IgH Translocations Research Articles

Temporal Genomic Dynamics Shape Clinical Trajectory in Multiple Myeloma.

To comprehensively unravel the temporal relationship between initiating and driver events and its impact on clinical outcomes, we analyzed 421 whole-genome sequencing profiles from 382 patients. Using clock-like mutational signatures, we estimated a time lag of 2-4 decades between initiating events and diagnosis. In patients with hyperdiploidy, we demonstrate that trisomies of odd-numbered chromosomes can be acquired simultaneously with other chromosomal gains, such as 1q gain. We provide evidence that hyperdiploidy is acquired after canonical IGH translocation when both events are present. Finally, patients with early 1q gain had adverse outcomes similar to those with 1q amplification (>1 extra-copies), but faring worse than those with late 1q gain. This underscores that the prognostic impact of 1q gain/amp depends more on the timing of acquisition than on the number of extra copies gained. Overall, this study contributes to a better understanding of the life history of MM and may have prognostic implications.

Current state of genetic analysis in multiple myeloma and future perspectives

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells. Recent advances in next-generation sequencing technologies have facilitated in-depth genetic exploration of MM, unveiling a more comprehensive genomic landscape that extends beyond classical chromosomal alterations, such as IGH translocations and hyperdiploidy. These studies have elucidated recurrent mutations across various functional pathways including those involving MAPK, NF-κB, cell cycle regulation, and epigenetic modulation. With respect to clinical utility, studies have shown that the number of genetic alterations and biallelic events in TP53 are associated with worse prognosis, and CRBN mutations with resistance to immunomodulatory drugs. We recently analyzed the full landscape of genetic alterations in relapsed and refractory MM using circulating tumor DNA (ctDNA), revealing TP53 mutations as the most frequent driver mutation. Notably, more than half of TP53 mutations were present in only ctDNA, suggesting a subclonal origin. Mutations in six genes, including KRAS and TP53, were associated with poor progression-free survival. In addition, the number of ctDNA mutations was identified as a prognostic factor independent of IGH translocations and clinical factors. Here we summarize recent progress in genetic analysis of MM, focusing on clinical relevance.

Primary central nervous system marginal zone lymphoma.

Marginal zone lymphoma (MZL) is the most common indolent lymphoma primarily arising in the central nervous system (CNS). To date, 207 cases of primary CNS MZL (PCNSMZL) were published, mostly as single case reports or small case series. It most commonly presents as extra-axial dural-based masses, more frequently in middle-aged women, displaying an insidious onset, with a long history of symptoms preceding the diagnosis. PCNSMZL can be radiographically mistaken for meningioma. PCNSMZL consists of CD20+ , CD3- small B lymphocytes with varying degrees of plasmacytic differentiation and low proliferation index. Trisomy 3, but not MALT1 or IgH translocation, is a common genetic abnormality. Other recurrent genetic abnormalities involve TNFAIP3 and NOTCH2. Ethiopathogenesis was poorly investigated. Due to its rarity, standard of care remains to be defined; it exhibits an excellent prognosis after varied treatments, such as surgery, radiotherapy, chemotherapy or their combinations. Nevertheless, each treatment should be considered after an accurate analysis of overtreatment risk. Short follow-up is a major limitation in reported PCNSMZL cases, which restrains our knowledge on long-term results and iatrogenic sequels. This review was focussed on presentation, differential diagnoses, pathological findings, treatment options and clinical outcomes of PCNSMZL; recommendations for best clinical practice are provided.

Single Cell Whole Genome Measurement of Genomic Heterogeneity and Clonal Evolution in Multiple Myeloma

Background: Sequencing studies have advanced our understanding of the genomic underpinnings of Multiple Myeloma (MM). While whole genome sequencing (WGS) has emerged as a comprehensive approach for profiling the genomic landscape of MM, WGS has limited sensitivity in defining the intrapatient genomic heterogeneity. Single cell RNA approaches can capture phenotypic heterogeneity but fail to recover most of the key genomic drivers. To overcome these historical limitations, we utilized a newer single cell whole genome direct library preparation (scWGS DLP+; Lacks et al. Cell 2019) sequencing technology able to detect early changes and study clonal population dynamics, providing a more precise understanding of the emergence and clinical impact of genomic events during MM evolution. Methods: scWGS DLP+ was applied to CD138 + Plasma Cells (PC) isolated from bone marrow samples of MM patients. Using newly developed computational approaches, we characterized the Single Nucleotide Variants (SNVs), copy number changes and complex Structural Variants (SVs) at a single cell level and use this information to reconstruct the evolutionary histories of each patient's myeloma. Results: We applied DLP to 7 MM patients obtaining 800-1600 single cell whole genomes per patient. All canonical IgH translocations identified by FISH were recovered in the scWGS data. Single cell copy number heterogeneity was observed in all but 1 patient, including heterogeneity affecting known drivers. The number of subclones ranged from 1 to 15, with an average of 6 subclones detected per patient (≥10 cells, ≥5MB distinct segmental difference). This is in striking contrast with bulk WGS where we are usually able to define no more than one or two subclones. Gain of 1q (3 copies) was observed in all patients but was either rare (1-3%, 3 patients) or clonal (>99%, 4 patients), with two clonal 1q patients exhibiting convergent subclonal 1q amplification (>3 copies). Loss of previously gained chromosomes was observed including loss of ancestrally gained chromosome 15 in hypodiploid Patient 2, and sporadic loss of 1q in patients with ubiquitous 1q gain. For 3 of 7 patients, hypodiploidy (HRD) had arisen before the most recent clonal expansion. HRD clones continued to diversify, accruing multiple additional events on HRD chromosomes including large or focal gains, or deletions subsequent to a gain. Interestingly, one case had 1 small hypodiploid clone co-existing with a completely different major clone with 1q and t(14;20) IgH translocation, suggesting the existence of two distinct clonal plasma cell populations (one malignant and one likely bening). Two of the 7 patients harbored both small (<20 cells) whole genome doubled (WGD) subclones, and small numbers of highly aneuploid likely produced by multi-polar cell division post WGD. We explored two patient's evolutionary histories in detail, highlighting the unique resolution of scWGS DLP+ to detect CNV but also SNV, mutational signatures and SVs. Patient 3 exhibited 4 distinct subclones with distant evolutionary origin as evidenced by the relatively small number of shared SNV. APOBEC signature mutations were detected in all 4 subclones suggesting APOBEC mutagenesis was still ongoing across the cell populations in this patient. In Patient 1, a complex SV on chromosome 17 resulted in loss of most of 17q and an amplification of 17q segments. The heterogeneous structure of chromosome 17 across clones suggests a late onset of this complex event and ongoing instability. Chromosome 16 exhibited a pattern of cell specific arm loss likely resulting from telomere loss. Interestingly, a minor clone showed complex amplification of 16p affecting TNFRSF17, suggesting that chromosome 16 is at an earlier stage of a process of instability that starts with cell specific arm loss, and ends with clonal expansion of a complex amplification SV targeting a gene with fitness benefit. Discussion: Applied to Multiple Myeloma, scWGS shows higher clonal heterogeneity than previously described with multiple clones exhibiting diverse genetic alterations. The findings underscore the genomic complexity and dynamic nature of MM, highlighting the need for sensitive techniques like scWGS to capture the full spectrum and chronological order of genomic events.

The Complex Structural Variant Chromothripsis Can be Defined on Targeted Sequencing Panels, Allowing Direct Clinical Translation in Order to Improve Multiple Myeloma Prognostication

Introduction: the complex structural variant (SV) chromothripsis is an independent predictor of progression-free (PFS) and overall survival (OS) in newly diagnosed multiple myeloma (NDMM); predictive in multivariate analysis when considering ISS, IgH translocations and TP53 status (Rustad BCD 2020). Chromothripsis is not included in current prognostic scores, despite a prevalence of 24% in NDMM. While gold-standard definition requires whole genome sequencing (WGS), we've previously shown that copy-number (CN) signatures are also able to accurately define chromothripsis in whole exome sequencing (WES, Maclachlan Nat Com 2021). As neither WGS nor WES are currently used in clinical medicine, we applied CN signatures to targeted sequencing, aiming for direct clinical translation of this key biological feature into clinical practice. Memorial Sloan Kettering (MSK) now offers the MSK-Heme-IMPACT targeted sequencing panel to all MM patients having a bone marrow biopsy (BMBx), as well as offering retrospective analysis for current patients having leftover DNA from prior BMBx. Methods: We analyzed 420 samples having either myTYPE or MSK-Heme-IMPACT targeted sequencing at MSK prior to July 2023. We excluded those with whole genome duplication, applied CN signatures, then for samples from NDMM performed multivariate analysis for PFS prediction by backwards stepwise regression. In samples with CN signatures predictive for chromothripsis and with DNA available from the same BMBx, we performed parallel WGS in order to check for chromothripsis. WGS sequencing was at 60-80x for tumor, 30-40x for normal, with analysis including Battenberg for CN analysis, with SvABA, BRASS and GRIDSS for SV calling. Additional parallel WGS is in progress for 45 samples with NDMM prior to DVRd or DKRd, in order to examine chromothripsis prediction and PFS impact in the context of highly effective induction. Results: From 420 samples, 48 were collected at the precursor stage, 205 with NDMM, and 167 with relapsed disease. 39 patients had 2 assays performed, while the remainder were unique patient samples. Within NDMM, the range of induction regimens received included lenalidomide and dexamethasone with bortezomib (VRd), carfilzomib (KRd) or daratumumab (DRd), along with quadruplet therapy (DVRd or DKRd). Targeted sequencing data detected all 6 key CN features observed in WGS and WES analysis. Similar to WES, there was a lower contribution from very high breakpoint counts per 10mB and longer lengths of oscillating CN segments, due to the lower resolution of targeted sequencing data. De novo extraction of CN signatures defined 1 signature containing multiple features consistent with chromothripsis; high breakpoint count per 10mB, more jumps between adjacent CN segments, longer lengths of oscillating CN segments and a predominance of small CN segments. When examining samples from NDMM, contribution from this signature was predictive of PFS in multivariate analysis when considering age, ISS, t(4;14), TP53 status and gain1q21 (hazard ratio > 4, p=0.003). 33 samples had a predictive probability for chromothripsis > 0.6 (the cut-off in WGS / WES having the highest sensitivity and specificity for prediction), with also having further DNA available. 30/33 (91%) were confirmed to harbor chromothripsis on manual inspection of WGS data. 19/30 (63%) with chromothripsis were BMBx from NDMM, while 11/30 (37%) were from relapsed disease. Discussion: the complex SV chromothripsis is a key genomic risk factor predicting for poor PFS and OS in MM, which is currently not being captured in routine practice or in clinical trials. Here, we demonstrate that chromothripsis can be predicted from targeted sequencing data, confirmed by gold-standard WGS analysis. Ongoing studies are expanding our cohort of NDMM with concurrent targeting sequencing and WGS, to define the sensitivity and specificity of targeted-sequencing-based CN signature prediction of chromothripsis. The additional cohort largely comprises patients treated with daratumumab-quadruplet induction therapy, aiming to confirm that chromothripsis and CN signatures retain prognostic significance in the context of this therapy. With this data is in hand, we will develop a CN signature fitting tool, similar to mmsig for mutational signatures (Rustad Comm Biol 2021), to allow easily accessible incorporation of chromothripsis assessment into clinical practice.

MASS-4 Is More Suitable Than MASS-3 for Prognostic Stratification in Transplant-Eligible Patients Withnewly Diagnosed Multiple Myeloma

Introduction: In 2022, Mayo Clinic proposed the Mayo Additive Staging System (MASS), a new staging system for patients with newly diagnosed multiple myeloma (NDMM). Based on the number of risk factors (International Staging System III, elevated lactate dehydrogenase, 1q gain/ amplification, high-risk IgH translocations, chromosome 17 abnormalities), they were divided into the 3-tier MASS (MASS-3) (no, 1, ≥2 high-risk factors for stage I, II, III, respectively) and 4-tier MASS (MASS-4) (no, 1, 2, ≥3 high-risk factors for stage I, II, III, IV, respectively). Real-world studies have shown that MASS-3 and MASS-4 are suitable for prognostic stratification in Chinese patients with NDMM, but there is no clear evidence of their utility in transplant-eligible patients with NDMM. Methods: A retrospective analysis of the clinical data of 215 NDMM patients who received “induction therapy-autologous hematopoietic stem cell transplantation (ASCT)” in our center was performed. The prognostic stratification value of the two stages was analyzed and compared in patients overall, with different transplant times, with different ages, and with different induction regimens. Results: 72 (33.5%), 66 (30.7%), and 77 (35.8%) patients were classified as MASS-3 I, II, and III, respectively. The median progression-free survival (PFS) was 77.7, 87.7, and 50.5 months, respectively(P=0.011), and the median overall survival (OS) was not reached, 109.6, and 69.7 months, respectively(P=0.003). The PFS and OS of patients with MASS-3 III were significantly shorter than those of stage I (P<0.05). 72 (33.5%), 66 (30.7%), 54 (25.1%) and 23 (10.7%) patients were classified as MASS-4 I, II, III, and IV, respectively. The median PFS was 77.7, 87.7, 52.6, and 34.5 months, respectively (P=0.004), and the median OS was not reached, 109.6, 106.0, and 40.6 months, respectively (P<0.001). The PFS and OS of patients with MASS-4 III were significantly shorter than those of stage I (P<0.05). The PFS of patients with MASS-4 IV was significantly shorter than that of stage I, II, or III (P<0.001). The OS of stage IV was significantly shorter than that of stage I or II (P<0.01), and tended to be shorter than that of III (P =0.06). Among 118 (64.1%) Revised International Staging System II patients, MASS-3 could not distinguish their prognosis (P>0.05), but MASS-4 could differentiate their prognosis (P<0.05), with MASS-4 IV patients having significantly shorter PFS and OS compared with stage I, II, or III (P<0.05). In patients with single ASCT, different ages, and different induction regimens, the prognostic stratification of MASS-4 was also better than that of MASS-3. However, there was no significant difference in PFS and OS between different MASS-3 or MASS-4 stages in patients with tandem ASCT. Conclusion: Among transplant-eligible patients with NDMM, the prognostic stratification value of MASS-4 was better than that of MASS-3, particularly distinguishing high-risk patients with poor prognosis. Compared with single ASCT, tandem ASCT may overcome the poor prognosis of high-risk MASS patients.

“Double Hit” Myeloma: Detection By FISH and Flow Cytometry in Circulating Myeloma Plasma Cells

“Double hit” myeloma is defined as the presence of 2 of the known high-risk genetic abnormalities in myeloma. This includes amp(1q), del(17p) and IGH translocations involving chromosomes 4, 16 and 20. Given the prognostic significance of these abnormalities, with poor overall survival, identification is crucial. Testing is traditionally by fluorescence in situ hybridization (FISH) on a single-site bone marrow sample at baseline or at specific disease timepoints. We explored whether amp(1q) and del(17p) “double hit” abnormalities could be detected in circulating myeloma plasma cells (CMPC). Aims: We assessed our novel imaging flow cytometry method that simultaneously integrates immunophenotyping and FISH. Called “immuno-flowFISH” this single cell method combines antigenic detection of neoplastic plasma cells, FISH for DNA loci of interest and imaging flow cytometry for automated assessment. Methods: Blood from 16 myeloma patients, at diagnosis or on therapy was studied. Following density gradient centrifugation, cells were incubated with CD38/CD138/CD319-AF647-conjugated antibodies to identify plasma cells, CD19-BV480 (to differentiate normal from neoplastic plasma cells) and CD3-BV510 (T-lymphocyte control). After fixation and cell membrane permeabilization, DNA was denatured (78 oC for 5 minutes). The cells were then incubated with FISH probes to 1q21 ( CKS1B) and 17p13 loci, and to the centromere of chromosome 17 (C17), and hybridized (24 hours for 37 oC). The nuclei were stained with SYTOX AADvanced and 50,000 to 500,000 cells acquired on the Amnis ® ImageStream ®X Mk II imaging flow cytometer (Cytek Biosciences). Digital images and quantitative data derived from computational algorithms (IDEAS software) were used to assess FISH signals overlying the counterstained nuclei. Results: A mean of 264,937 cells were acquired and 110,696 analysed. Cells with a neoplastic plasma cell phenotype (CD38/CD138/CD319-positive, CD19-negative) were present in all samples. The number of these CMPC ranged from 7 to 797, amounting to 0.011- 0.546% of all cells. FISH abnormalities were present in CMPC of 10 of the 16 cases (see Table). Isolated amp(1q) (three CKS1B FISH signals) was present in 4 cases, and isolated del(17p), (one 17p13 and two C17 FISH spots) in CMPC in 3 cases. “Double hit” abnormalities, with both amp(1q) and del(17p), were present in another 3 cases, with the following cytogenetic patterns (illustrated in the Figure): 1. amp(1q) and del(17p) in different cells (Case 8); 2. amp(1q) and del(17p) in the same cell (35.7% of CMPC), in addition to isolated amp(1q) (28.6% of CMPC) (Case 9); 3. amp(1q) and del(17p) in the same cells only (Case 10). All circulating myeloma plasma cells had diploid signals for the chromosome C17 centromeric probe and the CD3-positive T-cells diploid signals for all probes. Conclusion: Incorporating antigenic identification and FISH, with imaging flow cytometric analysis, can detect “double hit” amp(1q) and del(17p) in circulating myeloma plasma cells at high sensitivity (10 -5). This novel approach allowed sub-clonal interrogation, with amp(1q) and del(17p) “double hits” detected in the same (Cases 9, 10) and separate CMPC (Case 8). It could also identify sub-clonal acquisition of secondary del(17p) (Case 9), which may be a consequence of disease evolution or intra-tumoral clonal heterogeneity. FISH analysis of circulating plasma cells using a flow cytometric platform is achievable to low levels of disease through assessment of thousands of cells. It holds significant promise for sensitive holistic real-time blood surveillance to detect high-risk and sub-clonal “double hit” alterations at the single cell level. Blood monitoring for these genetic aberrations overcomes the limitations of single site marrow analysis and may provide insights into the disease trajectory, clonal evolution and prognosis.

The Temporal Evolution of Chromosome 1q Gain and Hyperdiploidy and Its Impact on Clinical Outcomes in Multiple Myeloma

INTRODUCTION: Multiple myeloma (MM) evolution is shaped by the acquisition and selection of distinct genomic events over time. While various temporal patterns have been identified, the precise chronological order in which key clonal genomic defining events are acquired, and their specific impact on clinical outcomes remain to be fully elucidated. METHODS: To decipher the genomic life history of MM and its impact on clinical outcomes, we interrogated the high coverage (80X) whole genome sequencing (WGS) of 378 MM patients. Overall, 319 and 59 WGS were generated from samples collected at diagnosis and at relapse, respectively. Newly diagnosed MM (NDMM) patients were treated upfront with proteosome inhibitors, lenalidomide, dexamethasone, +/- monoclonal antibodies. To estimate the relative and absolute temporal relationship among clonal events, we leveraged the molecular time approach, based on the corrected ratio between duplicated and non-duplicated single nucleotide variants (SNV). RESULTS: Overall, 300/378 (79%) patients had at least one large chromosomal gain defined as >1Mb with >50 clonal SNV eligible for molecular time analysis, for a total of 1493 events tested. Consistent with recent findings, using clock-like mutational signatures SBS1-SBS5, we estimated that the first gain in MM is typically acquired around the second or third decade of life, with a median time lag of approximately 33 years between acquisition and diagnosis. In 158/178 (89%) of hyperdiploid (HRD) patients, all trisomies of odd-numbered chromosomes were acquired simultaneously. Among patients with canonical IGH translocations and HRD, the molecular time when trisomies were acquired was usually late compared to HRD without canonical IGH translocations (p<0.0001). Next, we examined the temporal relationship between IGH canonical translocations and gains linked to the same IGH canonical translocation in 29 patients. We consistently observed that when IGH canonical translocations co-occurred with HRD (n=7), and/or 1q gain (n=8) in the same patient, the canonical IGH translocation was always found to be the initiating event, occurring earlier than the chromosomal gains. Interestingly, in 104/178 (58.4%) HRD patients, the earliest multi-gain event was not always restricted to odd chromosomes, but in involved other non-HRD chromosomes such as: 6p (n=43) and 1q (n=32), demonstrating that gain 1q, which is assumed to occur at progression, can also be acquired very early in disease life history. A total of 92 and 21 patients with 1q gain and 1q amp (>3 copies) were identified, respectively. In 14/21 (66%) with 1q amp, the first and second 1q extra copies were acquired in two distinct and independent time windows. Interestingly, patients with early 1q gain showed the same clinical outcomes as 1q amp, and inferior progression free survival outcomes compared to late 1q gain (p=0.01; Figure 1). In 18/21 1q amp the first 1q duplication was acquired early, suggesting that the adverse prognostic effect of 1q gain/amp in NDMM may be more dependent on the timing of its acquisition rather than the number of extra copies gained. To investigate late temporal patterns and differentiate selection versus acquisition of large gains at relapse after autologous stem cell transplant (ASCT), we interrogated 25/59 (42%) RRMM patients exposed to melphalan with detectable SBS-MM1. To establish the temporal order of events, we employed the melphalan mutational signature, SBS-MM1, as a unique temporal barcode (Diamond et al. Blood 2023). Overall, we observed that 21% of all loss of heterozygosity (LOH) events and 15% of all gains were acquired after ASCT (i.e., SBS-MM1 mutations were only detectable in the pre-gain/duplicated SNV). Notably, among these events, 1q gain was acquired after ASCT in 3/4 patients, indicating that the acquisition of 1q gain can occur even after administration of first-line therapy. CONCLUSIONS: In our study, we have uncovered distinct temporal patterns in the acquisition of early genomic drivers in MM. These patterns contribute to the reconstruction and better understanding of the life history of MM and may hold potential clinical and prognostic implications.

High Success Rates Utilizing Local Standard of Care Cytogenetic Testing for Risk Stratified Frontline Therapy for Newly Diagnosed Multiple Myeloma: Experience from the Ukmra RADAR Study

Background. Recent studies in genetically high risk (HR) multiple myeloma (MM) such as the UKMRA OPTIMUM study have reported high response rates with intensive induction and post-ASCT consolidation and maintenance strategies, providing the rationale for stratified therapy based on genetic risk. Whilst centralised testing in clinical trials offers ready uniformity and quality control, the use of local laboratories for testing within a clinical trial paves the way for genetic testing to be available for all patients, facilitating risk stratified therapy in routine care. We designed the UKMRA RADAR study to use local laboratories for cytogenetic (CGN) testing to assign treatment according to genetic risk. Methods. RADAR is an ongoing national, multi-center, risk-adapted, response-guided multi-arm, multi-stage (MAMS) phase II/III trial for patients with newly diagnosed MM eligible for ASCT. Patients receive induction with RCyBorD (lenalidomide, cyclophosphamide, bortezomib, dexamethasone), followed by high-dose melphalan and stem cell rescue. Post ASCT, HR patients are randomised to receive isatuximab or not, alongside RBorD consolidation and R maintenance whilst standard risk (SR) patients receive MRD response guided regimens. A protocol amendment (2022) included isatuximab throughout the HR pathway, removing the post-ASCT randomisation. Risk assessment, failure rates and turnaround time are overseen by a genomics working group (GWG) including clinical and specialist cytogenetic representation. Genetic risk testing is undertaken in local genetic labs on CD138 selected bone marrow (BM) plasma cells. HR is assigned based on the presence of at least two of: t(4;14), t(14;16), t(14:20), del(17p), del(1p) and gain(1q). Clone size cut-offs are 10% for IgH translocations and 20% for copy number changes. CGN results from local laboratories are centrally reviewed to assign risk in real-time. Indeterminate cases are discussed by the GWG. Repeat testing is mandated if the initial sample fails to yield a definitive risk result for risk. Subjects with no definitive result despite 2 samples are treated as SR. Results. As of 19 th June 2023, the trial has recruited 472 patients from 72 sites across the UK. Median age is 61 years, 59.3% male, 79.9% white, 11.7% other ethnicity and 8.5% missing ethnicity data. 25 local laboratories were used for CGN testing. Of those with CGN results 354/453 patients (78.1%) were assigned standard risk, 84 (18.5%) high risk and 15 (3.3%) risk category undefined. Risk stratification is ongoing for 19 patients. Of the high risk lesions gain(1q) was most prevalent (35%), followed by t(4;14)(10.6%), del(17p)(8.7%), del(1p32)(8.7%), t(14;16)(3.8%) and t(14;20)(0.8%). In 376/453 patients (83.0%), risk was assigned from a first BM sample. 77 (17.0%) patients required a second sample; the success rate of repeat samples is 71.4%, 22 (4.9%) patients were unable to be risk-stratified despite 2 samples. Figure 1 shows the success rate of first and repeat tests. The overall median turnaround time (from D1 cycle 1 until site notified of result) was 11 days (IQR 0 to 21). Sites were sent risk status prior to cycle 1 in 99 (21.9%) patients , 285 (62.9%) prior to cycle 2 and 341 (75.3%) cycle 3. Note this is calculated where treatment data is available. Conclusion. The RADAR study demonstrates that risk-stratified treatment approaches are feasible in the context of a national phase II/III clinical trial with the use of local laboratories for risk assignment. The vast majority of patients have been successfully allocated to a risk-adapted treatment pathway following a first FISH test (83.0%). Protocol v4 requires time-critical risk-stratification for addition of isatuximab to induction treatment from cycle 2 in high-risk patients, and this has proven to be achievable in almost 2/3 of patients with over ¾ by the end of cycle 2. The RADAR study also enables hospitals across the UK to access CGN testing via a network model of laboratories with standardization of testing and clinically relevant turnaround times. This model is applicable internationally in both public and privately funded healthcare systems and supports the infrastructure for accessible genetic risk stratification for all newly diagnosed MM patients. Ongoing studies within the RADAR trial are evaluating novel and clinically deliverable risk stratification protocols to inform risk stratified approaches in newly diagnosed MM.

The prognostic impact of t(11;14) in multiple myeloma: A real-world analysis from the Australian Lymphoma Leukaemia Group (ALLG) and the Australian Myeloma and Related Diseases Registry (MRDR).

The prognostic impact of t(11;14) in multiple myeloma (MM) needs to be better understood to inform future treatment decisions. The Australian Lymphoma Leukaemia Group embarked on a retrospective, observational cohort study using real-world data to interrogate treatment patterns and outcomes in 74MM patients with t(11;14) [t(11;14)-MM] diagnosed over 10 years. This was compared to 159 and 111MM patients with high-risk IgH translocations (IgH HR-MM) and hyperdiploidy (Hyperdiploid-MM), respectively, from the Australian Myeloma and Related Diseases Registry. No appreciable differences in age, gender, ISS, LDH levels, 1q21 or del(17p) status, or treatment patterns were observed between groups. Median PFS-1 was not different between groups but both t(11;14)-MM and IgH HR-MM had an inferior PFS-2vs. Hyperdiploid-MM: median PFS-2 8.2 months, 10.0 months, and 19.8 months (p=0.002), respectively. The 3-year OS were 69%, 71%, and 82% (p=0.026), respectively. In the t(11;14)-MM group, gain or amplification of 1q21 at diagnosis predicted for poorer OS (HR 3.46, p=0.002). Eleven patients had received venetoclax with 45% achieving better than a very good partial response. Results suggest that t(11;14) MM may confer an unfavorable risk profile and that the use of targeted therapies such as venetoclax earlier in the treatment algorithm should be explored.

CLINICAL AND BIOLOGICAL FEATURES AND OUTCOMES OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA: A REAL‐WORLD STUDY OF 2005 PATIENTS IN CHINA

Introduction: Chronic lymphocytic leukemia (CLL) is less common in Han Chinese compared with persons of Europeans. The data about the clinical and biological features and outcomes of Chinese with CLL are limited, thus promoting us to perform this analysis on a large cohort of 2005 patients with CLL in China. Methods: Clinical data of 2005 patients with CLL were analyzed in Blood Diseases Hospital, Chinese Academy of Medical Sciences from February 2000 to December 2020. Results: In this cohort, the median age of patients at diagnosis was 61(20-92) years, which was younger than that for Western CLL patients (65-70 years). Patients showed similar male predominance as Europeans with CLL with an M:F ratio of about 1.8. 69.3% of patients had Binet stage B or C at diagnosis, higher than those of predominately European descent (20%-40%). A higher proportion of mutated immunoglobulin heavy chain variable region (IGHV) (64.0%) was shown in patients with CLL in this cohort than Europeans. IGHV4-34 rather than IGHV1-69 was the most commonly used fragment. Compared with Europeans, patients in this cohort had a higher proportion of subset eight stereotype and a lower proportion of subset two. The most frequent abnormality detected by FISH was RB1 deletion (21.1%), followed by trisomy 12 (20.4%), IGH translocation (16.8%), del(17p) (11.4%) and del(11q) (10.9%), respectively. It was shown that the frequencies of the chromosomal abnormalities in this study population were similar to the frequencies in Western countries. Of the 1476 patients for whose treatment data were available, 1191 (80.7%) received treatment. Median time to first treatment (TTFT) for CLL patients was 7 months. Among patients treated, chemotherapy, immunochemotherapy and targeted therapy accounted for 69.6%, 14.1% and 16.3% of first line, yielding 68.4%, 90.0% and 94.2% of overall response rate (ORR), respectively. After median 75-month follow up, median progression free survival (PFS) was 42 months, 5-year and 10-year PFS rate was 35.5% and 12.5%, respectively. Median overall survival (OS) was 130 months, 5-year and 10-year OS rate was 74.9% and 52.3%, respectively. The outcomes were similar to those reported in previous Chinese and Western studies. As expected, PFS and OS were better in CLL patients receiving immunochemotherapy and targeted therapy than those receiving chemotherapy. In addition, patients who achieved partial remission (PR) or complete remission (CR) after first-line treatment had a longer PFS and OS. Interestingly, females with CLL had a longer OS than males. Conclusions: This is the largest real-world study involving Chinese patients with CLL so far, which might lay a foundation for clinical investigation of Chinese CLL in future. Although the patients were younger, had a later stage at diagnosis and had different genetic backgrounds compared with Europeans, the outcomes were not different from those reported in Western studies. Keyword: chronic lymphocytic leukemia (CLL) No conflicts of interests pertinent to the abstract.

FISH abnormalities in Agent Orange–associated multiple myeloma.

e20056 Background: Multiple myeloma (MM) is a plasma cell neoplasm that accounts for approximately 10% of all hematologic malignancies. Molecular investigations have identified a wide heterogeneity in MM at the genomic and epigenomic levels, often with IgH translocations and trisomies seen early in the pathogenesis. Etiological factors, though, are still not well characterized. Agent Orange (AO) was a herbicide widely used as a defoliant by the U.S. military during the Vietnam War. Studies have indicated a probable causative link between exposure to AO and the development of multiple myeloma; in fact, MM is now recognized by the VA as a service-connected diagnosis. However, there have been few small studies addressing whether there are any unique molecular findings in AO associated MM. We sought to determine if there were any specific myeloma FISH abnormalities seen in AO associated MM and if there were any differences in their respective survival. Methods: We included all patients diagnosed with MM from 2010-2022 at Louis Stokes VA Medical Center (Cleveland, OH). Data collected included: age, sex, race, year of diagnosis, AO exposure, bone marrow biopsy results and myeloma FISH panel results. We defined high risk MM based on the presence of t(14;16), t(14;20), del 17p/TP53 or gain 1q. Overall survival (OS) was calculated from date of diagnosis to death. Results: We included 162 patients with MM, among them 32 had AO exposure. There was no significant difference in age or race between exposed and non-exposed patients. MM FISH results were available for 137 patients. Overall, 20% of patients had high risk group cytogenetics and there was no significant difference based on AO exposure. However, there was a trend for increased TP53 mutations in those exposed to AO, although this did not reach statistical significance (8% vs. 3.6%, p = 0.3). Median OS was 72 months for non-exposed patients and 98 months for exposed patients, with no significant difference observed (p = 0.18). Conclusions: In this single institution, retrospective study, AO exposure was not associated with a higher incidence of high-risk cytogenetics by FISH in MM. There was a trend for increased TP53 mutation with AO exposure, but the cohort was small and did not reach statistical significance. In addition, AO exposure was not associated with a worse survival. Further studies are needed to clarify the effects of AO on the development of MM, including genomic and transcriptomic analysis to elucidate the pathobiology of this disease. [Table: see text]

Conditional survival in multiple myeloma and impact of prognostic factors over time

Overall survival estimates from diagnosis are valuable for guiding treatment, but do not consider the years already survived. Conditional survival (CS) provides dynamic survival predictions over time. This study was conducted to estimate CS at 1–8 years from diagnosis and the impact of baseline prognostic factors on CS in multiple myeloma (MM) patients. This is a retrospective study including 2556 MM patients diagnosed between 2004 and 2019. CS (t | s) was defined as the probability of surviving t years given survival of s years. Median age was 64 years. Median follow-up was 6.2 years and median overall survival from diagnosis was 7.5 years. The 5-year CS estimates at s = 0, 1, 2, 3, and 5 years were 0.64, 0.61, 0.61, 0.61, and 0.58, respectively. On multivariate analysis, age ≥ 65 and proteasome inhibitor+immunomodulatory-based induction were associated with decreased survival and increased survival, respectively, retained at 5 years. The adverse impact of 1q gain/amplification, high-risk IgH translocation, and ISS-3 was significant at 1 and 3 years but not 5 years. Chromosome 17 abnormality was associated with decreased survival only at 1 year. Among MM patients, 5-year CS was stable at 1–5 years from diagnosis. The prognostic impact of high-risk cytogenetic factors decreased with additional years survived.

Role of Conventional Cytogenetics and FISH in the Laboratory Work Up of Plasma Cell Dyscrasias

AbstractPlasma cell dyscrasias are a heterogeneous group of neoplasms characterized by abnormal proliferation of plasma cells with or without over production of monoclonal immunoglobulins. Chromosomal abnormalities are acquired either early in the course of the disease or during disease progression. Plasma cell dyscrasias are categorized into multiple cytogenetic subtypes that form an integral component of risk-stratified treatment protocols. The primary genetic events are IgH gene translocations and non-random gains of chromosomes 3/5/7/9/11/15/19 and or 21. The secondary genetic events consist of chromosome 1 abnormalities (1p deletion and 1q gain or amplification), deletion 17p/TP53, deletion 13q, and MYC gene rearrangements. Plasma cells being at the end of differentiation spectrum of B cells, have low proliferative potential precluding the use of karyotyping in identification of chromosomal abnormalities. Analysis of enriched plasma cells using interphase fluorescent in situ hybridization (FISH) is the technique of choice for identifying these abnormalities. It is essential to enrich plasma cells before the FISH analysis, and numerous plasma cell enrichment techniques have been described. In the paper, we review the cytogenetic approach to identify clinically significant genetic aberrations including the effective use of FISH panels and plasma cell enrichment techniques.

Imaging flow cytometry-based multiplex FISH for three IGH translocations in multiple myeloma

Three types of chromosomal translocations, t(4;14)(p16;q32), t(14;16)(q32;q23), and t(11;14)(q13;q32), are associated with prognosis and the decision making of therapeutic strategy for multiple myeloma (MM). In this study, we developed a new diagnostic modality of the multiplex FISH in immunophenotyped cells in suspension (Immunophenotyped-Suspension-Multiplex (ISM)-FISH). For the ISM-FISH, we first subject cells in suspension to the immunostaining by anti-CD138 antibody and, then, to the hybridization with four different FISH probes for genes of IGH, FGFR3, MAF, and CCND1 tagged by different fluorescence in suspension. Then, cells are analyzed by the imaging flow cytometry MI-1000 combined with the FISH spot counting tool. By this system of the ISM-FISH, we can simultaneously examine the three chromosomal translocations, i.e, t(4;14), t(14;16), and t(11;14), in CD138-positive tumor cells in more than 2.5 × 104 nucleated cells with the sensitivity at least up to 1%, possibly up to 0.1%. The experiments on bone marrow nucleated cells (BMNCs) from 70 patients with MM or monoclonal gammopathy of undetermined significance demonstrated the promising qualitative diagnostic ability in detecting t(11;14), t(4;14), and t(14;16) of our ISM-FISH, which was more sensitive compared with standard double-color (DC) FISH examining 200 interphase cells with its best sensitivity up to 1.0%. Moreover, the ISM-FISH showed a positive concordance of 96.6% and negative concordance of 98.8% with standard DC-FISH examining 1000 interphase cells. In conclusion, the ISM-FISH is a rapid and reliable diagnostic tool for the simultaneous examination of three critically important IGH translocations, which may promote risk-adapted individualized therapy in MM.

Cytogenetic Abnormalities in Multiple Myeloma: Incidence, Prognostic Significance, and Geographic Heterogeneity in Indian and Western Populations

Multiple myeloma (MM) is a genetically complex and heterogeneous neoplasm in which cytogenetics is a major factor playing an important role in the risk stratification of disease. High-risk MM based upon cytogenetic classification includes primary IGH translocations t(4;14), t(14;16), t(14;20), and secondary progressive aberrations such as gain/amp(1q), 1p deletion, del(17p), and hypodiploidy. Several studies have proved that interphase FISH can detect primary as well as secondary cryptic aberrations very efficiently in lowest 5–10% abnormal plasma cell population. The present large-scale study was undertaken to evaluate the incidence of cytogenetic abnormalities, to analyse the correlation of conventional karyotyping with FISH, and to seek the geographic heterogeneity in the incidence of primary as well as secondary aberrations in our Indian versus Western populations. We conducted prospective studies of 1,104 patients consecutively referred from the primary, secondary, and tertiary oncology centres from all over India. Interphase FISH was performed on isolated plasma cells. Karyotype analysis was done as per ISCN 2016 and 2020. FISH could detect cytogenetic abnormalities in 67.6% of the cases with an incidence of 59% non-hyperdiploidy. The incidence of IGH translocation was 26% versus literature frequency of 40–50% which was mainly due to a low incidence (6%) of t(11;14) in contrast to 15–20% in other series. Additionally, the association of secondary progressive aberrations in the hyperdiploid group rather than the non-hyperdiploid group in our patients is not a common finding. A biallelic inactivation of TP53 as an ultra-high risk factor was detected in old-aged patients. These observations disclose the novel findings and strongly indicate the racial disparity which leads to geographic heterogeneity. In contrast to FISH, conventional karyotyping could detect MM-related aberrations in 50% of cases, of which 44% revealed highly complex karyotypes with common aberrations of chromosome 1q. Overall, FISH was found to be a novel, easy approach with high success rate and capability of detection of all cytogenetic abnormalities that add valid information for the risk stratification of disease. This, in future, in combination with mutation profile and gene expression profile will help in further refinement of disease and identification of actionable targets.

Expression of integrin β-7 is epigenetically enhanced in multiple myeloma subgroups with high-risk cytogenetics

BackgroundOncogenic overexpression of integrin-β7 (ITGB7) in cases of high-risk multiple myeloma (MM) was reported to promote enhanced interactions between neoplastic plasma-B cells and stromal cells to develop cell-adhesion mediated drug resistance.MethodsExpression profiles of adhesion related genes were analyzed in a cohort of MM patients containing major IgH translocations or hyperdiploidies (HY), diagnosed at the premalignant monoclonal gammopathy of undetermined significance (MGUS; n = 103), smoldering multiple myeloma; (SMM; n = 190) or MM (MM; n = 53) stage. Differential expression was integrated with loci-specific alterations in DNA-methylation and chromatin marks in MM patients. A CRISPR-based targeted induction of DNA-methylation at the ITGB7 super-enhancer (SE) in MM.1S cells was employed to intersect the impact of cis-regulatory elements on ITGB7 expression.ResultsITGB7 was significantly (p < 0.05) upregulated in patients with t(14;16) and t(14;20) subgroups in all MGUS, SMM and MM stages, but sporadically upregulated in t(4;14) subgroup at the MM stage. We demonstrate a predetermined enhancer state on ITGB7 in primary-B cells that is maintained under bivalent chromatin, which undergoes a process of chromatin-state alterations and develops into an active enhancer in cases of the t(4;14) subgroup or SE in cases of the t(14;16) subgroup. We also demonstrate that while targeted induction of DNA-methylation at the ITGB7-SE further upregulated the gene, inhibition of ITGB7-SE-associated transcription factor bromodomain-4 downregulated expression of the gene.ConclusionsOur findings suggest an epigenetic regulation of oncogenic overexpression of ITGB7 in MM cells, which could be critical in MM progression and an attractive therapeutic target.

Evaluation of the Mayo Additive Staging System in patients with newly diagnosed multiple myeloma: A real-world analysis.

Recently, the Mayo Clinic introduced a new staging system (the Mayo Additive Staging System [MASS]) for patients with newly diagnosed multiple myeloma (NDMM) based on the number of high-risk (HR) abnormalities, including HR IgH translocations, 1q gain/amplification, chromosome 17 abnormalities, International Staging System (ISS)-III, and elevated lactate dehydrogenase. Patients with 0, 1, or ≥2 HR abnormalities were defined as stage I, II, or III, respectively. We aimed to validate the real-world prognostic value of the MASS. We retrospectively analyzed the cytogenetic and laboratory results of 544 patients with NDMM at a single center. Ninety (16.5%) patients had no HR factors (MASS I), 193 (35.5%) had 1 HR factor (MASS II), and 261 (48%) had ≥2 HR factors (MASS III). The median progression-free survival (PFS) and overall survival (OS) times were 48, 28, and 20 months and 137, 73, and 39 months in the three groups, respectively (p <.001). In the subgroup analysis, patients had different OS outcomes based on the MASS when grouped by age, renal function, or therapeutic regimens. The MASS identified patients with the worst outcomes among those rated revised ISS II. The MASS system is a reliable risk stratification tool for patients with NDMM in real-world clinical practice.

TP53 Gene Deletion or Mutation in Newly Diagnosed Multiple Myeloma Patients By FISH with Cytoscan Arrays and Targeted Panel Sequencing

Background Multiple myeloma (MM) is a plasma cell clonal malignant disease. In the past 20 years, the progression free survival rate and overall survival rate of patients have been significantly improved, however, due to the potential complex cytogenetic abnormalities, the clinical progresses are heterogeneous and the clinical benefits of patients are not consistent, especially for high-risk patients. In Chinese clinical practice, 17p-, t(4;14), t(14;16) are considered high-risk cytological abnormalities for newly diagnosed multiple myeloma (NDMM) patients according to R-ISS stage and 2022 Chinese guidelines for diagnose and treatment for MM. As a genome guardian, TP53 plays an important role in regulating cell cycle, apoptosis, aging, DNA repair and maintaining gene stability. But the threshold of deletion positive proportion with clinical significance by CD138-sorted FISH was unclear. TP53 mutation is also not regularly examined in Chinese patients. For that aim, our center has taken TP53 seriously as a heterogeneity problem for clinical discussion. Methods The clinical data of 248 NDMM patients in the First Affiliated Hospital of Soochow University of a VRD clinical study, with VRD in combination with autologous stem cell transplantation or VRD treatment for 8 cycles, from September 1, 2018 to August 31, 2021, were analyzed retrospectively. The samples for CD138-sorted FISH, CytoScan and targeted panel sequencing are obtained from the Multiple Myeloma Specialized Disease Bank of the National Center for Clinical Medical Research of Hematological Diseases. Results In this study, the deletion rate of TP53 was 13.0% (32/248), the mutation rate was 2.0% (5/248), the incidence of any TP53 event was 14.5% (36/248), and the incidence of double allele event was 0.8% (2/248). The detection rate of TP53 gene mutation was low, which was related to the short clinical application time of targeted panel sequencing with CD138-sorted samples. All patients with TP53 deletion or mutation were DS-III stage, with anemia (72.2%), hypoalbuminemia (58.3%) and renal insufficiency (38.9%). The most common accompanied abnormalities were 13q14- (63.9%), followed by t (4;14), 1q21+, t (11;14). Abnormal karyotypes were detected by FISH and CytoScan, indicating gene complexity and instability, and the clonal evolution, which is the root of disease recurrence and progression. The positive rate of TP53 mutation of one case study increased from 7.87% at the first recurrence to 53.44% at the second recurrence with 3rd line therapy (Figure 1a), indicating that TP53 gene lead to disease progression and the formation of multidrug resistance. In terms of induction effects, patients with TP53 gene abnormalities had ≥VGPR with 77.8%, lower than that of negative group (84.8%, P=0.0627)(Figure 1b). The median follow-up time is 20 months (1-42 months). Compared with negative ones, TP53 positive subgroup had an adverse PFS result (33 months vs not reached, P=0.0403), while the OS difference hasn't been clinical significant (both not reached, P=0.0541) (Figure 1c). The result showed that TP53 deletion with more than 50% was an independent adverse factor associated with poor prognosis of NDMM patients (PFS: HR=2.2441, 95%CI 1.117-5.335, P=0.0025; OS: HR=2.771, 95%CI 1.006-7.629, P=0.049). The prognosis of patients with TP53 deletion more than 50% was significantly worse than that of the negative group (PFS 25months vs not reached, P=0.0032, OS not reached P=0.0198), but TP53 deletion less than 50% had no difference compared with negative group. (Figure 1d).Conclusions Patients with TP53 deletion or mutation have obvious clinical symptoms and are prone to cytogenetic abnormalities such as 1q+, 1p-, -13, IgH translocation, chromosome abnormality and so on. TP53 deletion with more than 50% was an independent adverse factor associated with poor prognosis of NDMM patients, as a result, TP53 deletion more than 50% is the clinical significant threshold for clinical use. This study comprehensively describes the detection of genetic abnormalities and prognostic survival analysis of NDMM patients by using FISH, CytoScan and targeted panel sequencing. Identifying the real high-risk patients, we can earlier take targeted and more active measures, such as intensive induction treatment, tandem transplantation or CART treatment, to better deepen and consolidate the therapeutic effect for long-term survival benefits of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety, Feasibility, and Efficacy of Upfront Daratumumab-Based Therapy in Blacks with Dysproteinemia

Background: Black patients (pts) with dysproteinemia are underrepresented in clinical trials included in new drug applications and biological license application submissions. Even after approval, access to novel therapies remains a challenge. Daratumumab (dara) is an anti-CD38 monoclonal antibody, which has revolutionized the care of patients with both multiple myeloma (MM) and light chain (AL) amyloidosis. The underrepresentation of black pts in clinical trials of dara in newly diagnosed patients with dysproteinemia raises concerns regarding the safety, tolerability and efficacy of dara in this population. We report the results from a cohort of pts treated with dara in the management of newly diagnosed MM (NDMM) and AL amyloidosis. Methods: The Cancer and Aging Resilience Evaluation in Hematologic Malignancies (CARE-Heme) registry is an ongoing prospective registry enrolling pts ≥50 years of age with a diagnosis of hematologic malignancy undergoing treatment at a single institution. For this analysis, we included pts with NDMM and AL amyloidosis treated with dara-based combination therapy between January 2020 and January 2022. We obtained baseline disease- and patient-related characteristics. Toxicity was evaluated by chart review up to the first 6 cycles and adverse events (AEs) were graded using Common Terminology Criteria for Adverse Events (CTCAE v5.0). For patients receiving >1 cycle, response assessment was ascertained using International Myeloma Working Group (IMWG) uniform response criteria. All patients were followed until progression, death or last follow up and progression-free survival (PFS) and overall survival (OS) were measured using Kaplan Meier methods. Health-related quality of life (HRQoL) was measured using Patient-Reported Outcomes Measurement Information System (PROMIS) global 10 and quantified using physical health (PH) and mental health (MH) t-scores at baseline and 3 month follow up. Variables were compared in each race by using independent and paired sample t-tests as appropriate. Results: Over the study period, 36 black pts (NDMM=32; AL=4) and 50 white pts (NDMM=44; AL=6) received upfront dara-based combination therapy. There were no differences in age or sex, IGH translocations, but there was a higher incidence of cytogenetic high-risk disease among the black pts in our cohort (p=0.02). Black pts presented with more advanced disease at the time of presentation - hypercalcemia 33% vs. 14%, p=0.04; renal dysfunction 56% vs. 28%, p=0.01; anemia 67% vs. 38%, p=0.01). Incidence of bone disease was similar between the groups (p=0.69) (Table 1) Among blacks, the most utilized regimen was DaraVRd (56%), DaraRd (17%), DaraKRd (11%) and DaraVCd (11%). While for the white pts, it was DaraVRd (52%), DaraRd (12%), DaraKRd (8%) and DaraVCd (22%). Blacks had a similar incidence of ≥grade 3 non-hematologic AEs (p=0.21), with fatigue, diarrhea and leg edema being the most common. There is a trend towards higher ≥grade 3 hematologic AEs which did not reach statistical significance (p=0.05). After 6 cycles of therapy, overall response rate was comparable (100% vs. 94%, p=0.81) among the two groups (≥VGPR 47% vs. 62%, p=0.36). With 18 month median follow up, there was no difference in median PFS and OS, both not reached (Figure 1). Complete quality of life (QoL) t-scores were available at baseline for 55 pts (20 blacks and 35 whites). The baseline PH and MH related QoL scores were comparable between whites and blacks (p= 0.51; p=0.58, respectively). From baseline to 3 months follow up, PH t-scores improved in both whites as well as blacks although the difference was not statistically significant. Meanwhile, MH t-scores remained largely unchanged from baseline to follow up in both groups. Conclusions: We report the largest cohort to date of black pts with dysproteinemia systematically treated with frontline dara. Our data shows the feasibility of this strategy in a single institution setting with comparable safety, efficacy and HRQoL with the use of upfront dara-based combinations in black and white pts. Our data supports comparable clinical outcomes among black pts when treated with novel therapeutic combinations despite a higher proportion of high risk cytogenetic abnormalities in our cohort without an increase in AEs. Minority representation in cancer clinical trials as well as access to approved novel therapies can significantly help mitigate disparities in outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal