via the Immune Therapy Working Committee of the International Myeloma Working Group (IMWG). We gathered data pertaining to demographics, MM characteristics, MM response, NT signs/symptoms, diagnostic workup, and treatment. Result A total of 52 patients with delayed neurotoxicity were included from 14 institutions and 6 countries; 92% received ciltacel, 4% idecel, and 4% investigational CAR-T. Median age at CAR-T infusion was 65 years; 69% were male and 88% were Caucasian. Median bone marrow plasma cell (PC) burden was 15% prior to CAR-T (range 0-95%). Patients received a median of 4 prior lines of therapy (LOT), with 67% progressing on last LOT. Seventeen percent had pre-existing neurological diagnoses (including stroke, epilepsy, migraines). We identified sixteen cases of PD (94% with movement disorder, 69% with cognitive impairment, 75% with personality changes), occurring at a median of 26 days (range: 15-87) after CAR-T. Ninety four percent had CRS (grade (G)1 50%, G2 38%, G3 6%, G4 0%), while 19% had ICANS (G1 13%, G2 6%, G3-G4 0%). Median peak absolute lymphocyte count (ALC) was 9.5 x 109/L, peak C-reactive protein (CRP) 60.9 mg/L, and peak ferritin 1893.5 ug/L within the first 30 days. Concurrently, 3 upper respiratory infections (URIs) and 2 low-level HHV7 in the cerebrospinal fluid (CSF) were detected. A median of 73% of T-cells in the CSF were CAR-T, based on a flow cytometry assay. Ten patients received steroids (median 19 days after symptoms, 70% partial response, 20% no response, 10% unknown), 2 received intrathecal (IT) methotrexate-based therapy (median 32 days after symptoms, 1 with no response, 1 unknown), 5 received intravenous (IV) cyclophosphamide (median 31 days after symptoms, 40% full response, 20% partial response, 40% no response), 4 received high-dose IVIG ≥1g/kg for one or more dose (50% partial response, 50% no response), and 6 received dopamine agonists. There were 37 CN palsies (76% CN7, 15% CN6, 7% CN5, 2% CN3), occurring at a median of 37.5 days (range: 7-482) after CAR-T. Eighty one percent had CRS (G1 68%, G2 14%, G3-G4 0%); 11% had G1 ICANS (G2-G4 0%). Median peak ALC was 4.1 x 109/L, CRP 25.4 mg/L, and ferritin 543 ug/L within the first 30 days. We identified 2 concurrent URIs, 4 CMV viremia (50% with viral load &gt;1500 IU/mL), 1 HHV6 viremia, and 1 HSV in the CSF. Thirty-two (86%) received steroids for a median duration of 12 days, 50% with full response, 3% with no response, and 47% with partial response (of which 43% had later full recovery without further intervention). One received IT methotrexate and another received IV cyclophosphamide without response. Thirteen (41%) received IVIG, of which 38% was high-dose IVIG. Four patients with CN palsies developed peripheral neuropathy/GBS. Eight patients (15%) in this cohort were not heavily pre-treated (≤1 prior LOT); 7 developed CN palsies (6 after ciltacel, 1 after investigational CAR-T) and 1 PD (after idecel). These patients had median &lt;5% PC; none had extramedullary disease. Median ALC was 4.14 x 109/L, CRP 33 mg/L, and ferritin 448.5 ug/L within the first 30 days. Conclusions Delayed NT requires prompt recognition, evaluation for alternative causes, and treatment. In our cohort, the majority of patients were male and Caucasian, suggesting that sex and race may impact the likelihood of developing NT. Individuals with PDs had greater inflammatory response (CRS, ALC, CRP, ferritin) compared to those with CN palsies. CN palsies responded to steroids and/or IVIG, whereas PD had at best partial response to steroids, prompting additional therapy. These toxicities notably did occur in less heavily pre-treated patients, perhaps driven by immune fitness and greater circulating T-cells rather than MM burden. At the time of the annual meeting, data will be updated with additional NTs from less heavily pre-treated patients.

7510 Background: The randomized Phase 3 CANOVA study’s (NCT03539744) primary analysis showed multiple numerically improved efficacy endpoints with VenDex v PomDex, but the primary endpoint of mPFS by IRC was not statistically significant. Here, we report correlative biomarker analyses from CANOVA. Methods: CANOVA is a randomized, global, open-label Phase 3 study of VenDex v PomDex in pts with t(11;14)+ RRMM and ≥2 prior lines of therapy (LOTs). The primary endpoint was mPFS by IRC. Key secondary endpoints included ORR, ≥VGPR, mOS, and MRD negativity (<10-5). In post hoc mPFS sensitivity analysis, disease progression, death, and start of next LOT were defined as events. BCL2 gene expression by RNAseq (3.7 log2 FPKM prespecified median cutoff for BCL2high v BCL2low) and chr1q abnormalities by whole-exome sequencing (normal, gain, or amp) were assessed centrally from pretreatment, CD138-enriched BM aspirates. Results: mPFS, post hoc mPFS, and mOS in the VenDex arm were similar by BCL2 status, with numerically higher ORR, ≥VGPR, and MRD negativity rates in the BCL2highsubgroup. In contrast, mPFS and mOS within the PomDex arm were numerically longer in the BCL2lowsubgroup, despite equal ORR in both subgroups (Table). Presence of 1q abnormalities was evenly distributed across BCL2high v BCL2low subgroups in the VenDex arm (51% v 45%) but not in the PomDex arm (59% v 31%). Normal 1q and gain(1q) subgroups had numerically improved mPFS, mOS, ORR, ≥VGPR, and MRD negativity with VenDex; pts with amp(1q) had poor outcomes regardless of treatment, albeit the sample size was small. Conclusions: Pts with BCL2high or gain(1q) had numerically improved clinical efficacy with VenDex v PomDex. Clinical benefit was consistent across BCL2 subgroups ( BCL2high or BCL2low) with VenDex but not PomDex. Pts with amp(1q) fared poorly irrespective of treatment arm. Clinical trial information: NCT03539744 . [Table: see text]

Background Chimeric antigen receptor (CAR) modified T-cells are leading to a paradigm shift in the treatment of relapsed/refractory (RR) multiple myeloma (MM). A high proportion of patients treated with CAR T-cells, however, experience prolonged cytopenia, with the mechanism remaining poorly understood. Here, we aimed to explore potential biomarkers that might correlate with cytopenia following CAR T-cell therapy in RRMM. Methods We prospectively collected peripheral blood (PB) of RRMM patients treated with idecabtagen-vicleucel (ide-cel) at the following time points: prior to lymphodepleting chemotherapy (LDC) (baseline), after ide-cel on day 4, 7, 14 and 28, and monthly thereafter. Cytopenia was determined according to the CTCAE version 5.0. Flow cytometry was performed with the following markers: CD45, CD3, CD4, CD8, CD62L, CD45RA, CD19, CD14, CD138, CD38 and a BCMA-CAR-detection marker. Results We included 222 PB samples at different sampling time points from 35 RRMM patients, who were pretreated with a median of 5 therapy lines (range 2-10). All patients were triple-class exposed and, 34 (97%) and 9 (26%) patients underwent autologous and allogeneic stem cell transplant (SCT), respectively. First, we analyzed the relationship between baseline parameters and the duration of grade ≥3 cytopenia after ide-cel (n=35). Notably, patients who received allogeneic SCT or &gt;4 lines of therapy did not develop longer lasting cytopenia than the remaining patients. We found a correlation between the baseline hemoglobin level and the duration of grade ≥3 anemia (r=-0.55, P&lt;0.001). Similarly, low baseline platelet count indicated long duration of grade ≥3 thrombocytopenia (r=-0.48, P=0.003). Moreover, high baseline ferritin level correlated with long duration of grade ≥3 anemia (r=0.52, P&lt;0.001) and thrombocytopenia (r=0.51, P=0.002). Furthermore, the maximum ferritin level after ide-cel was an indicator for long lasting grade ≥3 anemia (r=0.73, P&lt;0.001) and thrombocytopenia (r=0.71, P&lt;0.001). Interestingly, we found significant correlations between the duration of grade ≥3 lymphopenia and baseline CD4+ T-cell frequency (r=0.41, P=0.02), CD8+ T-cell frequency (r=-0.38, P=0.04) and CD4+/CD8+ ratio (r=0.4, P=0.03). Noteworthy, patients with β2-microglobulin level &gt;3.5 mg/l displayed longer duration of grade ≥3 anemia (median: 9 vs 0 day, P=0.007) and neutropenia (median: 43 vs 12 days, P=0.02) compared with the remaining patients, suggesting that high tumor load might be a risk factor for prolonged cytopenia after ide-cel. Second, we divided the follow-up PB samples (n=187) into two groups: early (&lt;d60) and prolonged (≥d60) cytopenia to account for direct toxic effects related to LDC. A high ferritin level was associated with low hemoglobin level (&lt;d60: r=-0.45, P&lt;0.001, ≥d60: r=-0.62, P&lt;0.001) and low platelet count (&lt;d60: r=-0.58, P&lt;0.001, ≥d60: r=-0.81, P&lt;0.001) in both groups. In prolonged cytopenia (≥d60), lymphocyte count correlated with the T-cell count (r=0.7, P&lt;0.001), suggesting that prolonged lymphopenia was mainly attributed to the reduced T-cell count after ide-cel. Of note, the frequency of naïve CD4+ T-cells (CD3+CD4+CD62L+CD45RA+) positively correlated with neutrophil count (r=0.58, P&lt;0.001), hemoglobin level (r=0.37, P=0.03) and white blood cell count (r=0.5, P=0.002) in the ≥d60 group, suggesting that delayed immune reconstruction with reduced naïve CD4+ T-cells might contribute to prolonged cytopenia after ide-cel. Moreover, in the ≥d60 group, lymphocyte count was related with the frequency of CAR+CD4+ (r=-0.58, P&lt;0.001), CAR+CD8+ (r=0.58, P&lt;0.001), CAR-CD4+ (r=-0.72, P&lt;0.001), CAR-CD8+ (r=0.75, P&lt;0.001) T-cells, as well as the ratios of CAR+CD8+/CAR+CD4+ (r=-0.6, P&lt;0.001) and CAR-CD8+/CAR-CD4+ (r=-0.75, P&lt;0.001). Conclusion Here, we present one of the first prospective studies investigating the factors associated with prolonged cytopenia after CAR T-cell therapy in RRMM. High tumor load, preexisting cytopenia and high ferritin level are related with prolonged cytopenia after ide-cel. Delayed immune reconstruction, characterized by reduced naïve CD4+ T-cell count, indicates prolonged cytopenia following ide-cel therapy. Patients with high CD4+/CD8+ ratio are at risk of prolonged lymphopenia (with reduced T-cell count), which may be a risk factor for infectious complications and an issue for subsequent T-cell based immunotherapies.

Abstract MYC expression is frequently dysregulated in multiple myeloma (MM). In one comprehensive study, MYC structural variations (SV) were found in nearly half of MM cases (Affer et al. Leukemia 2014). The prevalence was higher in hyperdiploid (HRD) tumors (65%) compared to non-hyperdiploid (NHRD) tumors (36%). The large amount of tumor DNA required for all of the genomic studies performed may have biased the samples analyzed (e.g., to those with higher tumor burdens). To validate the findings of recurrent MYC SV in another dataset, we analyzed the CoMMpass data. We analyzed long-insert whole genome sequencing (WGS) data from diagnostic samples in 420 patients from the IA7 release (dbGAP phs000748) for SV. The results of clinical data, processed WES (SNV), RNASeq (gene expression) and WGS (copy number) data from IA8 (http://research.themmrf.org) were used to calculate survival, RAS and NFKB pathway mutation (WES), TC class (RNA), NFKB index (RNA) and hyperdiploid index (WGS). MYC SVs were identified in 38% of tumors. They were present in 53% HRD and 28% NHRD, and by TC in 55% D1, 43% D2, 36% MMSET, 26% MAF, 13% CCND. Juxtaposition of an Ig enhancer (IgH, IgK, IgL) close to MYC was the most common MYC SV, representing ~40% of the MYC SV. Other enhancers identified have mostly been reported previously, with the most frequent being NSMCE2 (12% of SV) and TXNDC5 (5% of SV). Intrachromosomal SV (deletions, inversions, duplications) not associated with any known enhancer were also frequent (18% of SV). As expected, MYC expression was higher in tumors with MYC SV compared to those without (~2.4 fold, p-value<0.0001). We used Gene Set Enrichment Analysis (GSEA) to identify activated pathways that might substitute for MYC in HRD patients without MYC SV and observed significant activation of the NFkB pathway. Interestingly, examining patients with RAS/MAPK pathway (NRAS, KRAS, BRAF, FGFR3 - abbreviated RAS) mutations (identified in 50% of all patients) the same pattern was observed: in the absence of RAS mutation, there was a significantly higher NFkB index. In general, the HRD tumors seem to have either activation of RAS and/or MYC, or activation of NFkB (Figure). There was no difference in overall survival in patients with versus those without MYC SV. We developed a clinically applicable sequencing platform to identify MYC SV, which cannot be reliably identified by FISH. We sought to validate this targeted capture approach, where in addition to the coding exons of 81 interesting genes described previously (M3P), we also pulled down the region surrounding MYC (2 Mb), IgH (0.5 Mb), IgK (50 kb) and IgL (100 kb) allowing us to additionally identify SV in MYC and Ig loci. Using this approach we identified IgH translocations in 29/30 samples with translocations previously identified by FISH (97%). Moreover, we identified MYC SV in 19/22 patients with SV previously identified by mate-pair WGS (86%). Importantly, sequencing identified the precise translocation breakpoint, and identity of the enhancer dysregulating MYC, which may be important variables. In one informative patient two different MYC SV were present at diagnosis, only one of which was still present following a partial response to four cycles of lenalidomide and dexamethasone. This suggests that the two MYC SV are in different subclones, one of which was much more sensitive to the treatment. Interestingly, the enhancer dysregulating MYC in the sensitive subclone harbors 5 strong Ikaros binding sites identified by ChIPseq, suggesting one intriguing mechanism for sensitivity to lenalidomide. To summarize, we verified in a large dataset that MYC expression is frequently dysregulated by SV in MM (38%), and the RAS/MAPK (50%) and NFKB (23%) pathways are frequently activated by mutations. Surprisingly, given their generally good prognosis, nearly half of HRD tumors seem to be MYC driven, while this is true for only a quarter of NHRD tumors. HRD tumors not driven by MYC or RAS appear to be driven by NFKB. Remarkably, the pathways most commonly activated by mutation in MM: CCND, MYC, RAS, NFKB are common to many cancers and have been studied extensively individually. To understand their clinical impact in MM we have developed a comprehensive custom capture sequencing panel that identified 97% of IgH translocations, 86% of MYC SV, and as well as SNV and CNV of 81 recurrently mutated genes. It will be important to include such a comprehensive genetic analysis to complement clinical trials in the future. Figure. Figure. Disclosures Stewart: Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Takeda Oncology: Consultancy; Janssen Pharmaceuticals: Consultancy.