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Background: A deeper understanding of the cytogenetic features has enabled robust risk stratification for patients with newly diagnosed multiple myeloma (NDMM). However, heterogeneity persists in the currently available prognostic tools and there is further room for personalization. We assess the utility of PC-PRO, a test to measure the proportion of monotypic plasma cells in the synthetic phase (S-phase) of cell cycle, as a prognostic marker for NDMM. Methods: Patients with active MM diagnosed between January 2013 and January 2023 with a flow cytometry-based S-phase assessment at diagnosis were included. Flow cytometric immunophenotyping was performed using the following antibodies: CD19, CD38, CD45, CD138, cytoplasmic kappa and lambda immunoglobulin, and DAPI (4',6-diamidino-2-phenylindole). The percentage of plasma cells in S-phase was determined by measuring the proportion of cells with DNA content of the monotypic plasma cells between the G0/G1 and G2/M peaks. Plasma cell clonality was detected through demonstrating CD38 and CD138 positivity along with immunoglobulin light chain restriction, abnormality of CD19/ CD45 expression and/or ploidy difference by DAPI staining. High-risk cytogenetic abnormalities (HRCA) by FISH were defined as follows: presence of deletion 17p (del17p), t(4;14), t(14;16), t(14;20), 1q gain/amplification, 1p deletion (when available). Additionally, the second iteration of the revised ISS (R2-ISS), incorporating both laboratory and cytogenetic features as well an adaptation of the recently proposed International Myeloma Working Group (IMWG) Classification for high-risk disease, was utilized for risk stratification. All time-to-event analyses were performed using the Kaplan Meier method and compared using the log-rank test. Univariable and multivariable Cox proportional hazards analyses were performed to assess the independent prognostic impact of S-phase. Results: A total of 823 patients were included in the study. The median follow-up was 6 years [95% Confidence interval (CI): 5.5-6.3 years] and estimated median overall survival (OS) was 8.3 years. The median S-phase value for the cohort was 0.8 % (interquartile range: 0.5-1.4%), with 135 (16%) patients harboring an S-phase of ≥2% at diagnosis. Applying the R2-ISS prognostic model to our cohort, 11% (79/706) patients were stratified to the R2-ISS high-risk cohort; 93 patients (out of 788, 12%) had 2 or more HRCA at diagnosis. Patients with a S-phase ≥2% at diagnosis had a median OS of 3.9 years (95% CI: 2.9-5.7) vs. 9.2 years [95% CI: 7.9-not reached (NR)] for patients with a S-phase <2% [Hazard ratio (HR): 2.2 (95% CI: 1.7-2.8), p<0.0001]. The median OS was inferior for cohorts with an increasing S-phase value: S-phase of 0.1-1%: HR: 1 (standard), S-phase 1.1-3%: HR 1.7 (95% CI: 1.3-2.1), S-phase >3%: HR 3.0 (95% CI: 2.2-4.1)]. On a multivariable analysis including S-phase ≥2%, age at diagnosis of MM (>65 years) and R2-ISS high-risk status, S-phase ≥2% was an independent predictor of inferior OS [hazard ratio (HR) 1.9 (95% CI: 1.4-2.6), p<0.0001]. Age >65 years [HR 1.9 (95% CI: 1.5-2.5), p<0.0001] and R2-ISS high-risk status [HR 1.8 (1.3-2.6), p=0.001] were also independent predictors of OS. Within the sub cohort of patients with 2 or more of the listed high-risk cytogenetic features (n=93, 12%), a S-phase ≥2% (n=24) was associated with a worse median OS of 1.6 years (95% CI: 0.7-NR) vs. 6.2 years (95 % CI:3.3-NR) for S-phase <2% (p=0.002). Conclusion: Flow cytometry-based determination of the proportion of monotypic plasma cells in S-phase is an easy-to-study and powerful prognostic tool for NDMM. A S-phase of ≥2% at diagnosis is a predictor of OS independent of age and R2-ISS high-risk stage. An S-phase of ≥2% was able to identify a distinct group with markedly inferior outcomes even within the sub cohort of patients with 2 or more high-risk cytogenetic features.

Background: TP53 mutations (TP53mut) are highly prevalent in therapy-related myeloid neoplasms (t-MN) compared to de novo MN (35-40% vs 7-13%) and are associated with a poor outcome. Understanding the risk factors involved in the pathogenesis of TP53mut t-MN is critical to prevent its development. Methods: We characterized t-MN cases by examining primary cancer type vs autoimmune disease diagnosis vs solid organ transplantation, treatment modality, and latency (interval between primary cancer/disease and t-MN diagnosis) to identify patient and disease-related factors associated with TP53mut t-MN. Allelic loss of TP53mut MN was defined according to International Consensus Classification (ICC) criteria (Arber et al., Blood 2022). Results: Of 587 t-MN patients, 33% (n=194) had acute myeloid leukemia (t-AML) and 67% (n=393) had myelodysplastic syndrome (t-MDS, blasts<20%). Primary diagnosis comprised of 243 (41.6%) solid cancers and 300 (51.4%) hematological malignancies, while 7% (n=41) of t-MN cases had autoimmune disease or underwent solid organ transplant. Overall, 94 (16.1%) patients received prior radiotherapy (RT) alone and 75.6% (n=444) received chemotherapy (CT) with/without RT. 109 patients (18.7%) underwent autologous stem cell transplant (ASCT). The median latency from primary diagnosis to t-MN was 83.2 months (IQR 41.3, 153.2), and there was a trend towards shorter latency in t-AML compared to t-MDS (70.5 vs 85.8 months; P=0.07). Of the t-MN patients, 280 (47.7%) harbored TP53mut, which was associated with significantly poorer survival compared to wild-type (TP53wt) t-MN (9.7 vs 21.9 months; P <0.001). In contrast to TP53wt (59.0% vs 41.0%), the majority of TP53mut t-MN presented with t-MDS vs t-AML (75.7% vs 24.3%; P <0.001). According to ICC criteria, multi-hit MDS (n=131; 47.8%) was the most common entity, followed by AML (n=68; 24.8%), MDS/AML (n=34; 12.4%), and single-hit MDS (n=8, 2.9%). Poor prognostic karyotype changes e.g., del 5q, del 7q, complex karyotype and monosomal karyotype, were more prevalent in TP53mut compared to TP53wt t-MN. Co-mutations in other genes were enriched in TP53wt t-MN. As TP53mut t-MN is associated with a dismal outcome, we assessed the factors associated with its development. There were no significant differences in median age at primary cancer/disease diagnosis (59.0 vs 59.9 years; P=0.4) or gender (females 43.3% vs 39.3%; P=0.3) between TP53mut and TP53wt t-MN. However, TP53mut patients were older at t-MN diagnosis (69 vs 67.4 years; P=0.05). Correlations between gene mutations and prior malignancies revealed a significant association between TP53mut and hematological primary cancers (odds ratio [OR] 1.6; P=0.006), especially multiple myeloma (MM, OR 4.9; P<0.001) and lymphoproliferative disease (LPD, OR 2.0; P=0.013). Among solid cancers, head and neck malignancies were significantly associated with increased risk of developing TP53mut t-MN (OR 7.7; P=0.01). Compared to RT alone, ASCT (OR 2.2; P=0.004) and CT (OR 2.0; P=0.008) were associated with an increased risk of TP53mut t-MN. Recent studies indicate that CT/RT confer a selective advantage to preexisting TP53mut hematopoietic stem and progenitor cells, allowing clonal expansion/evolution and progression to t-MN. We hypothesized that TP53mut t-MN with high-risk disease features is a function of TP53mut clonal expansion/evolution rate and would predict latency between primary cancer and t-MN. Indeed, the latency between primary cancer and t-MN diagnosis was longer in TP53mut (87.8 months, IQR 45.5, 154.1) compared to TP53wt (74.7 months, IQR 37.5, 146.9 months) t-MN (P=0.05). Interestingly, 54% and 29% of TP53mut t-MN had a latency of ≥5 and ≥10 years, respectively. There were no correlations between latency and TP53 variant allele frequency (VAF) (r=0.38 and P=0.7) or between TP53mut t-MDS and t-AML (85.2 vs 109.3 months; P=0.9). Together, latency between primary cancer and t-MN was not associated with TP53mut t-MN phenotype, VAF or other poor-risk disease features. Conclusion: Hematological malignancies, especially MM and LPD treated with high-dose CT, were strongly associated with TP53mut t-MN development, highlighting the importance of careful and ongoing screening in this population. Also, the long latency of TP53mut t-MN provides an opportunity to devise effective surveillance strategies and preventative interventions long before TP53mut t-MN development.

Background In 2014, the IMWG updated the criteria for diagnosing multiple myeloma (MM) and added three additional criteria to the traditional CRAB criteria. The new criteria called the SLiM criteria, include clonal bone marrow plasma cells ≥60%, involved to uninvolved free light chain ratio (rFLC) ≥100 (involved FLC must be ≥ 100 mg/L), and > one focal lesion on MRI studies (each lesion ≥ 5 mm). These criteria were deemed myeloma-defining events (MDE) in the absence of CRAB criteria. Autologous stem cell transplantation (ASCT) has been used for treating MM for over three decades and is safe and efficacious. We report on outcomes of outpatient ASCT in a cohort of patients with MM where therapy was initiated solely based on SLiM criteria. Methods We conducted a retrospective study of all patients diagnosed with MM based on SLiM criteria at Mayo Clinic, Rochester, MN. We compared this cohort to a matched cohort of newly diagnosed MM patients whose MDE was CRAB and who underwent an ASCT. For every patient whose MDE was SLiM, we matched two patients whose MDE was CRAB. The matching was done by age, gender, and melphalan dose. Results Between 2013 and 2022, 30 patients received an ASCT due to SLiM criteria at Mayo Clinic, Rochester (Durie Salmon Stage IA). The median age of our cohort was 63 (range 46-75) years, and 60% had an ISS of 1. Seventeen percent of the cohort was treated with DVRd induction. The median time from diagnosis to ASCT was 6.5 months (IQR 6-7), and all but one received full intensity conditioning with melphalan 200 mg/m2. 53% of patients completed the ASCT without requiring hospitalization, and 47% (n=14) of patients required hospitalization with a median duration of hospital admission of 6 days (IQR 5-14). Bacteremia was confirmed in 7 patients (23%). The matched cohort included 60 patients. Baseline characteristics were similar, with the exception of lower hemoglobin levels in the control group, as expected (13.1 vs 12, P=0.0017). No differences were seen in the number of cells collected (3.4 vs 3.67 X106 cells/kg, P=0.19) or the use of Plerixafor (80% vs 78%, P=0.8). The SLiM cohort had a shorter median time to neutrophil (15 vs 16 days, P=0.049) and platelet (15 vs 17 days, P=0.0004) engraftment. Similar hospitalization and bacteremia rates were seen. The overall response rate was 100%, with a complete response or better (sCR/CR) seen in 30% of patients. The matched cohort had an ORR of 98%, with sCR/CR of 37%. The MRD- rate was the same in both groups. More patients in the SLiM cohort achieved VGPR (50%) than in the CRAB cohort (27%). None of the patients died within 100 days of transplant. The 36-month OS was 100% in the SLiM group and 93.3% in the control group (95% CI 83.1%-97.4%), with a trend towards higher OS in the SLiM cohort (P=0.065). The 36-month PFS was 91.61% in the SLiM cohort (95% CI 69.93-97.87%) and 65.95% in the control group (95% CI 52.31%-76.53%). There was no difference in the PFS between the cohorts (P=0.414). Conclusion ASCT is efficacious and safe in MM patients transplanted only due to SLIM criteria. Improved MRD- and longer PFS were not seen despite lower ISS stage disease in the SLiM group.

Introduction: Light chain multiple myeloma (LCMM) is a distinct subtype of multiple myeloma (MM) characterized by the exclusive production of immunoglobulin light chains, unlike the common form of MM that produces the complete immunoglobulin. There is a paucity of literature on the specific tumor cell alterations leading to light chain-only disease as opposed to the typical presentation in MM. Additionally, data on treatment response and outcomes in this subgroup of patients is sparse. This study explores the differences in baseline characteristics, including cytogenetic abnormalities and treatment response between LCMM and multiple myeloma with heavy chain involvement. Materials and Methods: We reviewed patient charts to obtain clinical and laboratory information for individuals diagnosed with LCMM and those with heavy chain MM (comparison cohort) from 2004 to 2022. Patients were matched for age, sex, and year of diagnosis. Data collected included treatment assessment, overall survival, and progression-free survival (PFS). Associations between outcomes and categorical variables were analyzed using the chi-square test, while the Mann-Whitney U test was employed to compare medians. Progression-free survival following initiation of initial therapy and overall survival were assessed using Kaplan-Meier analysis. The Mayo Clinic Institutional Review Board (IRB) approved the study. Results: We identified 848 patients, representing 17.1% of newly diagnosed MM cases. The median age of the LCMM cohort was 63 years (range 16-92), with a female-to-male ratio of 1:5. The LCMM cohort had higher levels of lactate dehydrogenase (LDH), beta-2 microglobulin (p<0.0001), higher baseline creatinine (p<0.0001) and calcium (p<0.0001). The two cohorts had no significant difference in the International Staging System (ISS) or revised ISS (R2-ISS). Additionally, hemoglobin (Hb) and white blood cell count at presentation were higher in the LCMM cohort. Chromosome 1 abnormalities were lower in the LCMM cohort: 1q gain (OR-0.7; 95% CI: 0.6-0.9) and 1p deletion (OR-0.7; 95% CI: 0.6-0.9, p=0.02). Likewise, the frequencies of trisomies and hyperdiploidy were lower in the LCMM cohort, with odds ratios of 0.32 (p=0.012) and 0.37 (p<0.001), respectively. The frequencies of translocations t(4;14) (OR-0.35, p<0.001) and t(14;16) (OR-0.6, p=0.03) were lower in LCMM compared to heavy chain MM. In contrast, the frequencies of t(11;14) (OR-3.4) and t(6;14) (OR-4.9) and deletion of 13q(OR-1.3) was higher in the LCMM cohort. There was no significant difference in the occurrence of del(17p)/TP53 abnormalities. The median PFS after the first regimen was shorter in the LCMM cohort (23 months vs. 27 months, p=0.03), and this difference remained significant after adjusting for baseline adverse prognostic indices and treatment regimen. Median PFS in LCMM patients with monoclonal antibody (Mab) as part of their treatment was 37 months vs. 23 months (Proteasome Inhibitor or immunomodulator-based regimen without Mab), though this difference is not statistically significant p=0.87. No significant difference was found in overall survival between the two groups. Conclusion: This study highlights unique features of light chain multiple myeloma, including increased frequencies of specific cytogenetic abnormalities. Further evaluation of observed differences in cytogenetic abnormalities may enhance our understanding of LCMM and potentially guide baseline treatment choices to improve outcome.

Summary In 2014, the International Myeloma Working Group (IMWG) updated the criteria for diagnosing myeloma and added three additional criteria to the traditional Calcium elevation, Renal impairment, Anemia, Bone disease (CRAB) criteria, called the Sixty % marrow plama cells, Light chain ratio >60, Mri demonstates lytic lesions (SLiM) criteria (clonal bone marrow plasma cells ≥60%, involved to uninvolved free light chain ratio (FLCr) ≥100 and >1 focal lesion on magnetic resonance imaging (MRI)). We report on the outcomes of 30 patients who underwent autologous stem cell transplantation (ASCT) where therapy was initiated solely based on SLiM criteria and compared them to a matched cohort of 60 patients whose myeloma‐defining event was CRAB. The SLiM cohort had a shorter median time to neutrophil (15 vs. 16 days, p = 0.049) and platelet (15 vs. 17 days, p = 0.0004) engraftment. The 36‐month overall survival (OS) was 100% in the SLiM group and 93.27% in the control group (95% CI 83.06%–97.42%), with a trend towards longer OS in the SLiM cohort ( p = 0.065). The 36‐month progression‐free survival (PFS) was 91.61% in the SLiM (95% CI 69.93%–97.87%) and 65.95% in the control group (95% CI 52.31%–76.53%). There was no difference in the PFS between the cohorts ( p = 0.414). ASCT is efficacious and safe in MM patients transplanted only due to SLIM criteria. Early intervention in this asymptomatic cohort did not appear to result in deeper responses or better PFS compared to outcomes in symptomatic patients.

Abstract As patients with relapsed/refractory multiple myeloma (RRMM) continue to live longer, they might get exposed to most available drugs and drug classes during the disease course. For such late line RRMM or among patients without access to novel therapies, retreatment with a drug that the disease had previously been refractory to might be one option. In this retrospective study, we describe 315 patients with RRMM at our institution who were retreated with a drug that the disease had been previously refractory to. We found an overall response rate of 56.2% and a median progression-free survival (PFS) of 11 months with retreatment. Patients with a longer time on initial therapy with the index drug (>28.4 months) had a superior PFS with retreatment (median PFS, 16.9 vs 8.1 months; P < .001). Similarly, patients with a longer time gap between the initial line of therapy with index drug and retreatment with index drug (>46.1 months) had better PFS with retreatment (28.2 vs 8.9 months; P = .016). In conclusion, retreatment with a previously refractory drug is a viable therapeutic option for RRMM, with the most significant benefit derived in disease demonstrating sensitivity to initial drug exposure and among those with a longer gap between initial drug exposure and retreatment.

7558 Background: Survival in patients with multiple myeloma (MM) continues to improve with the newer therapies, but there is no clear evidence of a cure and patients continue to relapse. However, most patients have the most extended period without progression with their first-line therapy, and subsequent therapies often provide a shorter duration of response due to the use of drugs with overlapping mechanisms of action and, more importantly, a shorter first remission, pointing toward more aggressive disease biology. With newer immunotherapies being used at 1st relapse, this may change. We designed this study to explore the natural history of MM after the 1st relapse and define the predictors of outcome after the initial relapse. Methods: We identified all patients in the Mayo Clinic database diagnosed between Jan 2004-June 2019 who had had initial disease progression. The study cohort included 2005 patients. We explored the overall survival (OS) from the time of documented disease progression or the start of second-line treatment in patients who had not met IMWG criteria before second-line therapy. Front-line therapy was grouped into those with either an IMiD or PI, both IMiD and PI, daratumumab with IMiD and PI, and none of these agents. The IMiD and PI were always used with dexamethasone with or without an alkylator. Results: The median age was 63 (range 24-95) years and 60% were male. The median estimated follow-up from diagnosis for all patients was 86 mos. (95% CI; 82, 88) and the median time to progression from the start of therapy was 25 mos. (95% CI; 24, 26). The median OS from the first progression was 45 mos. (95% CI; 42, 50), 36 mos. for those diagnosed before 2009, and 52-53 mos. for those diagnosed later. On univariate analysis, age <70 at 1st relapse, RISS I, novel agents in initial therapy, CR in the first line, diagnosis after 2009, initial remission >18 mos, and initiation of therapy before IMWG progression were all associated with improved OS after 1st relapse (Table). On multivariate analysis, age <70, RISS I, initial remission >18 mos, and initiation of therapy before IMWG progression were all associated with improved OS after 1st relapse. Conclusions: The study provides an estimate of the outcomes and significant predictors of outcomes after 1st relapse in patients with MM. These factors should be taken into consideration when designing clinical trials in this patient population. In particular, these factors identify a high-risk group of patients not always identified by baseline characteristics and should be the focus of future trials. [Table: see text]

AbstractBackgroundPrecursor plasma cell disorders such as monoclonal gammopathy of undetermined significance (MGUS) always precede the development of active malignancies such as multiple myeloma (MM). There is a need for novel biomarkers to identify those patients with such precursor plasma cell disorders who rapidly progress to MM. Plasma‐derived extracellular vesicles (EVs) may serve as a reservoir of potential biomarkers that can shed light on the pathogenesis and disease biology of MM.MethodsThis study isolated small EVs (SEVs) and large EVs (LEVs) from the platelet‐poor peripheral blood plasma of MGUS (n = 9) and MM (n = 12) patients using the size exclusion chromatography‐based method and evaluated their proteome using a label‐free proteomics workflow.ResultsIn total, 2055 proteins were identified in SEVs, while 2794 proteins were identified in LEVs. The transferrin receptor (or CD71) protein was upregulated in both populations of EVs derived from MM patients compared to MGUS patients and was of prognostic significance. Similarly, three isoforms of serum amyloid A (SAA) protein, SAA1, SAA2, and SAA4, were also highly upregulated in SEVs within MM patients relative to MGUS patients. Finally, CD40 expression was also higher in the LEVs derived from MM patients than in MGUS patients.ConclusionsThis study demonstrates the feasibility of successfully isolating both SEVs and LEVs from the peripheral blood of patients with plasma cell disorders and quantifying protein biomarkers within these EVs that could be of prognostic and diagnostic interest.

PURPOSE Patients with Waldenström macroglobulinemia (WM) have disparate outcomes. Newer therapies have emerged since the development of International Prognostic Scoring System, and MYD88 L265P mutation is now frequently assessed at diagnosis, warranting reexamination of the prognostic parameters. PATIENTS AND METHODS We reviewed records of 889 treatment-naïve patients with active WM, consecutively seen between January 01, 1996, and December 31, 2017, to identify clinical predictors of overall survival (OS) in univariate analyses. Patients with complete data for the parameters significant on the univariate analyses (n = 341) were included in a multivariable analysis to derive a prognostic model, subsequently validated in a multi-institutional cohort. RESULTS In the derivation cohort (n = 341), age (hazard ratio [HR], 1.9 [95% CI, 1.2 to 2.1]; P = .0009), serum lactate dehydrogenase (LDH) above upper limit of normal (HR, 2.3 [95% CI, 1.3 to 4.5]; P = .007), and serum albumin <3.5 g/dL (HR, 1.5 [95% CI, 0.99 to 2.3]; P = .056) were independently prognostic. By assigning a score of 1 point each to albumin <3.5 g/dL (HR, 1.5) and age 66-75 years (HR 1.4) and 2 points for age >75 years (HR, 2.6) or elevated LDH (HR, 2.3), four groups with distinct outcomes were observed on the basis of the composite scores. Five-year OS was 93% for the low-risk (score 0), 82% for low-intermediate risk (score 1), 69% for intermediate-risk (score 2), and 55% for the high-risk (score ≥3; P < .0001) groups. In the validation cohort (N = 335), the model maintained its prognostic value, with a 5-year OS of 93%, 90%, 75%, and 57% for the four groups, respectively ( P < .0001). CONCLUSION Modified Staging System for WM (MSS-WM), utilizing age, albumin, and LDH is a simple, clinically useful, and externally validated prognostic model that reliably risk-stratifies patients with symptomatic WM into four groups with distinct prognosis.