Revised International Staging System Stage Research Articles

The quantitative parameters based on marrow metabolism derived from synthetic MRI: A pilot study of prognostic value in participants with newly diagnosed multiple myeloma.

The value of SyMRI-derived parameters from lumbar marrow for predicting early treatment response and optimizing the risk stratification of the Revised International Staging System (R-ISS) in participants with multiple myeloma (MM) is unknown. We prospectively enrolled participants with newly diagnosed MM before treatment. The SyMRI of lumbar marrow was used to calculate T1, T2, and PD values and the clinical features were collected. All participants were divided into good response (≥VGPR) and poor response (<VGPR) groups after four treatment cycles. Univariate, multivariate analyses and ROC were used to identify prognostic significance. Mann-Whitney U-tests were used to compare the SyMRI parameters between genders. The value of optimizing the risk stratification was analyzed by Fisher's exact tests at each R-ISS stage. Fifty-nine participants (good response, n = 33; poor response, n = 26) were evaluated. The bone marrow plasma cell percentage, β2-microglobulin, T1 and T2 value were difference between two groups (all p < 0.05). The T1 (odds ratio 1.003, p = 0.005) and T2 values (odds ratio 0.910, p = 0.002) were independent predictors and the AUC and cut-off values were 0.787, 967.2 ms and 0.784, 75.9 ms, respectively. There were no significant differences in SyMRI parameters between genders. Participants with both T1 value ≥967.2 ms and T2 value ≤75.9 ms in the R-ISS II stage were potentially to get poor response. Synthetic MRI is a promising tool for predicting early treatment response to MM and promoting R-ISS II stage risk stratification.

Therapeutic Effect and Adverse Event Rate of Different Treatment Methods in Patients with Multiple Myeloma and Renal Insufficiency

Introduction: This study involves the collation and analysis of clinical characteristics and laboratory findings in patients with multiple myeloma (MM) combined with renal insufficiency. The objective was to assess the impact of various treatment methods on patient outcomes and the incidence of adverse events in individuals with MM and renal insufficiency. Methods: We analyzed the correlation between clinical characteristics, gene loci, fluorescence in situ hybridization, treatment methods, and prognosis in patients with MM and renal insufficiency. The differences in hematological and therapeutic efficacy indexes between two groups subjected to different treatments were evaluated. The assessment of treatment effectiveness was based on the total effective rate, calculated as the sum of stringent CR rate, complete remission rate, very good partial remission rate, and partial remission rate. Results: (1) The renal insufficiency group exhibited higher percentages of bone marrow abnormal plasma cells, lactate dehydrogenase (LDH), blood calcium, white blood cell count, percentage of neutrophils, and blood β2-microglobulin (β2-MG) levels compared to the normal renal function group. Conversely, hemoglobin levels and lymphocyte percentage were lower in the renal insufficiency group. Binary logistic regression analysis identified hemoglobin, blood calcium values, blood β2-MG, and LDH as independent risk factors for the development of renal insufficiency in patients with MM (p < 0.05). (2) Based on the Durie-Salmon staging criteria, the proportion of Stage III patients was the highest (up to 81.8%), indicating that patients with MM usually suffer from insidious disease, often with high tumor load and late-disease stage at the time of consultation. International Staging System (ISS) and Revised ISS staging also revealed a higher proportion of Stage III patients in the renal insufficiency group (p < 0.05), indicating a worse long-term prognosis in patients with MM and renal insufficiency. (3) Before treatment, there was no significant difference between the two groups in the analysis of various indices. Complications such as sepsis, herpes zoster, peripheral neuropathy, thrombosis, secondary pulmonary infection, and cardiac complications were significantly lower in the BCD group (Bortezomib + Cyclophosphamide + Dexamethasone) compared to the BD group (Bortezomib + Dexamethasone) (χ² = 6.333, p < 0.05), suggesting fewer complications with the BCD regimen. (4) The clinical treatment effects analysis indicated that the BCD group demonstrated a more significant impact than the BD group in the treatment of MM. Conclusion: The application of the BCD regimen in the treatment of MM has shown significant efficiency, effectively alleviating clinical symptoms with fewer adverse reactions and high safety.

Age-Based Comparison of Dara-Rvd, Krd and Rvd Induction Therapies during the First Line of Therapy for Multiple Myeloma Patients

Background Since the development of proteasome inhibitors, the combination of lenalidomide (R), bortezomib (V), and dexamethasone (d) for induction has been the standard of care when treating patients with multiple myeloma. This combination has been shown to improve the clinical outcomes and quality of life of multiple myeloma patients. More recently, new generations of proteasome inhibitors, such as carfilzomib (K), and the development of monoclonal antibodies have created new opportunities for treatment that provide better outcomes with fewer side effects. The addition of daratumumab (Dara) to the RVd induction therapy has shown more potent results, increasing response rates and outcomes. However, there is a lack of evidence about the influence that age may have on the efficacy of these therapies. Methodology Using HealthTree Cure Hub for Multiple Myeloma (PMID: 35271305), we analyzed real-world data from 1100 patients with multiple myeloma. Patients were categorized into two groups based on age (&amp;lt;65 and ≥65). We compared ‘Time to Next Treatment’ (TTNT) among patients who received DaraRVd, KRd, or RVd as induction therapy. The analysis was conducted using Kaplan-Meier curves in R. Age groups were also subclassified by high-risk cytogenetics according to mSMART staging by fluorescence in situ hybridization (FISH), and the Revised International Staging System (R-ISS) stage. Chi-square tests were used to assess the association with R-ISS and mSMART stages. Results We analyzed the data of 1100 patients with MM, of which 718 patients (65.3%) were age &amp;lt;65 and 382 patients (34.7%) were age ≥65. The &amp;lt;65 group had a median age of 55±7, and the ≥65 group had a median age of 70±5. The majority of patients were female (n=586, 53.3%). The median year of diagnosis was 2018 (2009-2022). In the &amp;lt;65 group, the majority of patients were White (88%), and other big groups were Blacks (5.8%), and Hispanics or Latinos (2.6%). Similarly, in the ≥65 group, the majority of patients were White (93.0%), and other big groups were Blacks (3.3%), and Hispanics or Latinos (2%). In the &amp;lt;65 group, 55 patients had DRVd as induction therapy, 77 KRd, and 586 RVd. In the ≥65 group, 38 patients received DRVd as induction therapy, 39 KRd, and 305 RVd. R-ISS staging was available for 588 patients. In the &amp;lt;65 group, 139 patients (36.7%) were classified as R-ISS stage I, 170 patients (44.8%) stage II, and 70 patients (18.5%) stage III. In the ≥65 group, 75 patients (35.9%) were stage I, 104 patients (49.8%) were stage II, and 30 patients (14.3%) were stage III ( p=0.37). mSMART staging was available for 1035 patients, of whom patients with high-risk, double, and triple hit represented 16.2%, 5.0%, and 0.3%, respectively ( p = 0.35). Regarding stem cell transplant (SCT), 571 patients (51.9%) underwent SCT. In the &amp;lt;65 group, 404 patients (56.3%) received SCT; of those, 18 (32.7%) received DRVd, 21 (53.3%) KRd, and 345 (58.9%) RVd. In the ≥65 group, 167 patients (43.7%) received SCT; of those, 12 (31.6%) received DRVd, 23 (59%) KRd, and 132 (43.3%) RVd as induction therapy. For patients aged &amp;lt;65, the median TTNT was not yet reached for the DRVd group, 33 mo for the KRd group, and the RVd group was longer at 48 mo ( p=0.049). For patients aged ≥65, the median TTNT was not yet reached for the DRVd group, and 54 mo for the KRd group, which did not significantly differ from the RVd group, which had a median TTNT of 47 mo (p=0.52). Conclusion This study found that in the &amp;lt;65 age group, RVd induction therapy led to a longer TTNT compared to KRd, while in the ≥65 age group, KRd showed a longer TTNT than RVd. When considering the SCT usage rate, which increases TTNT by at least 12 months on average, KRd did not significantly improve outcomes over RVd in both age groups. However, when evaluating KRd induction, it's worth noting that KRd showed an improved outcome with a longer TTNT in the ≥65 age group compared to the &amp;lt;65 age group, despite toxicity concerns. These results align with the ENDURANCE trial, which also indicated that KRd did not significantly improve outcomes in standard-risk patients compared to VRd. Though the TTNT for the DRVd group is yet to be reached, the current trend suggests promising results for DRVd as a first-line therapy over KRd and RVd in both age groups. Nevertheless, further research is needed to validate and gain better insight into these observed trends.

Age-Based Comparison of Stem Cell Transplantation during the First Line of Therapy for Multiple Myeloma Patients

Background High-dose chemotherapy followed by stem cell transplantation (SCT) has been the standard first-line therapy for eligible multiple myeloma (MM) patients for over three decades. However, most studies evaluating SCT in MM have focused on patients under 65 years old, despite the increasing number of older patients diagnosed with MM. Retrospective data suggest that SCT can offer good survival outcomes with acceptable toxicities in patients over 65. This registry retrospective study aims to compare the time to next treatment (TTNT) of SCT versus non-SCT treatments in MM patients, assessing those aged &amp;lt;65 and ≥65 years old. Methodology Using HealthTree Cure Hub for Multiple Myeloma (PMID: 35271305), we analyzed real-world data from 1279 patients with multiple myeloma. Patients were categorized into two groups based on age at the start of their first line of therapy (&amp;lt;65 and ≥65). Kaplan-Meier ‘Time to Next Treatment’ (TTNT) R analysis was employed to compare patients who underwent stem cell transplant (SCT) and those who did not (NSCT) within each age group. SCT patients received a high-dose melphalan preparative regimen (140-200 mg/m2). Age groups were also subclassified by high-risk cytogenetics, using mSMART staging by fluorescence in situ hybridization (FISH), and Revised International Staging System (R-ISS) stage. Chi-square tests were used to assess the association with R-ISS and mSMART stages. Results We analyzed the data of 1279 MM patients, of whom 830 (64.9%) were &amp;lt;65 and 449 (35.1%) were ≥65. The &amp;lt;65 group had a mean age of 55±7, whereas the group ≥65 had a mean age of 70±5. 52.5% were female. The majority of patients were White (78.2% in the &amp;lt;65 group and 81.77% in ≥65), with other relevant groups including Blacks (5.8% in the &amp;lt;65 group and 4.2% in the ≥65 group), and Hispanics or Latinos (4.0% in the &amp;lt;65 group and 2.8% in the ≥65 group). The median year of diagnosis was 2018 (2006-2022).R-ISS staging was available for 664 patients and not dissimilar between groups ( p = 0.69): in the &amp;lt;65 group, 159 (37.2%) patients were classified as R-ISS stage I, 188 (44.0%) patients stage II, and 81 (18.9%) patients stage III. In the ≥65 group, 81 (34.3%) were stage I, 118 (50.0%) stage II, and 37 (15.7%) stage III. 1196 patients had mSMART staging available, of whom, patients with high-risk, double, and triple hit, represented 15.9%, 4.6%, and 0.4%, respectively. Age group high-risk characteristics proportions were not dissimilar ( p = 0.7). In the &amp;lt;65 group, 69.2% had a transplant during their first line of therapy, while in the ≥65 group, 48.8% had a transplant. For patients aged &amp;lt;65, the mean TTNT was 32.5 mo (SD 25) in the SCT group, and 16 mo (SD 21.6) in the NSCT group. For patients aged ≥65, the mean TTNT was 28.6 mo (SD 18.9) in the SCT group, and 16.5 mo (SD 18.3) in the NSCT group. The TTNT survival at 4 years was significantly higher in patients that experienced an SCT in both groups, &amp;lt;65 (SCT=40%, NSCT=18%, p = &amp;lt;0.0001) and ≥65 (SCT=43%, NSCT=14%, p = &amp;lt;0.0001). Conclusions Our findings add to the compelling evidence that SCT demonstrates favorable outcomes in both age groups of MM patients. The mean TTNT difference of SCT vs NSCT observed in the &amp;lt;65 group is 16.5 mo, and in the ≥65 group, it is 12.1 mo. Furthermore, patients who underwent SCT in both age groups had significantly higher TTNT survival rates at 4 years, doubling the rates to 40% in the &amp;lt;65 group and 43% in the ≥65 group, emphasizing the substantial benefits of SCT as a first-line therapy for multiple myeloma. These results contribute to the growing body of evidence supporting the efficacy and acceptability of SCT in the management of multiple myeloma across all age groups. It also emphasizes the importance of considering SCT as a viable treatment option for eligible MM patients, including those aged 70 and above, to improve long-term outcomes.

Performance of Newer Staging Systems for Myeloma in a Contemporary, Large Cohort of Patients in the United States

CONCLUSION The most widely used multiple myeloma (MM) staging system, the Revised International Staging System (R-ISS), is based on lactate dehydrogenase (LDH), albumin, high-risk genetic markers by FISH, and beta-2 microglobulin (B2M). However, it does not account for additional risk impacted by multiple genetic abnormalities, or the risk imparted by presence of gain of chromosome 1q, and most patients are staged as R-ISS Stage 2. Two new staging systems, the Mayo Additive Staging System (MASS), and the Second Revision of the International Staging System (R2-ISS) have been recently proposed. A comparison of the performance of these two systems has not previously been done. We aimed to externally demonstrate the application of these staging systems and compare their performances in a large, contemporary cohort of patients in the United States. We conducted a retrospective cohort study using the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database, comprising de-identified patient-level structured and unstructured data, curated via technology-enabled abstraction and originating from approximately 280 US cancer clinics (~800 sites of care). The study included newly diagnosed MM patients initiating treatment between January 1, 2016 and October 1, 2022. We used the Kaplan-Meier method to evaluate real-world overall survival (rwOS) and patients were followed from first-line treatment initiation (index date) until the first of death, end of the study period or last recorded activity. The log-rank test to compare survival curves across derived stages. Multivariable analysis was conducted using stratified Cox models to account for non-proportional hazards by age with covariate adjustment for race/ethnicity, sex, practice type (academic or community) and diagnosis year (2016-2019 vs 2020-2022). Discrimination and calibration were evaluated in crude models using Harrell's c-index and the Hosmer-Lemeshow goodness-of-fit test, respectively. There were 497 patients with MM included. Patient characteristics are listed in Panel A. The distribution of patients across R-ISS stages were as follows, 24%, 63% and 13% for Stage 1, 2 and 3 respectively. rwOS differed across R-ISS stage (log-rank p = 0.0006) and the median OS (OS) was not reached (NR), 63, and 37 months for R-ISS stage 1, 2, and 3, respectively. 34%, 35% and 31% for MASS 1, 2, and 3, respectively. The corresponding survival curves were significantly different (p &amp;lt; 0.0001), with associated mOS of 77, 61 and 45 months for MASS stages 1, 2, and 3, respectively. R2-ISS includes four risk categories (stages I-IV) and in our cohort, 20% (n = 100) were stage I (low), 126 (25%) were stage II (low-intermediate), 229 (46%) were stage III (intermediate), and 42 (9%) were stage IV (high). Survival across stages were significantly different (p&amp;lt;0.0001), though the survival curves for low and low-intermediate, and intermediate-high and high, were clustered, suggesting comparable outcomes in stages I-II and stages III-IV. mOS for R2-ISS stages I, II, III, and IV was NR, 69, 50 and 51 months respectively (Panel B). In fully adjusted analyses, as compared to MASS I, the hazards of death were 2.0 (95% CI 1.3-3.2) for MASS II and 2.7 (1.7-4.2) for MASS III. The hazards of death were similar for R2-ISS low and low-int (HR for low-int vs low: 1.2 [0.7, 2.3]). As compared to R2-ISS low, the hazards of death were similarly higher for int-high and high (HRs: 2.4 [1.4, 4.1] and 2.6 [1.3, 5.2], respectively). Discrimination and calibration were similar across all staging systems (c = 0.6, and Hosmer-Lemeshow p&amp;gt;0.05 for all three staging systems). Application of contemporary MM staging systems in a large cohort of US patients shows that they are prognostic for OS in MM. MASS demonstrated a greater separation for OS across stages, whereas R2-ISS intermediate-high and high were largely overlapping. Although our results demonstrate similar accuracy and reliability of MASS and R2-ISS, the discrimination of patients across different stages seen with the newer staging systems, as opposed to R-ISS, calls for greater use of these newer staging systems in routine clinical practice.

Real-World Utilization of Daratumumab in Front-Line Treatment of Newly Diagnosed Multiple Myeloma: A Retrospective Observational Study

Introduction: Daratumumab (DARA), a CD38 monoclonal antibody, has demonstrated remarkable efficacy among newly diagnosed (ND) and relapsed/refractory multiple myeloma (MM) patients. The introduction of a quadruplet therapy with an addition of DARA per the GRIFFIN trial has improved the treatment paradigm. However, the real-world data on treatment patterns and utilization of DARA in front-line treatment are limited. This study aimed to evaluate the real-world utilization of DARA in front-line treatment and examine factors that may impact the utilization of DARA-based regimen in NDMM. Methods: We conducted a retrospective observational study of all patients, age ≥ 18, with clinical MM who were newly diagnosed and treated within the Yale New Haven Health (YNHH) system between August 1, 2020 and August 31, 2022. We manually reviewed clinical presentation, age at diagnosis, gender, race, ethnicity, Revised International Staging System (R-ISS) stage, Eastern Cooperative Oncology Group (ECOG) performance status (PS), insurance type, practice setting, immunoglobulin (Ig) isotype, hemoglobin (Hb), creatinine (Cr), and calcium (Ca) at diagnosis, presence of bone lesion, bone marrow plasma cell (BMPC) %, cytogenetic abnormalities, transplant eligibility, and treatment response based on the International Myeloma Working Group (IMWG) criteria at 3 months after front-line therapy. Descriptive statistics were performed with Pearson's χ²-test using GraphPad PRISM version 9.0.0. Results: We identified 241 patients with NDMM during the study period within the YNHH system. Overall median age at diagnosis was 69 years (interquartile range: 61-78). 60.2% (n=145) were male, 68% (n=164) identified themselves as white and 90% (n=217) as non-Hispanic. 51.9% (n=125) had R-ISS stage II and 65.6% (n=158) had ECOG PS of 0-1. 63.1% (n=152) were treated at a community practice setting and 53.9% (n=130) had commercial insurance. 55.6% (n=134) had IgG isotype and 41.1% (n=99) had unfavorable risk cytogenetics which was defined as a 17p deletion, t(4;14), t(14;16), t(14;20), gain or amplification of 1q, 1p deletion, and chromosome 1 translocations. 28.2% (n=68) received front-line quadruplet therapy: DARA+lenalidomide (LEN)+bortezomib (BORTE)+dexamethasone (DEX) (n=54), DARA+cyclophosphamide+BORTE+DEX (n=10), or DARA+LEN+carfilzomib (CARFIL)+DEX (n=4). 58.5% (n=141) received triplet therapy, 8.3% (n=20) received doublet therapy, 0.83% (n=2) received monotherapy, and 4.1% (n=10) opted for hospice care. 41.5% (n=100) received DARA in front-line treatment: quadruplet as above (n=68), triplet of DARA+LEN+DEX, DARA+BORTE+DEX, or DARA+CARFIL+DEX (n=31), and doublet of DARA+DEX (n=1). Factors including gender (male vs. female, p=0.018), practice setting (academic vs community, p=0.014), R-ISS stage (I vs II vs III vs unknown, p=0.003), Ig isotype (IgG vs IgA vs light chain vs other, p=0.006), cytogenetic abnormalities (standard risk vs unfavorable risk, p=0.02), and transplant eligibility (transplant eligible vs transplant ineligible, p=0.001) were associated with the adoption of DARA in front-line treatment. While 51.7% (n=46) of the patients treated at an academic practice setting received DARA in front-line treatment, only 35.5% (n=54) of the patients treated at a community practice setting received such treatment. 69% (n=69) of those who received DARA-based regimen in front-line treatment achieved at least a very good partial response (VGPR) at 3 months compared to 54.6% (n=77) of those who received non-DARA-based regimen. There were no significant differences in age, race, ethnicity, ECOG PS, insurance type, laboratory data (Hb, Cr, and Ca) at diagnosis, presence of bone lesion, and BMPC % between the group treated with DARA-based regimen and the group treated with non-DARA-based regimen. Conclusion: This analysis of real-world data from patients with NDMM highlighted underutilization of DARA in front-line treatment, especially at a community practice setting. Gender, practice setting, R-ISS stage, Ig isotype, cytogenetic abnormalities, and transplant eligibility were significantly associated with the adoption of DARA in front-line treatment. Additionally, utilization of DARA in front-line treatment was associated with a better treatment response at 3 months, suggesting that interventions to promote the utilization of DARA will help improve outcomes of NDMM patients.

R-ISS Stage-Dependent Single-Cell Sequencing Analysis Uncovers Oncogenes and Potential Immunotherapeutic Targets in Multiple Myeloma

Multiple myeloma (MM) accounts for ~10% of all haematologic malignancies. Little is known about high intratumour heterogeneities in patients stratified by the Revised International Staging System (R-ISS). Herein, we constructed a single-cell transcriptome atlas to compare differential expression patterns among stages. We found that a novel cytotoxic plasma cell (PC) population exhibited with NKG7 positive was obviously enriched in stage II patients. Additionally, a malignant plasma cell population with significantly elevated expression of MKI67 and PCNA was associated with unfavourable prognosis and Epstein-Barr virus (EBV) infection in our collected samples. Moreover, Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) was found and verified to promote proliferation of MM cell lines, suggesting RRM2 may serve as a detrimental marker in MM. The percentages of CD8+ T cells and NKT cells decreased along with R-ISS stages, reflecting the plasticity of the tumour immune microenvironment. Importantly, their crosstalks with myeloid cells and PC identified several potential immunotargets such as SIRPA-CD47, and CD74-MIF, respectively. Collectively, this study provided an R-ISS-related single-cell MM atlas and revealed the clinical significance of novel PC clusters, as well as potential immunotargets in MM progression.

Loss of Mir-221/222 Cluster Expression Results in Short-Term Disease Progression and Poor Post-Treatment Outcome in Multiple Myeloma

Despite the notable progress that has been achieved in the realm of MM treatment, the persistence of elevated relapse rates and therapy resistance remain a substantial hindrance to effective management of the patients. Therefore, the development of modern tools to ameliorate patients' prognosis and predict treatment outcome is of first clinical priority. MicroRNAs (miRNAs) have emerged as powerful post-transcriptional regulators of gene expression, while recent advances in high-throughput sequencing techniques have unveiled their prognostic utility in numerous pathologies. Herein, using a miRNA-seq we have investigated miRNA profiles in association with Revised International Staging System (R-ISS), aiming to reveal potential MM-related miRNAs able to improve patients' risk stratification. Bone marrow (BM) aspiration samples were collected from 120 MM patients at diagnosis (screening cohort). Mononuclear cells were isolated using Ficoll-Paque, while CD138 + plasma cells were positively selected using anti-CD138 mAbs magnetic beads. miRNA-seq was performed in CD138 + cells from 8 R-ISS I, 8 R-ISS II and 8 R-ISS III MM patients. Following 3‘-end polyadenylation of total RNA, miR-221/222 levels were quantified in our screening cohort by RT-qPCR. Disease progression (relapse and/or death) and patients’ mortality were assessed as clinical endpoint events, while internal validation was accomplished by bootstrap Cox proportional regression analysis. Aash et al. 2023 (n=86) and Kruykov et al. 2016 (n=149) served as external validation cohorts. miRNA-seq revealed miR-221/222 to be concurrently downregulated in R-ISS III versus R-ISS I/II MM patients (miR-221: FC=0.356; miR-222: FC=0.357; Fig.1B,C). The analysis of our screening cohort documented that CD138 + miR-221/222 loss is significantly associated with higher risk for short-term disease progression ( p=0.010; Fig.1D) and poor survival ( p=0.001; Fig.1E) of MM patients. Furthermore, the analysis of the two independent validation cohorts (Aass et al. cohort A, p=0.019; and Kryukov et al. cohort B, p=0.013) clearly confirmed the worse treatment outcome of the patients with miR-221/222 loss (Fig.1F,G). Moreover, miR-221/222-fitted multivariate models demonstrated the ability of miR-221/222 cluster to ameliorate the clinical routine of the established MM prognostic markers, including “R-ISS stage”, “high-risk cytogenetics” [+1q21, t (4;14) del(17p13), t(14;16), t(11;14), del(13q)] and “response to 1 st line therapy” (IMWG guidelines). In this context, the evaluation of CD138 + miR-221/222 levels significantly improved the risk-stratification of MM patients, resulting in the advanced positive prediction of patients' poor treatment outcome within R-ISS III (PFS: p=0.006, OS: p=0.019; Fig.2A,B) and high-risk cytogenetics groups (PFS: p=0.025, OS: p=0.022; Fig.2C,D). Finally, focusing on patients' response to 1 st line therapy stratification, loss of miR-221/222 could efficiently define optimal (sCR/CR/VGPR) and poor (PR/SD/PD) responders' subgroups (PFS: p&amp;lt;0.001, OS: p&amp;lt;0.001; Fig.2E,F). In conclusion, we identified miR-221/222 loss in CD138 + plasma cells as a powerful independent predictor of patients' risk for disease progression and poor treatment outcome, while miR-221/222-fitted multivariate prognostic models resulted to improved patients' risk-stratification and prediction of MM treatment outcome.

Efficacy of Daratumumab-Based Regimens in Anti-CD38 Treatment-Naïve Relapsed/Refractory Multiple Myeloma with High-Risk Cytogenetics

Background: Daratumumab-based combination with proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs) have revolutionized the treatment outcomes of relapsed/refractory multiple myeloma (RRMM). Several daratumumab-based triplet combinations have been approved for the management of RRMM, but outcomes of daratumumab-based triplets in patients with high-risk cytogenetics RRMM (HC-RRMM) are not well described in the literature. This study aimed to evaluate the clinical outcome of daratumumab-based regimens in patients with HC-RRMM who are daratumumab-naïve. Methods: A retrospective review of 110 patients with HC-RRMM who received daratumumab-containing regimens from 6/2016 through 2/2023 at the University of Kansas Medical Center, in collaboration with the U.S Myeloma Innovations Research Collaborative (USMIRC) was conducted. Daratumumab was combined with bortezomib/dexamethasone (DVd), carfilzomib/dexamethasone (DKd), and pomalidomide/dexamethasone (DPd) for treatment of RRMM. HC-RRMM was defined as patients with one or more cytogenetic abnormalities (on FISH panel) including -17/del(17p), t(4;14), t(14;16), t(14;20), or amplification of 1q. Responses to therapy including overall response rate (ORR), complete response or better (≥CR), and very good partial response (VGPR) were evaluated using the International Myeloma Working Group (IMWG) criteria. Descriptive statistics were used to summarize patient and disease characteristics, along with efficacy outcomes. Progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier methods. Results: Of the 110 patients with HC-RRMM, the median age was 66 years (range 43-84), 83 (75%) were Caucasian, 60 (54%) had IgG isotype, 41 (37%) had revised international staging system (R-ISS) stage III disease, 35 (32%) had extramedullary disease (EMD), 57 (52%) patients had one high-risk cytogenetic (HC) abnormality, 49 (44%) had 2 HC abnormalities, while four (4%) had 3 HC abnormalities. The median number of previous lines of therapy was 2 (1-4). Eighty-eight patients (80%) were lenalidomide refractory, while 53 patients (48%) had double refractory disease to both a PI and IMiD treatment. A total of 19 (17%), 27 (25%), and 64 (58%) patients received DVd, DKd, and DPd, respectively. The overall response rate (ORR) for the entire patient population was 73%, 45% had VGPR or better, and 35% achieved ≥CR. Median follow-up was 28 months (12.07-53.57), the median OS was 28 months (95% CI 23.2 - 43.9) and PFS was 8.03 months (95% CI 5.8 - 12.2) for all treatment groups. The median PFS for 1 HC vs ³ 2 HC was 14.8 vs 4.57 months (HR 1.72, 95%CI 1.17-2.72 p = 0.006), respectively. Similarly, median OS for 1 HC vs ³ 2 HC was 43.93 vs 22.47 months (HR 1.87, 95%CI 1.15-3.05, p = 0.011), respectively. (Figure 1). On multivariate analysis, R-ISS stage III, -17/del(17p), and the presence of more than one HC abnormality were associated with poor OS. The most common cause for treatment discontinuation was progressive disease, accounting for 73% of patients in the whole cohort. As for each daratumumab-based triplet, discontinuation due progression occurred in 78%, 48%, and 83% in DVd, DKd, and DPd, respectively. Other causes of discontinuation included &amp;gt; grade 3 neuropathy, which occurred in 16% of patients receiving DVd, and cardiac events, which occurred in 11% of patients receiving DKd. Treatment-related mortality occurred in 2% of patients in the whole cohort. At the time of evaluation, 14 patients remain on treatment. Conclusion: Advanced stage R-ISS disease at diagnosis, presence of -17/del(17p), and 2 or more HC abnormalities were associated with poor prognosis reflected by worse PFS and OS in HC-RRMM treated with daratumumab-based therapies. A larger cohort or a prospective study in patients with HC-RRMM is needed to compare long-term outcomes between daratumumab-based therapies (DKd, DVd, and DPd).

Development of a Semiquantitative Whole-Body MRI Scoring System for Multiple Myeloma.

Background In patients with multiple myeloma (MM), the serum marker β2-microglobulin does not always accurately reflect tumor load. In contrast, whole-body (WB) MRI has shown high sensitivity for detecting bone lesions. Purpose To develop and validate a semiquantitative WB MRI scoring system for newly diagnosed MM and to compare it with the International Staging System (ISS) and Revised ISS (R-ISS). Materials and Methods This study included two retrospective groups (group 1, July 2015 to September 2021; group 2, February 2020 to September 2021) and one prospective group (group 3, October 2021 to February 2022) of patients with newly diagnosed MM. A new scoring system for MM was developed using spine MRI scans in group 1 and WB MRI scans in group 2 that integrated three features: (a) background marrow pattern, (b) number of focal bone lesions, and (c) presence of extramedullary or paramedullary lesions. The summed total score ranged from zero to nine. The interobserver agreement for each feature was assessed using Fleiss or Cohen weighted κ. WB MRI total scores in group 3 were compared across ISS and R-ISS stages using two-way analysis of variance. Results Groups 1, 2, and 3 included 103 patients (mean age, 62.1 years ± 9.1 [SD]; 60 men), 36 patients (mean age 65.4 years ± 11.3 [SD]; 19 women), and 39 participants (mean age, 62.0 years ± 11.7 [SD]; 20 men), respectively. The interobserver agreements for the three features composing the scoring system were substantial (κ range, 0.69-0.80). WB MRI total score increased with increasing ISS stage (mean score for ISS 1, 2, and 3 was 2.2, 4.2, and 5.8, respectively; P = .009) and R-ISS stage (mean score for R-ISS 1, 2, and 3 was 2.1, 3.8, and 5.9, respectively; P = .005). Conclusion The developed WB MRI scoring system for MM demonstrated substantial observer agreement and corresponded well with ISS and R-ISS stages. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Dragan and Messiou in this issue.

Socioeconomic factors associated with a late-stage multiple myeloma diagnosis: An analysis of the National Cancer Database.

e20036 Background: Multiple myeloma is an aggressive monoclonal plasma cell proliferative disorder that is the second most common hematologic malignancy. On a global scale, multiple myeloma led to an estimated 106,000 deaths in 2018 alone. The exact cause of multiple myeloma is not well understood. Later stage of diagnosis is correlated with worse outcomes; thus, it is critical to assess the socioeconomic factors associated with diagnosis at early versus late stages. Methods: Using the National Cancer Database, we aimed to identify associations between socioeconomic factors of patients that present with Revised International Staging System (R-ISS) stage I multiple myeloma in comparison to R-ISS stage III at diagnosis. In this study, 5,512 patients from the National Cancer Database who were diagnosed with R-ISS stage I and stage III multiple myeloma were analyzed based on age, ethnicity, race, education, insurance type, income, education, geographic location, facility type, sex, Charlson-Deyo score, and urban or rural setting. Demographic factors of patients that presented with stage I and stage III disease were analyzed using chi square, ANOVA, and multivariate analyses. All patients included in the study were diagnosed with multiple myeloma between 2004 and 2020. Results: We identified significant (P &lt; 0.05) associations between insurance type, median income, education, rural setting, and Charlson-Deyo score with diagnosis of R-ISS stage III multiple myeloma. For insurance type, private insurance, other government insurance, and Medicaid had lower percentages of R-ISS stage III diagnosis than patients without insurance (P &lt; 0.001). Medicaid and over government insurance were up to 70% less likely to present with stage III MM than patients without insurance (P &lt; 0.001). Regarding income and education, patients from a zip-code associated with an income of &lt; $38,000 and zip-codes with lower levels of high school diploma had higher rates of stage III multiple myeloma diagnosis (P &lt; 0.001). Patients from completely rural or less than 2,500 urban population adjacent to a metro area (P &lt; 0.005) and not adjacent to a metro area (P &lt; 0.025) showed significant increase in later stage multiple myeloma diagnosis than those from a metro setting with population above one million. Patients with Stage III at presentation were older than patients with stage I on average (P &lt; 0.001). There were no significant differences seen based on race, sex, ethnicity, or region in the United States. Conclusions: Factors associated with increased likelihood of later stages of diagnosis of multiple myeloma include insurance type, median income, education, and rural location. Future analysis should further investigate the specific barriers to early patient diagnosis and treatment due to insurance type, education level, and rural setting.

EARLY RELAPSE WITHIN 18 MONTHS (ER18) IS A POWERFUL DYNAMIC PREDICTOR FOR PROGNOSIS AND COULD REVISE STATIC RISK DISTRIBUTION IN PATIENTS WITH NEWLY‐DIAGNOSED MULTIPLE MYELOMA

The duration of response to treatment is a major prognostic factor and early relapse (ER) strongly predicts inferior survival in multiple myeloma (MM) patients. But the definitions of ER in MM varied from study to study. In this study, we aimed to identify the best ER timepoint which we integrated with initial traditional risk features to formulate a novel prognostic classification incorporating both static and dynamic risk. The study was based on the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199) and a total of 629 patients diagnosed with NDMM were included in this study. We first summarized all studies about ER published to date and found that relapse within 18 months from the initial treatment or within 12 months from SCT was mostly used to define early PD in many studies. Our findings indicate that ER18 could effectively balance the bias of ER definitions for patients with or without ASCT, as well as fulfill all requirements for a dynamic risk predictor. The ER18 population (114/587; 19.4%) presented with more aggressive biologic features compared to a reference cohort (P < 0.001), with a significant short median overall survival (OS) of 28.9 months. We also described the specific transitions from static risk profile to dynamic risk distribution in our cohort and then constructed a mixed-risk pattern to identify four novel populations with distinct survival outcomes (P < 0.001). A total of 367 (67.0%) patients presented with at least one high-risk feature: those with ISS III stage, elevated LDH, and HRCAs were classified as baseline high-risk (BHR) group; 86 (23.4%) patients experienced ER18 and further defined as mixed high-risk (MHR) population, and the remaining patients were classified as static high-risk (SHR). Within patients without BHR features, the dynamic risk event (ER18) occurred in 21(11.6%) patients, defined as functional high-risk (FHR). As expected, the MHR population had the worst outcomes with a median OS of 25.9 months (P < 0.001). Of note, FHR patients had similar survival compared to SHR patients (OS: not reached vs. 71.4 months; P = 0.235; Figure 3B), supporting the importance of dynamic risk factor (ER18) as a prognostic factor and further suggesting that lack of durable response could exert an adverse impact on prognosis similar to baseline high-risk variables. Moreover, we confirmed that ER18 refined the predictive accuracy of the Revised International Staging System stage (R-ISS). Encore Abstract - previously submitted to EHA 2023 Keywords: Diagnostic and Prognostic Biomarkers, Multiple Myeloma, Risk Models No conflicts of interests pertinent to the abstract.

LINKER-MM1 study: Linvoseltamab (REGN5458) in patients with relapsed/refractory multiple myeloma.

8006 Background: Linvoseltamab is a BCMA×CD3 bispecific antibody with encouraging efficacy and a manageable safety profile in patients (pts) with relapsed/refractory multiple myeloma (RRMM) (Bumma et al. ASH 2022). Two Phase (Ph) 2 full dose cohorts (50 mg and 200 mg) in the LINKER-MM1 (NCT03761108) trial were studied to optimize dose selection. Methods: Ph 2 enrolled adults with MM who progressed on/after ≥3 lines of therapy (LoT) including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody (Ab), or were at least triple class (IMiD/PI/anti-CD38 Ab) refractory. A protocol amendment permitted pts who progressed during 4–12 wks on 50 mg to dose escalate to 200 mg. Primary endpoint was objective response rate (ORR). Key secondary endpoints included duration of response (DoR) and minimal residual disease status. Results: As of 1 Sept 2022, 252 pts have enrolled (Ph 1: 73; Ph 2: 179 [200 mg: 75; 50 mg: 104]). Median age was 66 yrs (range 37–90), 12% had extramedullary plasmacytomas, 12% high-risk cytogenetics, 37% bone marrow plasma cell percentage (BMPC) ≥50%. Median soluble BCMA concentration (sBCMA) was 0.43 mg/L (range 0–10.2), median prior LoT: 5 (range 1–16), and 81% were ≥triple class refractory. Numerically higher efficacy was observed with 200mg, including in high disease burden subgroups; ORR was 64% (200 mg cohort; n = 58, includes 12 Ph 1 pts) and 50% (50 mg cohort; n = 104). Subgroup analyses showed higher ORR in the 200 mg cohort versus 50 mg for sBCMA ≥0.4 mg/L (52% vs 37%), BMPC &gt; 67% (64% vs 35%) and revised ISS stage III (71% vs 27%). Median DoR was not reached for both cohorts (median follow-up: 2.3 months [200 mg], 4.7 months [50 mg]). Probability of maintaining response at 6 months was 89% (200 mg) and 85% (50 mg). Eight pts dose escalated from 50 to 200 mg; 6 (75%) achieved a response. Treatment-emergent adverse events (TEAEs) occurred in 95% (Grade [Gr] ≥3: 66%) of pts in the 200 mg cohort (n = 87, includes 12 Ph 1 pts) and 100% (Gr ≥3: 80%) in the 50 mg cohort. The most common TEAEs were cytokine release syndrome (200 mg: 37% [Gr 3: 1%]; 50 mg: 53% [Gr 3: 2%]), fatigue (200 mg: 32% [Gr ≥3: 0]; 50 mg: 33% [Gr ≥3: 0]) and anemia (200 mg: 28% [Gr ≥3: 24%]; 50 mg: 40% [Gr ≥3: 36%]). Grade ≥3 ICANS occurred in 2 pts (2%) in the 200 mg cohort and 1 pt (1%) in the 50 mg cohort. TEAEs leading to treatment discontinuation occurred in 7% (200 mg cohort) and 8% (50 mg cohort) of pts. Infections occurred in 43% (Gr ≥3: 26%) in the 200 mg cohort and 59% (Gr ≥3: 31%) in the 50 mg cohort. Conclusions: Linvoseltamab 200 mg showed better efficacy compared with 50 mg, including in pts with high disease burden. The 200 mg dose had consistent efficacy across high-risk subgroups and induced responses in pts who progressed on 50 mg. Safety was consistent across Ph 2 doses. The recommended linvoseltamab dose for further development is 200 mg. Updated data with longer follow-up and complete enrollment of the 200 mg cohort will be presented at the meeting. Clinical trial information: NCT03761108 .

The R2-ISS in a Multicenter Cohort of Chinese Patients With Newly Diagnosed Multiple Myeloma.

Multiple myeloma (MM) is a complex disease with highly heterogeneous tumor biology, especially involving cytogenetic abnormalities.1 Consequently, MM patients display markedly diverse clinical characteristics, therapeutic responses, and outcomes.2,3 In this context, the international staging system (ISS) was developed to predict the prognosis of MM patients in 2005,4 which was later updated and named revised ISS (R-ISS) in 2015.5 Although the R-ISS has widely been used as a powerful tool to guide daily practice till present, some considerable limitations (eg, a large proportion of R-ISS II patients with varied outcomes, not reflecting the significance of 1q gain/amplification and concurrent high-risk cytogenetic abnormalities [HRCAs]) have been emerging.6–9 In this context, several new prognostic scoring systems have been reported,10,11 the most recent of which is the second revision of ISS (R2-ISS) updated by the European Myeloma Network (EMN).12 In the R2-ISS,12 5 risk variates with the highest impact on both progression-free survival (PFS) and overall survival (OS) were weighted according to their OS impact, including ISS III 1.5, ISS II 1.0, del(17p) 1.0, lactate dehydrogenase high 1.0, t(4;14) 1.0, and 1q+ (either 1q gain or amplification) 0.5. However, t(14;16) was not included because patients with this HRCA had only a trend toward a shorter PFS than those without it, but not statistically significant, although its role was significant in predicting OS. According to the R2-ISS, patients could be categorized into 4 groups with different risk scores that is, 0 (I), 0.5 to 1.0 (II), 1.5 to 2.5 (III), and 3.0 to 5.0 (IV). In 2 independent cohorts, the R2-ISS was able to sharply stratify newly diagnosed MM (NDMM) patients into these 4 groups with significantly different OS and PFS, including R2-ISS I (19.2% or 11.1% of all patients), II (30.8% or 26.5%), III (41.2% or 51.6%), and IV (8.8% or 10.7%). Moreover, the R2-ISS was able to predict the OS of both transplant-eligible and transplant-ineligible patients, and patients who received different upfront treatments (eg, proteasome inhibitors [PIs], immunomodulatory drugs [IMiDs], or both). Of note, this scoring system could further discriminate OS and PFS of R-ISS II patients, underlining its value in restratifying this large heterogeneous group of NDMM patients. With these advantages, this new simple algorithm would be expected to be applied soon in clinical practice to improve the performance of the currently using risk stratification systems such as R-ISS (especially further stratification of R-ISS II patients). However, since the R2-ISS was developed and validated in the European population of NDMM patients enrolled in multiple clinical trials, its prognostic property remains to be verified in other populations and in a real-world setting. In this context, the R2-ISS has recently been validated using real-world data in Australian and New Zealand population.13 Considering the significance of 1q+ in the R2-ISS, the Chinese population of NDMM patients may be particularly susceptible to this scoring system due to their high frequency (~50% of NDMM patients) of 1q+ and its prognostic value as reported earlier by our group.14 To this end, we carried out a retrospective analysis of the real-world data collected from daily practice to further validate the R2-ISS in a cohort of 1005 MM patients newly diagnosed between November 27, 2009 and November 20, 2019, at 6 centers nationwide in China (Table 1). This study was approved by the Institutional Review Boards of the First Hospital of Jilin University (Approval No. 2016-087). All patients had given written informed consent to the use of clinical data according to the Declaration of Helsinki. The inclusion criteria of this study were patients who had complete baseline information for R2-ISS scoring, particularly involving cytogenetics in CD138+ cells by fluorescence in-situ hybridization (FISH) that must include the probes for del(17p) (cutoff, 20%), t(4;14) (cutoff, 7.3%), and 1q+ (cutoff, 5.5%) including gain (3 copies) and amplification (≥4 copies) as described previously,14 and who must receive novel agents (PIs, IMiDs, or both) for upfront treatment. It is noteworthy that the cutoffs for some HRCAs such as t(4;14) and 1q+ was lower than those usually recommended, which might, at least in part, contribute to a relatively higher percentage of high-risk patients (eg, 1q+) in this cohort, thus representing one limitation of this study. All patients were treated in the real-world setting, of whom 511 (50.8%), 177 (17.6%), and 317 (31.5%) received PI-, IMiD-, and PI plus IMiD-based induction, and 122 (12.1%) received autologous stem cell transplantation (ASCT). According to the International Myeloma Working Group consensus criteria,15 114 (12.4%), 207 (22.6%), 244 (26.6%), 235 (25.6%), 58 (6.3%), and 59 (6.4%) of 917 evaluable patients had a stringent complete response, complete response, very good partial response, partial response, minimal response, and stable disease, respectively. PFS was defined as the time from diagnosis until disease progression, relapse, or death due to any cause. Patients who did not progress or relapse were censored on the last date when they were seen alive and event free. OS was defined as the time from diagnosis until death due to any cause or last follow-up.Table 1: Characteristics of Patients With Newly Diagnosed Multiple Myeloma in Our Cohort (n = 1005)With a median follow-up of 35.5 months (95% confidence interval [CI], 32.8-38.2), median PFS and OS were 25.2 (95% CI, 23.1-27.3) and 53.0 (95% CI, 48.1-57.9) months, respectively. A total of 1005 patients with NDMM were categorized into R-ISS I (118, 11.7%), II (624, 62.1%), and III (263, 26.2%), with the largest proportion of patients in the R-ISS II group.12 As expected, the R-ISS could clearly stratify NDMM patients on both PFS (Suppl. Figure S1A) and OS (Suppl. Figure S1B), with P < 0.001 for each comparison between R-ISS I, II, and III. According to the R2-ISS,12 all patients (n = 1005) were then scored and divided into 4 groups: R2-ISS I (75, 7.5%), II (160, 15.9%), III (582, 57.9%), and IV (188, 18.7%). Compared with those reported by the EMN,12 there were relatively fewer patients with low (R2-ISS I) and low-intermediate risk (R2-ISS II) but more patients with intermediate-high (R2-ISS III) and high risk (R2-ISS IV) in this cohort. Moreover, every group of patients in this cohort had also relatively shorter PFS and OS, consistent with the fact that majority of patients had more advanced disease, primarily due to late diagnosis, but much fewer patients received ASCT (a main limitation of this study) mostly due to unaffordability, in our cohort than those reported by the EMN (Suppl. Table S1). Of note, the differences in PFS (Figure 1A) and OS (Figure 1B) were significant for almost all comparisons between the 2 groups (P < 0.001), except R-ISS I versus II (PFS, P = 0.056; OS, P = 0.075), probably due to a relatively small number of low-risk patients (eg, ISS or R-ISS I) in our cohort. Moreover, the R2-ISS largely remained its risk-stratifying property in the subgroups of patients with different treatments, particularly in distinguishing the patients with R2-ISS III or IV from those with R2-ISS I or II. In addition, the R2-ISS might work well in patients who did not receive ASCT, for either age >65 years (Figure 1C and Suppl. Figure S2A) or age ≤65 years (Suppl. Figure S2B, C), compared with those who received ASCT (Suppl. Figure S3A, B). Similarly, the R2-ISS also separated patients with different risk levels in the ones who received either PI- or IMiD-based induction (Figure 1D and Suppl. Figure S4A) better than those who received PI plus IMiD-based induction (Suppl. Figure S4B, C). However, due to the small number of patients in some subgroups, these results should be interpreted with caution. Nonetheless, these observations support that the R2-ISS could well discriminate NDMM patients with different risk levels and predict their outcomes (both PFS and OS) at diagnosis, although treatments might influence its performance.Figure 1.: Survival of newly diagnosed multiple myeloma (NDMM) patients according to the R2-ISS. (A, B) PFS (A; median: 48.7, 37.5, 24.3, and 16.3 mo for R2-ISS I–IV, respectively) and OS (B; median: 139.0, 82.2, 51.8, 29.5 mo for R2-ISS I–IV, respectively) of all patients (n = 1005). (C) OS of patients with age >65 y (n = 314; median: 125.3, not reached [NR], 43.3, and 30.5 mo for R2-ISS I–IV, respectively). (D) OS of patients who received either proteasome inhibitor (PI)- or immunomodulatory drug (IMiD)-based induction (n = 688; median: 139.0, 82.8, 49.7, and 27.1 mo for R2-ISS I-IV, respectively). (E, F) PFS (E; median: 39.6, 25.3, and 21.3 mo for R2-ISS II–IV, respectively) and OS (F; median: 82.2, 53.8, and 40.5 mo for R2-ISS II–IV, respectively) of R-ISS II patients (n = 624). OS = overall survival; PFS = progression-free survival; R2-ISS = second revision of international staging system.One of the main aims for developing the R2-ISS is to better stratify R-ISS II patients,12,13 which account for about 60% of patients with considerably heterogeneous outcomes in this cohort. We thus validated whether the R2-ISS would be able to restratify the R-ISS II patients and predict their outcomes more precisely. In R-ISS II patients (n = 624), there were 117 (18.8%), 486 (77.9%), and 21 (3.4%) patients with R2-ISS II, III, and IV (Suppl. Figure S4D). The differences in PFS (Figure 1E) and OS (Figure 1F) were statistically different between R2-ISS II versus III or IV (P < 0.01 for each comparison), consistent with those reported by the EMN.12 However, no significant difference was observed between R2-ISS III and IV (P > 0.05 for both PFS and OS), similar to the results from the training set, but not the validation set, in the study reported by the EMN.12 Moreover, a comparison of patient outcomes between R-ISS and R2-ISS suggests that the capability to further restratify R-ISS II patients might represent an advantage for the R2-ISS (Suppl. Table S2). Therefore, these observations support the notion that the R2-ISS could restratify patients with R-ISS II, particularly in the case of distinguishing R2-ISS III and IV from R2-ISS II. In summary, this study provides the evidence for the value of the R2-ISS recently updated by the EMN in the risk stratification of NDMM patients, particularly those categorized as R-ISS II by the R-ISS staging system, in an entirely independent cohort of patients with considerable differences in baseline characteristics (eg, more advanced disease and HRCAs) and treatments (ie, in the real-world setting, rather than clinical trials in the EMN study12). Thus, this new simple prognostic tool warrants further attention in future investigations and practice. AUTHOR CONTRIBUTIONS PY, FZ, YD(1), GG, HX, XL, SY, WX, YM, XQ, ML, YD(2), and FJ performed the research. FJ, PY, and YD(2) analyzed and interpreted the data. FJ and YD(2) conceived and planned the study design, and wrote the article. All authors approved the article. DATA AVAILABILITY Original data are available upon reasonable request to corresponding authors. DISCLOSURES The authors have no conflicts of interest to disclose. SOURCES OF FUNDING This work was supported by the National Natural Science Foundation of China (Grant Nos. 81471165, 81670190, 81670189, 81870160, 81971108, and 82270207) and Science and Technology Development Program of the Jilin Province (Grant Nos. 20190201042JC, 20190201163JC, and 20210509010RQ), and Interdisciplinary Integration and Innovation Project of Jilin University.

A real-world data analysis of predictors of early mortality after a diagnosis of multiple myeloma.

Despite the increased availability and use of novel therapies for multiple myeloma, early mortality is a pervasive challenge with a significant impact on older adults. Reported rates and predictors of early mortality have varied in the literature, with most studies seldom focusing on community-treated patients. In this retrospective cohort analysis of a real-world electronic health record-derived deidentified database of 7512 patients newly diagnosed with multiple myeloma between January 1, 2011, and February 2, 2021, and treated primarily in US-based community oncology practices, factors associated with early mortality (defined as death within 6 months after the multiple myeloma diagnosis) were examined with the use of binary logistic regression. The median age was 70years overall. We found an overall early mortality rate of 8.3%, with 73% of early deaths occurring in those aged ≥70years. Among the early deaths, only 49 patients (8.7%) had documented disease progression before death (median time to progression, 30days [interquartile range, 7-53 days]). Baseline factors associated with higher odds of early mortality included an Eastern Cooperative Oncology Group performance status (ECOG PS)≥2, Revised International Staging System (R-ISS) stage III, an age ≥ 70 years, receipt of proteasome inhibitor-doublet therapy, a light-chain isotype, and the presence of renal dysfunction (estimated glomerular filtration rate < 30mL/min). Among those aged ≥70years, ECOG PS≥2 and R-ISS stage III remained the strongest predictors of early mortality. Early mortality disproportionately affects older adults (aged ≥70years) with multiple myeloma. Interventions to support this population are needed to reduce disparate survival outcomes. Factors associated with an increased risk of dying within 6 months (early mortality) of a new diagnosis of multiple myeloma (MM) among 7512 mostly community-treated patients with MM were evaluated. The early mortality rate was 8.3%; among those deaths, 49 patients (8.7%) had documented evidence of MM progression before death. The risk of early mortality was greatest for older patients (aged ≥70years) and those with a poor performance status, poor kidney function, a higher disease stage, and light-chain MM and those receiving two-drug MM therapies. These findings highlight the need for supportive interventions geared toward older adults with MM.

The prognostic utility of dynamic risk stratification at disease progression in patients with multiple myeloma

ABSTRACTObjectives:There may be a shift in risk stratification at progression compared to that at diagnosis in patients with multiple myeloma (MM). We aimed to evaluate whether re-staging and stage migration is of prognostic impact.Methods:Real-world data from the National Longitudinal Cohort of Hematologic Diseases-multiple myeloma were collected; 263 consecutive patients demonstrating disease progression were finally included. Staging at diagnosis and re-staging at progression were performed using the International Staging System (ISS) and Revised International Staging System (RISS).Results:Based on ISS re-staging, the median post-progression survival (mPPS) of patients with stage I, II, and III was 44.2, 21.7, and 11.6 months, respectively (P < 0.0001). Based on RISS re-staging, the mPPS of patients with stage I, II, and III was 50.3, 22.2, and 11.4 months, respectively (P < 0.0001). The mPPS in patients with improved, maintained, and deteriorated ISS stage migration from diagnosis was 33.6, 20.9, and 16 months, respectively (P = 0.0051) and that with improved, maintained, and deteriorated RISS stage migration was 48.4, 23.1, and 13.9 months, respectively (P < 0.001). Compared to patients with maintained or improved disease stage, those with deteriorated ISS/RISS migration showed significantly higher incidence of Del(17P) at progression and worse PPS. Multivariate analyses indicated both re-staging and stage migration by ISS/RISS at progression were independent predictors for PPS.Conclusions:We demonstrated that ISS/RISS re-staging showed superior prognostic utility over ISS/RISS staging in predicting PPS. Patients with deteriorated stage migration or maintained advanced stage at progression may need more individualized treatment.

The Cancer-Related Circrna Cirs-7 (CDR1-AS) Is Differentially Expressed in CD138+ Cells of Patients with Plasma Cell Disorders and Predicts Unfavorable Overall Survival in Multiple Myeloma

Introduction: During the last decades, different non-coding RNAs have been implicated in the biology and prognosis of multiple myeloma (MM). Circular RNAs (circRNAs) constitute a class of non-coding RNAs with a high potential as molecular biomarkers. Recently, ciRS-7 (also known as CDR1-AS), an important circRNA regulating miR-7-5p and other cancer-related miRNAs, was shown to be downregulated in MM patients’ cells exhibiting acquired resistance to immunomodulatory drugs (IMiDs). Our goal was to study the expression of this circRNA in MM, compare the results with those of patients with smoldering myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) and evaluate its prognostic significance. Methods: Bone marrow aspirate (BMA) samples were collected from 177 adult patients with plasma cell disorders. The presence of high-risk cytogenetic abnormalities, namely del(17p), t(4;14), t(14;16), and (+1q), was assessed using fluorescence in situ hybridization (FISH). MM patients were classified according to the ISS and revised ISS (R-ISS) staging systems. Whole-body low-dose computed tomography was used to assess osteolysis. Next, CD138-positive selection of plasma cells among mononuclear cells of BMA samples was performed. Moreover, three human MM cell lines (L-363, H929 and U266) were propagated. Total RNA was extracted from CD138+ enriched BMA samples and the MM cell lines, and reverse-transcribed. A first-round PCR was used to pre-amplify ciRS-7 and GAPDH (i.e. reference gene) transcripts, before their quantification via real-time qPCR. In both reactions for ciRS-7 amplification, divergent PCR primers were used, to achieve high specificity and accuracy. ciRS-7 expression was measured in relative quantification units (RQU). Results: The cohort of patients consisted of 111 newly diagnosed MM, 35 SMM and 31 with MGUS. In total, 107 out of the 177 cases (60.5%) were male and 70 (39.5%) were female. The median age of all patients at diagnosis was 70 years (range: 35-93 years). According to the R-ISS staging system, 24 (21.6%) MM patients had R-ISS stage I, 62 (55.9%) R-ISS stage II and 25 (22.5%) had R-ISS stage III. Seventy-seven (69.4%) MM patients presented with osteolytic disease at diagnosis. Regarding front-line therapy of MM patients, 12/111 (10.8%) received proteasome inhibitor (PI)-based therapy, 7 (6.3%) received IMiD-based treatment, 74 (66.7%) were treated with combinations of PI and IMiD, and 18 (16.2%) received anti-CD38-based treatment. The intracellular levels of the ciRS-7 circRNA were different between MM, SMM and MGUS patients’ CD138+ plasma cells (median values were: for MM patients 0.40 RQU vs. 1.74 RQU for SMM patients vs. 2.79 RQU for MGUS patients; P<0.001). Moreover, ciRS-7 levels in U266 and H929 cells were much lower (2,165- and 26,616-fold) than in L-363 cells. ROC analysis showed that ciRS-7 expression can effectively discriminate between MM and SMM patients (AUC=0.65, 95% CI=0.56-0.75, P=0.007). ciRS-7 levels did not significantly differ among MM patients with different ISS or R-ISS stages and were not associated with any assessed cytogenetic abnormality or the presence of osteolytic lesions. Regarding the progression-free (PFS) and overall survival (OS), out of 106 MM patients with survival data, patients with high levels of ciRS-7 have lower survival probabilities. As shown in Figure 1, the median PFS of MM patients with high ciRS-7 (high: defined as higher of the median value) was 19 months vs. 25 months for patients with low ciRS-7 (lower values than the median) (P=0.046); similarly, the mean OS of ciRS-7 (high) MM patients was 25 months vs. 30.5 months for ciRS-7 (low) MM patients (P=0.008). Bootstrap multivariate Cox regression analysis showed that the unfavorable prognostic value of ciRS-7 expression with regard to OS is independent of R-ISS stage and age of MM patients (HR=2.6, BCa 95% CI=0.91-4.75, bootstrap P=0.041). Conclusions: Expression levels of ciRS-7, a cancer-related circRNA, in CD138+ plasma cells are significantly different among patients with MM, SMM and MGUS. Most likely, high ciRS-7 levels predict an unfavorable prognosis in MM, independently of the R-ISS stage and age. Combining our results with the limited existing literature providing evidence for ciRS-7 implication in response to IMiD therapy, its biological role in MM deserves further elucidation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

IV Antibiotic Use during Autologous Hematopoietic Stem Cell Transplantation Is Associated with Inferior Survival in Patients with Multiple Myeloma

Autologous Hematopoietic stem cell transplantation (HSCT) following high-dose chemotherapy is an integral part of multiple myeloma (MM) treatment. While many factors impact HSCT success, low gut microbiome diversity has been shown to correlate with worse outcomes post-transplant (Khan et al, Blood 2021). HSCT patients receive intravenous (IV) antibiotics in response to neutropenic fever or bacterial infections, which can drive a lower microbiome diversity post-transplant (El Jurdi et al, BBMT 2018). Given the link between antibiotic exposure, low microbial diversity, and outcomes, we hypothesized that antibiotic exposure during transplant may adversely affect survival. To test this hypothesis, we performed a single-center retrospective study of transplant outcomes and IV antibiotic exposure at the University of Wisconsin from 2010-2017. Two hundred eighty-six patients underwent a first autologous HSCT using melphalan conditioning. All subjects received levofloxacin prophylaxis. Two hundred thirty-seven subjects received IV antibiotics including cefepime or piperacillin/tazobactam and vancomycin predominantly to treat neutropenic fever. Forty-nine patients did not require IV antibiotics. Patient demographics and disease factors were fairly balanced between the IV antibiotic and no antibiotic group, including age, sex, body mass index (BMI), presence of high-risk cytogenetics, number of prior lines of therapy, and use of maintenance therapy post-transplant. There was a higher proportion of Revised International Staging System (R-ISS) stage 1 myeloma in the no antibiotic cohort (12/39, 31%) versus the antibiotic cohort (37/179, 21%) but this was not statistically significant (p = 0.28). We observed an adverse effect of antibiotic exposure on overall survival (OS) (Figure 1, hazard ratio (HR) 0.41 IV antibiotic vs no antibiotic, 95% confidence interval (CI) 0.19 - 0.77), but not progression-free survival (PFS) (HR 0.95, 95% CI 0.62 - 1.4). Greater number of prior lines of therapy, higher R-ISS stage, and the absence of maintenance therapy each observed an adverse effect on OS when adjusting for IV antibiotic exposure (Table 1). On univariate analysis, high risk cytogenetics such as t(4;14), del17p, and t(14;16) was associated with inferior OS (HR no vs yes 0.625, 95% CI 0.40-0.99, p=0.041) but lost statistical significance when modelled together with IV antibiotic exposure HR no vs. yes 0.64, 95% CI 0.41-1.02), presumably due to sample size. After adjusting for age, presence of high-risk cytogenetics, number of prior lines, and use of maintenance therapy, the adverse effect of antibiotics maintained its statistically significant impact (Table 1). When adjusting for R-ISS stage, a similar adverse effect was noted but this was no longer statistically significant, possibly due to low numbers of reported R-ISS stage 3 in the no-antibiotic cohort (n=6). We conclude that IV antibiotic exposure confers an adverse effect on overall survival post-transplant. Inspection of the survival curve from the proportional hazards model (Figure 1) suggests this is unrelated to immediate post-transplant infectious complications. This finding supports a growing body of literature describing adverse long-term clinical impact of antibiotic exposure and on outcomes in cellular therapy, which we hypothesize is related to deleterious effects of antibiotic exposure on the gut microbiome. Larger prospective studies are necessary to further examine this relationship on myeloma outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Co-Occurrence of 1q21+/1q23+ and t(4;14) Abnormalities with Specific Clone Size Is Predictive of Shorter Response to Transplant in Patients with Multiple Myeloma

Introduction: The presence or absence of recurrent chromosomal abnormalities (CA) as detected by karyotype and/or fluorescence in-situ hybridization (FISH) has emerged as one of the most clinically relevant prognostic factors for patients with newly diagnosed multiple myeloma (MM). The Revised-International Staging System (R-ISS) defined high-risk disease as the presence of at least one of the following: deletion(17p), translocation t(4;14)(p16;q32), or translocation t(14;16)(q32;q23). Amplification or gain of chromosome 1q (1q21+/1q23+) has also been growing in its clinical relevance, with 1q21+ found in approximately 35-40% of patients. As a result, this study evaluated differences in survival outcomes and disease characteristics in patients with both 1q+ (1q21+ or 1q23+) and t(4;14), compared to those patients with only 1q+ or t(4;14). Methods: A retrospective chart review was performed on 243 newly diagnosed MM patients with the cytogenetic abnormalities of interest obtained from established FISH data from bone marrow aspirate samples at diagnosis. Primary endpoints were Progression-Free Survival (PFS) and Overall Survival (OS) after autologous stem cell transplant (ASCT), and Kaplan Meier methods were used to calculate PFS and OS. Secondary endpoints included the identification of disease characteristics between single CA and combined abnormalities. To specifically analyze the quantitative CA cutoff values and the correlation of clone size to survival outcomes, we established subgroupings with positivity defined as 1q21+ or 1q23+ present in more than 20% of cells and t(4;14) present in more than 30% of cells. Patients who satisfied both cutoff criteria were labeled as 'double-hit', and patients with CA present, but clone sizes less than the prespecified cutoffs for both CA, were denoted as 'CA(low)'. All tests were two-sided with p-values <0.05 considered statistically significant. Results: The median age at diagnosis was 61.5 years, 54% were male, and 84% of patients identified as non-Hispanic White. Of the total cohort and independent of quantitative CA cutoff, 1q+ (1q21+ or 1q23+) only was the most prevalent CA in 198 (81%) of patients, t(4;14) only in 13 (5%) patients, and both 1q+ (1q21+ or 1q23+) and t(4;14) in 32 (13%) patients. One hundred seventy (70%) patients underwent ASCT, followed by maintenance therapy in 85% of them. Pre-transplant best hematologic responses did not differ amongst CA groups. There was no difference in baseline hemoglobin, serum creatinine, calcium, albumin, lactate dehydrogenase, or beta-2 microglobulin amongst the CA groups. No differences in outcomes were noted without including size clone cutoffs. There was a statistically significant difference in univariable analysis in PFS and OS from ASCT in patients with 1q21+ and t(4;14) 'CA(low)’ (n=76, 31%) having better survival outcomes compared to the corresponding 'double-hit’ group (n=25, 10%) (PFS: HR=0.52, 95% CI: 0.30-0.92, p=0.025; OS: HR=0.41, 95% CI: 0.21-0.81, p=0.010). This pattern in PFS and OS after ASCT was also seen in patients with 1q23+ and t(4;14) 'CA(low)’ (n=119, 49%) faring better compared to its 'double-hit’ group (n=19, 8%) (PFS: HR=0.47, 95% CI:0.26-0.83, p=0.009; OS: HR=0.34, 95% CI:0.18-0.66, p=0.001). Patients with t(4;14) only (>30%) (n=19, 8%) within the 1q23+ cohort also demonstrated longer PFS and OS after ASCT as compared to its 'double-hit’ group (PFS: HR=0.42, 95% CI:0.20-0.91, p=0.027; OS: HR=0.38, 95% CI:0.15-0.94, p=0.037). After adjusting for age and R-ISS staging, the difference between 1q23+ and t(4;14) 'CA(low)’ vs 'double-hit’ and t(4;14) only within the 1q23+ cohort vs 'double-hit’ remained significant in multivariable analysis in PFS after ASCT ('CA(low)’ group: HR=0.50, 95% CI:0.25-0.99, p=0.048; and t(4;14) only group: HR=0.41, 95% CI:0.18-0.98, p=0.045). Conclusion: Our findings reveal the differences seen in MM patients with single CA compared to the combined high-risk aberrations with both 1q21+/1q23+ and t(4;14). The effects of quantitative clone sizes on survival outcomes were displayed as patients with smaller clone sizes (i.e. 'CA(low)’ subsets) had superior survival outcomes than those patients with 'double-hit’ 1q21+ (or 1q23+) >20% and t(4;14) >30%. It is thus imperative for clinicians to be mindful of not only the presence of high-risk CA but also the size of the aberrant clone influencing subsequent MM disease characteristics.

Treatment of Primary Plasma Cell Leukemia with Carfilzomib and Lenalidomide-Based Therapy: Results of the Final Analysis of the Prospective Phase 2 EMN12/HOVON-129 Study for Patients Aged 18-65 Years

Introduction. Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell disorder with a very poor prognosis. The median PFS for transplant-eligible patients (pts) is approximately 9 months. The aim of the EMN12/ HOVON-129 study was to improve the outcome of pPCL by incorporating carfilzomib and lenalidomide in induction, consolidation, and maintenance. The trial enrolled 61 pts aged 18 years and older, with different treatment for those aged 18-65 (n=36) and ≥66 years (n=25). Here we report the results of the final analysis for pts aged 18-65 years. Methods. The EMN12/HOVON-129 study is a prospective, non-randomized, phase 2, multicenter study, for previously untreated pPCL pts. Inclusion criteria were newly diagnosed pPCL (defined as >2x109/L circulating monoclonal plasma cells or plasmacytosis >20% of the differential white cell count) and WHO performance status 0-3. Main exclusion criteria were severe cardiac or pulmonary dysfunction; and creatinine clearance of <15 ml/min. There were no restrictions based on blood counts. Pts aged 18-65 years were treated with induction therapy with four 28-day cycles of carfilzomib-lenalidomide-dexamethasone (KRd; carfilzomib 20/36 mg/m2 on days 1,2,8,9,15,16; lenalidomide 25 mg days 1-21; dexamethasone 20 mg on days 1,2,8,9,15,16,22,23). KRd induction was followed by tandem autologous stem cell transplantation (ASCT), 4 cycles of KRd consolidation, and then maintenance with carfilzomib (27 mg/m2 on days 1,2,15,16) and lenalidomide (10 mg on days 1-21/28 days) until progression. Pts who were eligible for allo-SCT, could also receive one ASCT, followed by 2 KRd consolidation cycles, reduced-intensity conditioning allo-SCT, and carfilzomib/lenalidomide maintenance. The primary endpoint was PFS, and secondary endpoints were response rate, OS, and toxicity. Results. From October 2015 till August 2021, we enrolled 36 pts with pPCL aged ≤65 years. Median age was 60 years; 67% had bone disease; and WHO performance status was ≥2 in 33% of pts. Pts had a high tumor burden with a median plasma cell percentage in BM of 80%. The median peripheral blood plasma cell count was 4.1x109/L (range 1.6-60.0); median platelet count was 111x109/L (range 20-517); and median eGFR was 54.0 ml/min (range 15.0-123). Pts had high-risk disease as evidenced by elevated LDH in 58%; and high frequency of high-risk genetic lesions (del(17p) in 47%, t(4;14) in 9%, t(14;16) in 19%, gain/ampl(1q) in 61%). Two or more high-risk cytogenetic abnormalities were present in 38%. The frequency of t(11;14) was 26%. In addition, 17% of pts had extramedullary plasmacytomas. ISS stage 3 was present in 64%, and revised ISS stage 3 in 50%. Response to induction was ≥PR in 72%, ≥VGPR in 64%, and ≥CR in 14%. Twenty-four pts (67%) received high-dose melphalan (HDM)/ASCT; 12 pts (33%) underwent a second course of HDM/ASCT; and 5 (14%) received allo-SCT after first HDM/ASCT. Eighteen pts (50%) received maintenance treatment. Best response on protocol was ≥PR in 83%, ≥VGPR in 81% and ≥CR in 50%; 10 (28%) pts achieved MRD-negative (10-5) CR. With a median follow-up of 40.8 months (range 8-2-74.5), the median PFS was 15.5 months (95% CI 9.4-38.4), which was sufficient to reject our null hypothesis (median PFS=9 months). With 19 pts having died (14 due to disease progression, 4 due to infections, and 1 due to cardiac disorder), median OS was 28.4 months (95% CI 15.1-not reached). In exploratory analyses, the presence of elevated LDH, t(14;16), and del(17p) were associated with both inferior PFS and OS. For patients who underwent first HDM/ASCT, median PFS and OS were 32.9 and 34.1 months from date of ASCT, resp. Adverse events mainly occurred during the first cycle of KRd, and decreased thereafter. Overall, grade ≥3 adverse events were observed in 67% of pts, including infections (25%) and cardiovascular disorders (14%). One patient developed a second primary malignancy (MDS). As of July 24 2022, 25 pts (69%) pts discontinued protocol treatment, mainly because of progression, but none because of treatment-related toxicity. Conclusions. KRd induction provides efficient and rapid disease control, which allows two-thirds of pts to undergo a first course of HDM/ASCT. Toxicity occurred mainly during the first cycle of induction, and was manageable with appropriate interventions. However, median PFS and OS remain low in pPCL, compared to MM. This trial was registered at https://trialsearch.who.int as NTR5350 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal