Diagnosed Myeloma Patients Research Articles

Kidney function in newly diagnosed myeloma patients: factors associated with kidney impairment and recovery

Kidney disease is a common complication of multiple myeloma (MM) and a risk factor for increased morbimortality. In this retrospective cohort study based on medical records, we analyzed the kidney function of patients with renal disease related to MM during the first year of treatment. All patients included were consecutively admitted to the outpatient services of two hospitals between January 2009 and January 2019 and met the diagnostic criteria for MM regardless of the reason for seeking medical help. We excluded patients who had kidney disease or who were on dialysis before MM diagnosis. We investigated the factors associated with renal function recovery using multivariate analysis. We evaluated 167 patients (median age of 66 ± 11.49 years). Almost half of the patients had arterial hypertension (76; 45.5%). The majority had International Staging System (ISS) grades 3 (73; 43.7%) or 2 (60; 35.9%). Seventy-four (44%) patients had an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m² at the time of MM diagnosis. Fifty-two patients (31%) underwent hematopoietic stem cell transplantation (HSCT). After 12 months, 4 (2.3%) patients needed dialysis, and 18 (10.7%) died. The factors associated with an eGFR < 60 ml/min/1.73 m² were anemia, hyperuricemia, 24-hour proteinuria > 1.0 g, and extramedullary plasmacytoma. However, only baseline renal function (eGFR > 60 ml/min/1.73 m2) and HSCT were associated with greater recovery of renal function at 12 months of follow-up.

Joint AI-driven event prediction and longitudinal modeling in newly diagnosed and relapsed multiple myeloma

Multiple myeloma management requires a balance between maximizing survival, minimizing adverse events to therapy, and monitoring disease progression. While previous work has proposed data-driven models for individual tasks, these approaches fail to provide a holistic view of a patient’s disease state, limiting their utility to assist physician decision-making. To address this limitation, we developed a transformer-based machine learning model that jointly (1) predicts progression-free survival (PFS), overall survival (OS), and adverse events (AE), (2) forecasts key disease biomarkers, and (3) assesses the effect of different treatment strategies, e.g., ixazomib, lenalidomide, dexamethasone (IRd) vs lenalidomide, dexamethasone (Rd). Using TOURMALINE trial data, we trained and internally validated our model on newly diagnosed myeloma patients (N = 703) and externally validated it on relapsed and refractory myeloma patients (N = 720). Our model achieved superior performance to a risk model based on the multiple myeloma international staging system (ISS) (p < 0.001, Bonferroni corrected) and comparable performance to survival models trained separately on each task, but unable to forecast biomarkers. Our approach outperformed state-of-the-art deep learning models, tailored towards forecasting, on predicting key disease biomarkers (p < 0.001, Bonferroni corrected). Finally, leveraging our model’s capacity to estimate individual-level treatment effects, we found that patients with IgA kappa myeloma appear to benefit the most from IRd. Our study suggests that a holistic assessment of a patient’s myeloma course is possible, potentially serving as the foundation for a personalized decision support system.

The Ratio of Urea Nitrogen to Albumin Is a Better Predictor of OS in MM Patients Than That of Urea Nitrogen Alone

Background Multiple myeloma (MM) is a malignant proliferative disease of plasma cells. Abnormally cloned plasma cells secrete large amounts of monoclonal immunoglobulins in the bone marrow of MM patients. Serum urea nitrogen (sUN) is a byproduct of protein metabolism, and its effect on MM patients' prognoses remains unknown. Therefore, we analysed MM patients' clinical data to explore the role of sUN and serum urea nitrogen/serum albumin (sUAR) in the baseline tumor load and MM prognosis of MM patients. Methods We downloaded the clinical data of 762 MM patients from the MMRF database. After excluding those without baseline sUN, 452 patients were finally included in the study. Smoothed curve fitting, threshold analysis, Tamhane's T2 test, multivariate adjusted Cox regression analysis, Kaplan‒Meier (K-M) curves, and receiver operating characteristic (ROC) analysis were applied in the study. Results There were 452 newly diagnosed MM patients included in this study. In most patient groups, sUN and sUAR were positively linked with β2-microglobulin (β2-MG) and lactic dehydrogenase (LDH) according to smoothing curve fitting and threshold analysis. The higher the ISS stage, the greater the values of sUN and sUAR. Furthermore, smoothed curve fitting and threshold analysis showed that sUN was correlated with OS, although sUAR had a stronger correlation with OS and could be applied to a broader group. The results of a multivariate adjusted Cox regression analysis demonstrated that sUN and sUAR were independent prognostic factors for OS. The K-M curve confirmed the correlation between higher sUN and sUAR levels and worse OS. β2-MG and LDH are generally recognized prognostic factors of OS. ROC analysis revealed that sUN might boost β2-MG and LDH's predictive value and sUAR had a higher predictive value. Conclusion This retrospective study based on the MMRF database showed that high sUN and sUAR levels were positively associated with β2-MG, LDH, and ISS staging, and sUAR exhibited a stronger correlation with OS than sUN alone. Key words Serum urea nitrogen, ratio of serum urea nitrogen to serum albumin, multiple myeloma, overall survival, β2-microglobulin, lactic dehydrogenase

Senescent Immune Signature in Frail and Vulnerable Newly Diagnosed Myeloma Patients: A Cohort Analysis from the UK-MRA Myeloma XIV Fitness Study

Introduction Physical frailty is a key factor driving treatment tolerability and outcome in multiple myeloma (MM). There is a close interplay between physiological aging, frailty and immune dysfunction, with the presence of a malignant disease overlay adding an additional dimension to the host response biology. The UKMRA Myeloma XIV FiTNEss study is the first phase 3 randomised clinical trial to explore the utilisation of frailty assessment as a tool to guide and optimise treatment decision making and deliverability. Here we report on the relationship between physical frailty and T cell dysfunction in a cohort of patients within this landmark study. Methods Multiparameter flow cytometry was used to assess the baseline T cell phenotype in the peripheral blood of 49 participants with NDMM receiving treatment within FiTNEss. Patients were assessed for frailty using the IMWG frailty score and additionally assessed for clinical vulnerability using the UKMRA MRP score (Cook et al, Lancet Haematol. 2019). The IMWG frailty score combines activities of daily living assessment and co-morbidity burden with age to generate a validated, prognostic frailty score. The UKMRA MRP is a risk profile which uses routinely collected clinical data including age, WHO performance status, ISS stage and CRP to define prognostic risk categories with the high-risk category encompassing frailer individuals. Normal T cell subsets were assessed based on CD45RA and CD28 phenotype while dysfunctional subsets (exhausted and senescent) were defined using CD28 and KLRG1. Results The median age of participants was 79 (range 68-90) and 55% were male. The distribution by IMWG was fit 18%, unfit 33%, frail 49% and by MRP was low risk 31%, intermediate risk 28%, high risk 38%. Absolute lymphocyte count (ALC) decreased with increasing frailty (p=0.02), with no patients classified as fit by IMWG or low risk by MRP criteria having a lymphocyte count below the lower limit of normal. No relationship was seen between ALC and age. The ratio remained stable across the IMWG cohorts, suggesting a global reduction in lymphocyte subsets. An accumulation of CD8 TEMRA cells was seen in the MRP high risk cohort (p=0.0085). No differences were seen between cohorts based on the IMWG frailty score. The accumulation of CD8 TEMRA cells indicates a loss of T cell differentiation plasticity and is associated with a cytotoxic and pro-inflammatory immune response. CD4 dysfunctional subsets were comparable across the cohorts. CD8 dysfunctional subsets were most marked in the frail and high-risk cohorts. The MRP high-risk cohort had a skewed ratio of exhausted to senescent cells (p=0.02), with a reduction in CD8 exhausted populations compared to the fit and unfit cohorts (p=0.0477) and a trend towards increased senescent cell burden (p=0.07). This was echoed within the IMWG frail cohort where elevated numbers of senescent CD8 cells were identified (p=0.02). No relationship was seen between CD8 senescent burden and age, CRP, ISS or WHO PS when each variable was assessed independently, suggesting that the presence of this immune population is not directly related to disease burden or physiological aging alone, but reflects a more complex interplay between host response biology and disease characteristics. Principal component analysis demonstrated a high degree of immunological heterogeneity within the MRP low and intermediate risks cohorts, while the high-risk cohort had a more uniform immunological profile (Figure 1A). Significant overlap between a proportion of the non-high-risk cohorts and high-risk cohorts was seen and requires further exploration. A multi-variable correlation analysis identified correlations between the CD4:8 ratio and CD8 cell senescent burden, MRP and ISS, highlighting the important interplay between immunological dysfunction, clinical vulnerability and disease burden (Figure 1B). Conclusion The T cell immunological landscape of the most vulnerable patient populations with newly diagnosed MM is characterised by an accumulation of senescent CD8 T cells which cannot be attributed to age or disease burden alone. Immune senescence is known to be associated with a chronic inflammatory state which may drive the acquisition of the physiological changes, such as sarcopenia, which characterise a frailty phenotype. This provides an opportunity for targeted intervention to address the biological drivers of disease related frailty.

Impact of Bone Modifying Agent Initiation Time, Frequency, and Duration on Skeletal-Related Events in Patients with Multiple Myeloma

Background: Skeletal related events (SREs) including pathologic fractures, surgery or radiation to bone, and spinal cord compression contribute to diminished quality of life in patients with multiple myeloma. Bone modifying agents (BMA) such as denosumab or the bisphosphonates zoledronic acid and pamidronate, are used to inhibit osteoclast activity to prevent SREs. The Bone Working Group of the International Myeloma Working Group suggests monthly administration of zoledronic acid for 12 months in newly diagnosed myeloma patients. This is followed by an option to discontinue or decrease administration frequency to every 3, 6, or 12 months if a very good partial response or better is achieved. The ideal start time of BMA from diagnosis and the duration of administration has not been adequately established to optimize reduction of SREs. Methods: This was a retrospective, single-center study that included newly diagnosed myeloma patients treated at the Mayo Clinic between 9/1/2018 and 9/1/2020 who had received at least one dose of a BMA. The primary objective was to evaluate the impact of BMA dosing frequency and duration on SREs. Secondary objectives included time to BMA initiation, time to relapse or progressions following BMA start, and safety. Data was summarized using frequencies and percentages for categorical data, and medians and interquartile ranges (IQR) for continuous data. A spline plot and cut-point analysis were used to assess the association of time from multiple myeloma diagnosis to BMA initiation with skeletal related outcomes. Rates of SREs were estimated using the Aalen-Johansen method, where death was treated as a competing risk. Associations of factors with SREs were assessed using Cox proportional hazards regressions, and these associations were summarized using hazard ratios (HR) and corresponding 95% confidence intervals (CI). Variables that could change throughout follow-up including BMA frequency, cumulative BMA dose, and duration of BMA were treated as time-dependent covariates in the Cox proportional hazards models, where the information for these variables was updated each time an additional dose of BMA was given. All analyses were performed using SAS version 9.4 software (SAS Institute, Inc.; Cary, NC) and R version 4.2.2 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria). Results: Sixty-seven patients were included with a median age of 65 years old. The most frequently used BMA was zoledronic acid (88.1%), followed by pamidronate (7.5%), and denosumab (4.5%). Fifty-five patients (82.1%) had bone disease at baseline. Within 2 years of starting BMA, SREs occurred in 42.2% of patients with baseline bone disease and 8.3% of patients without (p=0.054). Median time to BMA initiation after diagnosis was 45 days (IQR 14-105) in patients with baseline bone disease and 87 (IQR 32-496) in patients without. Among the 26 patients with a SRE, median time from start of BMA to SRE was 170 days (IQR 32-496). No significant association was found between time to initiation and development of a SRE (Figure 1). BMA dosing frequencies of every 3 months and 6 months had a HR for SREs of 1.67 and 0.47, respectively compared to every 1 month, (P-values &amp;gt;0.25). After excluding patients without baseline bone disease, compared to every 1 month dosing, dosing every 3 months and every 6 months increased the risk of SRE, although the differences were not statistically significant (3 months: HR=1.92, 95% CI 0.76-4.88, p=0.17; and 6 months: HR=1.26, 95% CI 0.14-10.94, p=0.84). Patients without bone disease at baseline remained on BMAs for a median of 1.8 years while patients with bone disease received BMAs for a median of 2 years. There was no statistically significant difference found with varying duration or cumulative dose and SRE development (Table 1). Relapse or progression occurred in 32.1% of patients within 2 years of starting BMA, while death occurred in 7.5% of patients. Osteonecrosis of the jaw occurred in 1 patient with bone disease at baseline who received zoledronic acid every 3 months for a duration of 596 days. Conclusions: No significant association between time of BMA initiation, dosing frequency, or duration on development of SREs were observed. This suggests delaying the start time of BMAs to allow for dental clearance and initial treatment would not increase risk of SREs. Prospective trials are needed to confirm these findings.

The Oligosaccharyltransferase Complex: A Novel Vulnerability in Multiple Myeloma

Abstract Multiple myeloma (MM) is described as a clonal expansion of malignant plasma cells in the bone marrow characterized by several clinical symptoms: bone lesions, hypercalcemia, anemia, serum monoclonal gammopathy, immune suppression, and multiple organ failure. Despite the success of advanced treatments, disease relapse is common and incurable. Thus, there is an unmet clinical need to identify novel targets for relapsed/refractory MM treatment. The oligosaccharyltransferase (OST) complex catalyzes the transfer of N-glycan to a nascent translated protein which is a critical step in N-glycosylation, the most abundant post-translational modification of secretory and membrane-bound proteins. Aberrant expression of the OST complex or N-glycosylation is a diagnostic marker for solid tumors. However, the roles of the OST complex and N-glycosylation in MM development are virtually unknown. The mammal OST complex has two isoforms: OST-A and OST-B, with distinct catalytic subunits. Both isoforms share six subunits: OST4, RPN1, RPN2, DDOST, DAD1, and TMEM258. Analyzing the publicly available genomic data, we found that the shared subunits of the OST complex are abundantly expressed in MM cell lines and MM patient-derived cells. The expression levels of the OST subunits in relapsed MM patients are significantly higher than those in newly diagnosed MM patients. Intriguingly, patients expressing elevated levels of the OST complex are highly correlated with poor prognosis. These findings lead us to hypothesize that the OST complex might play a crucial role in MM. To address this hypothesis, we used the CRISPR/Cas9 system to knockout the OST's shared subunits and found that MM cells are dependent on the OST complex. Deletion of DDOST and DAD1 (two central structural subunits of the OST complex) impaired MM cell growth, arrested the cell cycle, and induced apoptosis. Using the subcutaneous xenograft model, we found that knockout of DDOST or DAD1 suppressed MM growth in vivo and extended the survival of tumor-bearing mice. Intriguingly, suppression of the OST complex's enzymatic activity by a specific inhibitor, NGI-1, recapitulated the phenotypes of the OST complex deletion. Of note, NGI-1 sensitizes the MM cells and bortezomib-resistant MM cells (both MM cell lines and primary patient cells) to bortezomib treatment. Mechanistically, we found that disruption of the OST complex in MM cells significantly suppressed transcriptomic signatures of MM pathology (NF-κB signaling, glycolysis, MYC targets, and cell cycle) and induced apoptosis pathway as well as inflammatory pathway (interferon alpha and gamma). Intriguingly, we found that all known genes responsible for the bortezomib-resistant phenotype were significantly downregulated upon the suppression of the OST complex. In conclusion, we identified the OST complex as a novel vulnerability in MM cells. Targeting the OST complex incorporation with Bortezomib might provide a novel and effective combined treatment for relapsed/refractory MM patients. We're currently investigating the underlying mechanisms of how the OST complex regulates MM pathology and developing patient-derived xenograft models to validate the therapeutic efficacy of combined treatment (NGI-1 and Bortezomib).

Lysosomal Associated Membrane Protein Family Member 5 (LAMP5) As a Novel Mediator of, and Target in High Risk Multiple Myeloma (MM)

Background: Our recently published studies of single cell clonotypic and transcriptional evolution of multiple myeloma precursor disease (Dang et al. Cancer Cell, 2023), as well as related multi-omic studies of more advanced disease, identified a number of genes as potential contributors to progression. Among these is LAMP5, a gene on chromosome 20 that is markedly and specifically overexpressed in the malignant, monoclonal plasma cells in a high proportion of patients. As LAMP5 expression has also been associated with osteolytic bony disease in myeloma, we sought to delineate its potential contributions to the pathobiology of myeloma, which remain incompletely understood. Methods: The impact of LAMP5 knockdown and over-expression was studied using myeloma cell line models both in vitro and in vivo. Moreover, we generated a monoclonal antibody to LAMP5 after finding it was exposed on the myeloma cell plasma membrane, and converted this agent into an antibody drug conjugate (ADC) linked to monomethyl auristatin E (MMAE) or pyrrolobenzodiazepine ( PBD) dimers. Finally, we used the sequence of the single-chain variable fragment to generate LAMP5-targeted chimeric antigen receptor (CAR)-guided T-cells. Results: Analysis of the Multiple Myeloma Research Foundation's CoMMpass SM database indicated that high LAMP5 expression (defined as in the top quartile) in newly diagnosed myeloma patients was significantly associated with markers of increased disease burden, including a higher beta-2-microglobulin (p = 0.047), C-reactive protein (p = 0.0399), serum calcium (p &amp;lt; 0.0001), marrow plasmacytosis (p &amp;lt; 0.001), and a trend towards increased circulating plasma cells (p = 0.075). Moreover, high LAMP5 expression correlated with a shorter progression-free (p = 0.0006) as well as overall survival (p = 0.0006). Similarly, analysis of the University of Arkansas for Medical Sciences gene expression data indicated LAMP5 was increased in the hyperdiploid and proliferative groups that are associated with a poor prognosis. Inducible shRNA-mediated LAMP5 knockdown in myeloma cell lines conferred a survival disadvantage and activated apoptosis. RNA-sequencing analysis identified multiple dysregulated Hallmark pathways, including the G2M checkpoint, the mitotic spindle, apoptosis, mTORC1 signaling, and the unfolded protein response. Proteomic consequences of LAMP5 knockdown included Caspase-7, -8, and -3 cleavage, and increased abundance of Smac, Bim, and PUMA. By contrast, many G2M checkpoint proteins were down-regulated, including Aurora A, Checkpoint-1, Cell division cycle-6, and WEE1 kinases, and decreased levels of phospho-S807/S811 Rb protein were seen. Also, RNA-sequencing revealed mTORC1 pathway dysregulation, and proteomic studies showed decreased activity of AKT and AKT2, mTOR, and p70 S6 kinase. Notably, LAMP5 suppression was associated with reduced levels of expression of an RFP-LC3 fusion protein consistent with a role for LAMP5 in autophagy. In contrast, high LAMP5 expression was associated with improved colony formation in vitro ( A), and promoted disease progression in vivo. Since the LAMP5 promoter had consensus retinoic acid sites, we tested all-trans retinoic acid and found it suppressed LAMP5 protein expression, and reduced in vitro clonogenicity. Finally, since other LAMPs can under some circumstances be found at the plasma membrane, we performed flow and LAMP5 was indeed detected on the surface of unpermeabilized LAMP5-positive myeloma cells. We thus developed a panel of monoclonal antibodies that recognized the extracellular domains of LAMP5, and converted one of these into antibody drug conjugates (ADCs) linked to either MMAE or PBD. Both ADCs reduced the viability of LAMP5-positive myeloma cells in a time- and concentration-dependent manner ( B), activated immunogenic cell death in vitro, and also showed anti-tumor activity in vivo. Importantly, LAMP5-directed CAR T-cells similarly and specifically eliminated only LAMP5-positive myeloma cells with efficacy that was comparable to that of B-cell maturation antigen-targeted CAR T-cells. Conclusions: These pre-clinical in vitro and in vivo data support the possibility that LAMP5 represents a novel mediator of myeloma clonogenicity and high-risk behavior, and that it could serve as a rational therapeutic target leveraging immune therapies that recognize the extracellular domains of cell surface LAMP5.

Dynamic Frailty Assessment in Transplant Non-Eligible Newly Diagnosed Myeloma Patients: Initial Data from UK Myeloma Research Alliance (UK-MRA) Myeloma XIV (FiTNEss): A Frailty-Adjusted Therapy Study

Background Multiple myeloma (MM) is a blood cancer that predominates in the older adult with significant morbidity and mortality. Frailty is increasingly recognized as a predictor for long- and short-term outcomes, with those who are frailer at risk of greater toxicity, treatment discontinuation and poorer survival. Identifying and tailoring treatment for frail older patients with MM remains an unmet need. The International Myeloma Working Group frailty score (IMWG FS) is a prognostic biomarker for survival, but no evidence exists for its predictive biomarker potential. In addition, defining frailty at a single timepoint (baseline) by the IMWG FS may mask disease overlay and the improvements seen with therapy delivery. Understanding both improvements and deteriorations in frailty during treatment may have important implications for dynamic treatment delivery. Study Design and Methods The UKMRA Myeloma XIV FiTNEss trial (NCT03720041) is a phase III, multi-centre, randomised controlled trial for newly diagnosed patients with MM ineligible for a stem cell transplant. The primary objectives of the study are 1) to compare early treatment cessation (within 60 days of randomisation) between patients randomised to standard (reactive) and frailty-adjusted (adaptive, based on IMWG FS) induction therapy delivery with the triplet ixazomib, lenalidomide and dexamethasone (IRd) and 2) to compare progression-free survival for maintenance lenalidomide (R) and lenalidomide plus ixazomib (IR). Baseline revised IMWG FS (considering only those scoring &amp;gt;=3 frail) and UKMRA Myeloma Risk Profile (MRP) were determined. Here we report the changes in IMWG FS for the patients recruited to the standard (toxicity-reactive) arm, including demographic data and the identification of an ultra-frail group. Results The FiTNEss trial opened on 04/08/2020 and at the time of data cut off (01/06/2023) recruitment is active at 84 sites, with 638 patients randomised. Baseline characteristics for the randomised patients are shown in Table 1. The median age of patients is 76 years (range 62, 93) with 34.8% aged 76-80 and 22.3% over 80. The IMWG FS at baseline for the full trial cohort was FIT 182/638 (28.5%), UNFIT 207/638 (32.4%) and FRAIL 249/638 (39.0%). Revised IMWG FS at baseline was Fit 28.5%, Unfit 56.0% and Frail 15.5% with MRP non-high risk (Fit or Unfit, nHR) in 64.3% and MRP HR (Frail) in 35.7% in patients with data available. For descriptive analysis of FS dynamism, we assessed the impact on FS of delivery of IRD in the control arm (n=319), calculating the FS at 2, 4, 6 and 12 months. The majority of changes were seen at 2 months across the frailty categories. For Fit patients, 20.9% demonstrated a deterioration in FS score at any timepoint. For Unfit patients, 26.7% demonstrated a deterioration in FS score whilst 16.2% demonstrated an improvement in FS at any timepoint. For Frail patients, 15.4% demonstrated an improvement in FS at any timepoint (Figure 1). Of those who demonstrated a deterioration in FS, 59.1% experienced a treatment related safety event. In those who demonstrated an improvement in FS, 26.3% experienced a treatment related safety event. Of the 250 whose FS remained constant 34% experienced a treatment related safety event. For frail patients, 119 could be stratified further and 57% were classified as Ultra-Frail (IMWG FS Frail and MRP HR). Conclusion The FiTNEss trial demonstrates the feasibility of recruiting older, less fit patients to clinical trials. The IMWG FS does demonstrate a dynamic biomarker potential both representing improved functionality in relation to disease response to therapy, as well as deterioration consequential to treatment-emergent toxicity. In addition, the concept of ultra-frail represents an exciting possibility to further stratify patients who may need additional support in order to improve their outcomes. Further work in these two areas is on-going as the trial dataset matures.

Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone Induction and Consolidation with Tandem Transplant in High-Risk Newly Diagnosed Myeloma Patients: Final Results of the Phase 2 Study IFM 2018-04

Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with favorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improved response rate and progression free-survival in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improved outcome of HR TE NDMM patients (EMN02). The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) evaluated an intensive strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Treatment strategy included Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara-KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance for 2 years. The primary endpoint was the feasibility of this intensive strategy. Results: Fifty patients with previously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers. Median age was 57 (range 38 -65). Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n=20, 40%), t(4;14) (n=26, 52%) or t(14;16) (n=10, 20%). Four (8%) patients had extramedullary disease. At data cut-off, the study met the primary endpoint with 36 (72%) patients completing second transplant. Twenty-one patients (42%) discontinued the study, due to stem-cell collection failure (n=8), disease progression (n=8), adverse event (n=4), consent withdrawal (n=1). Grade 3-4 Dara-KRD induction/consolidation related adverse event (&amp;gt;5% of patients) were neutropenia (44%), anemia (22%), thrombocytopenia (24%) and infection (14%). Four patients discontinued treatment due to severe adverse event (COVID-19 infection, drug-induced hepatitis, JC virus related encephalopathy, intracerebral hemorrhage). Seven patients died, 5 due to disease progression and 2 due to infection. Responses deepened over time with an overall response rate before maintenance of 100%, including 81 % complete response. Among evaluable patients (33/36), pre maintenance Minimal Residual Disease negativity rate (NGS, 10 -6) was 94%. After a median follow up of 32 months, the 24-months PFS is 87% (78-87%) and the 24-months OS is 94% (87-100%). Conclusions: Dara-KRD induction/consolidation with tandem transplant was feasible in TE NDMM patients with high-risk cytogenetic profile, and resulted in high MRD negativity rate and high progression free survival.

The Impact of Epstein-Barr Virus Infection on Second Cancer Development in Newly Diagnosed Myeloma Patients Treated with Lenalidomide in the UK NCRI Myeloma XI Trial

Background Several factors have been linked to second primary malignancy (SPM) development in myeloma patients, including advanced age, immunocompromise and therapy, such as melphalan and lenalidomide (len). The impact of infection, including EBV is yet to be elucidated. Here we address this in the context of the UK NCRI Myeloma XI Trial for newly diagnosed transplant eligible (TE) and transplant non-eligible (TNE) patients. Methods Myeloma XI was a phase III, randomised, multi-centre, parallel group design, open-label trial comparing cyclophosphamide, thalidomide, len, carfilzomib and bortezomib induction combinations and len maintenance treatment in TE and TNE patients. TE patients received high dose melphalan supported by autologous stem cell transplantation (ASCT). Patients in both pathways were randomised to maintenance with len or observation. In total, 4358 patients entered. Planned SPM analysis was conducted in May 2019, with 318 patients developing an SPM prior to that point. Median follow-up from trial entry was 60 months (IQ range 47-76). A nested cohort analysis was performed to determine EBV infection and immunity status in 170 SPM patients for which serum samples were available. Forty-two trial patients who did not develop an SPM were used as a control group. EBV assessment time-points included pre-induction, post induction, 4 months post ASCT (TE only) and 1 year post induction. Peripheral blood serum samples were tested for EBV EBNA IgG Antibody/index (LIAISON®), EBV VCA IgM Antibody/Index (LIAISON®) and EBV positivity was determined using the artus® EBV RG PCR Kit from Qiagen. Active or recent EBV infection was evidenced by a positive EBV IgM antibody and/or EBV PCR. Results Of the 170 patients, 208 SPM were noted with 147 patients developing 1 SPM and 23 patients developing ≥2. One hundred and five patients developed an SPM following maintenance randomisation, with 76 receiving len and 29 being observed. The remaining 65 patients developed an SPM prior to maintenance. Eighty-four SPMs were diagnosed in 68 TE patients and 124 SPMs in 102 TNE patients. Of the 170 SPM patients, 8 had evidence of recent or active infection at the time of testing, evidenced by either IgM EBV antibodies (n=5), positive EBV PCR (n=2) or both (n=1). The median EBV DNA copies/ml was 353 (range 337-428). The median IgM antibody titre was 71.5U/ml (26 - &amp;gt;160). No patients in the control group had evidence of recent EBV infection (p=0.36). Of the 8 patients with evidence of EBV infection, 6 developed &amp;gt;1 SPM, Table 1. Five had been treated in the TE pathway, with all developing post maintenance randomisation, and 4 of the 5 receiving len maintenance. None of the 3 TNE patients received len maintenance, with 2 developing an SPM prior to maintenance randomisation. The median time from EBV testing to SPM diagnosis was 17·9 months (0.5-51.7). Two of the EBV positive patients developed a haematological SPM: myelodysplastic syndrome and Hodgkin lymphoma. Four patients developed a solid malignancy: lung, breast, ovary, and colon. The remaining cases were non-melanoma skin cancers, Table 1. Immune status (EBV IgG) was also determined. In TE patients, the median EBV IgG titre was 65.3U/ml at diagnosis (&amp;lt;3 - 600, n=48), falling to 28.1U/ml following induction (&amp;lt;3 - 326, n=41) and recovering to 44.2U/ml one year post ASCT (&amp;lt;3 - 600, n=22). In TNE patients, the median IgG titre at diagnosis was 39.1U/ml (&amp;lt;3 to 517, n=72), falling to 31.2U/ml 4 months post induction (&amp;lt;3 - 287, n=42) and recovering to 51.3U/ml after 1 year (&amp;lt;3 - 554, n=41). In the SPM patients the IgG EBV titres were noted to be &amp;lt;20U/ml in 5 of the 8 patients. Three of the eight patients had no detectable EBV IgG level (&amp;lt;3U/ml) Conclusions These data suggest that EBV infection is unlikely to be a risk factor for SPM development in myeloma patients. This is supported by the finding that EBV IgG titres were consistent with immunity in most patients (&amp;gt;20U/ml) and even in the patients with possible EBV infection, EBV DNA was only identified in 3 patients, and at a low level. In addition, the SPM developed are not classically associated with EBV infection or reactivation. It is noted that EBV infection status was not always determined at the time of SPM development. Despite this, the data does show that EBV immunity recovers following therapy, even in the post ASCT setting. EBV monitoring is therefore not supported by this work, although in patients who develop ≥2 SPM, further clarification is required.

Targeted NGS Panel Guides Risk-Adapted Treatment Intention in Newly Diagnosed Myeloma Patients

Introduction While overall survival has improved, patients with high-risk multiple myeloma (MM) have poor outcomes. Fluorescent in situ hybridisation (FISH) is widely used to identify high-risk genomic features at diagnosis, but a significant minority of patients classified with standard-risk disease progress rapidly and in retrospect may have warranted more intense frontline therapy. Recently, we implemented the Myeloma Genome Project Panel (MGPP) into clinical workflows - a myeloma-specific targeted sequencing panel capturing 228 genes, 6 translocation regions and 56 copy number abnormalities (CNAs) in a single assay [PMID: 35522533]. Given that MGPP captures many prognostic regions beyond the limited number assessed by FISH, there is potential to better identify high-risk patients. However, the utility of MGPP in supporting clinical risk designation and therapy choice when compared with FISH in newly diagnosed MM is unknown. Methods A prospective cohort study was conducted to compare the impact of MGPP vs. FISH on baseline risk stratification and treatment intention, in 55 unselected newly diagnosed MM patients. For MGPP, libraries were generated from 100ng DNA from bone marrow (BM) derived CD138 + MM cells and matched germline peripheral blood (Roche KAPA HyperCap Target Enrichment/Hyperplus kit). Reads were aligned to hg38, and somatic mutations, CNAs and translocations called with a custom pipeline. ISO-accredited FISH analysis was performed in NHS laboratories. In a multicentre multidisciplinary team (MDT) meeting, four blinded haematologists independently reviewed each clinical case presented twice with either FISH or MGPP, in a random order. Clinicians designated risk status and treatment intentions using a structured proforma. Therapeutically actionable variants could be selected as per the MyDRUG trial [ClinicalTrials.gov: NCT03732703]. A consensus MDT outcome for high-risk or more intensive therapy required at least 3 out of 4 concordant decisions. Results Data is presented here for 23 of 55 patients. The mean age was 68.9 years, 57% were transplant eligible, with R-ISS-1 (35%), R-ISS-2 (26%) and R-ISS-3 (39%). Firstly, MGPP had greater technical success than FISH, reporting successfully in 100% vs. 83% cases from the same diagnostic BM samples respectively (n=4 assay failures with FISH). Secondly, MGPP reported more genomic features than FISH, detecting 231 vs. 18 somatic variants at 127 vs. 7 regions, respectively. Thirdly, MGPP captured equivalent loci at greater resolution, detecting subclonal CNAs missed by FISH (Figure 1). In a head-to-head comparison with FISH, these additional genomic insights from MGPP influenced clinical treatment decisions. A clinician-led MDT reclassified 9 (39%) patients designated as standard-risk by FISH to high-risk status when presented with MGPP (Table 1). Reclassified patients were enriched for prognostically significant MYC translocations (17%) and subclonal 17p loss (22%), 1p loss (17%) and 1q gain (13%) CNAs that were missed by FISH. Altered risk designation influenced frontline treatment intention; clinicians opted for intensification of induction therapy in 13% (FISH) vs. 48% (MGPP) high-risk patients, and considered tandem autologous transplant as an option in 0% (FISH) vs. 23% (MGPP) transplant-eligible patients. FISH identified a therapeutically actionable variant in 3 (13%) patients [venetoclax, n=3]. MGPP identified 13 (57%) additional patients with opportunity for targeted therapy [MEK inhibitor, n=11; BRAF V600E inhibitor, n=2], which the MDT considered as a treatment option in all cases if available in trial. The full dataset and analysis will be presented at time of the conference. Conclusions We demonstrate that MGPP impacts clinical risk designation and treatment intention in newly diagnosed MM. MGPP had greater technical assay success than FISH and captured a greater range and depth of somatic variants. Importantly, these additional insights led a clinical MDT to reclassify 39% patients as high-risk, consider intensification regimen in 39% cases and potential for actionable targeted therapy in 57% patients. Our results support MGPP as a robust alternative to FISH in supporting risk-adapted treatment decisions. We will implement MGPP in additional large prospective cohorts over the next year, to better understand its prognostic utility and feasibility in routine clinical workflows.

High levels of CRBN isoform lacking IMiDs binding domain predicts for a worse response to IMiDs-based upfront therapy in newly diagnosed myeloma patients

In recent years, the immunoderivative (IMiD) agents have been extensively used for the treatment of multiple myeloma (MM). IMiDs and their newer derivatives CRBN E3 ligase modulator bind the E3 ligase substrate recognition adapter protein cereblon (CRBN), which has been recognized as one of the IMiDs’ direct target proteins, and it is essential for the therapeutic effect of these agents.High expression of CRBN was associated with improved clinical response in patients with MM treated with IMiDs, further confirming that the expression of IMiDs’ direct target protein CRBN is required for the anti-MM activity. CRBN’s central role as a target of IMiDs suggests potential utility as a predictive biomarker of response or resistance to IMiDs therapy. Additionally, the presence of alternatively spliced variants of CRBN in MM cells, especially those lacking the drug-binding domain for IMiDs, raise questions concerning their potential biological function, making difficult the transcript measurement, which leads to inaccurate overestimation of full-length CRBN transcripts. In sight of this, in the present study, we evaluated the CRBN expression, both full-length and spliced isoforms, by using real-time assay data from 87 patients and RNA sequencing data from 50 patients (n = 137 newly diagnosed MM patients), aiming at defining CRBN’s role as a predictive biomarker for response to IMiDs-based induction therapy. We found that the expression level of the spliced isoform tends to be higher in not-responding patients, confirming that the presence of a more CRBN spliced transcript predicts for lack of IMiDs response.

Integrative analysis of the prognostic value and immune microenvironment of mitophagy-related signature for multiple myeloma

BackgroundMultiple myeloma (MM) is a fatal malignant tumor in hematology. Mitophagy plays vital roles in the pathogenesis and drug sensitivity of MM.MethodsWe acquired transcriptomic expression data and clinical index of MM patients from NCI public database, and 36 genes involved in mitophagy from the gene set enrichment analysis (GSEA) database. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was conducted to construct a risk score prognostic model. Kaplan–Meier survival analysis and receiver operation characteristic curves (ROC) were conducted to identify the efficiency of prognosis and diagnosis. ESTIMATE algorithm and immune-related single-sample gene set enrichment analysis (ssGSEA) was performed to uncover the level of immune infiltration. QRT-PCR was performed to verify gene expression in clinical samples of MM patients. The sensitivity to chemotherapy drugs was evaluated upon the database of the genomics of drug sensitivity in cancer (GDSC).ResultsFifty mitophagy-related genes were differently expressed in two independent cohorts. Ten out of these genes were identified to be related to MM overall survival (OS) rate. A prognostic risk signature model was built upon on these genes: VDAC1, PINK1, VPS13C, ATG13, and HUWE1, which predicted the survival of MM accurately and stably both in training and validation cohorts. MM patients suffered more adverse prognosis showed more higher risk core. In addition, the risk score was considered as an independent prognostic element for OS of MM patients by multivariate cox regression analysis. Functional pathway enrichment analysis of differentially expressed genes (DEGs) based on risk score showed terms of cell cycle, immune response, mTOR pathway, and MYC targets were obviously enriched. Furthermore, MM patients with higher risk score were observed lower immune scores and lower immune infiltration levels. The results of qRT-PCR verified VDAC1, PINK1, and HUWE1 were dysregulated in new diagnosed MM patients. Finally, further analysis indicated MM patients showed more susceptive to bortezomib, lenalidomide and rapamycin in high-risk group.ConclusionOur research provided a neoteric prognostic model of MM based on mitophagy genes. The immune infiltration level based on risk score paved a better understanding of the participation of mitophagy in MM.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Background: A growing body of evidence has indicated impaired function or compositional changes of monocytes in inflammatory disorders, such as acute respiratory syndrome and covid-19. In myeloma tumor microenvironment, activation of type I interferon pathway and dysregulated expression of major histocompatibility complex type II genes are observed in classical monocytes, which result in loss of antigen presentation of monocytes. The proportions of BAFF+PD-L1+ monocytes in the bone marrow also correlate with survival of myeloma patients following chimeric antigen-receptor T cell therapy. Nevertheless, the mechanisms underlying PB and BM monocytes defects in myeloma remain poorly addressed, at least in part by the lack of large scale scRNA-seq studies. To resolve the heterogeneous bone marrow and peripheral blood monocyte subpopulations and their transcriptional factors between healthy donors and multiple myeloma patients. Methods: We conducted scRNA-seq on monocytes of 7 newly diagnosed myeloma patients and 12 healthy donors. Specifically, 3 and 5 bone marrow aspirates and 9 and 7 peripheral blood samples of 12 healthy controls and 7 newly diagnosed patients were obtained, respectively. Results: Heterogeneous bone marrow and peripheral blood monocyte subpopulations and their transcriptional factors were resolved. The function characteristics of monocyte were compared between MM patients and healthy donors, which indicated a stress signature induced by multiple myeloma. Furthermore, we identified two monocyte differentiation pathways, and discovered that bone marrow monocyte feature type I IFN-associated differentiation dysregulation in patients with MM as well as dysregulated patterns at transcriptome. Finally, we included 10 MM patients as a validation cohort, by tracking the stress signature over time in those patients undergoing first-line treatment, we founded that the stress signature was partially overcome by antitumor therapy. Conclusion: Our results provided further insight into transcriptional and differentiation changes occurring in the bone marrow and peripheral blood monocytes from patients with multiple myeloma and hint and mechanisms of immune evasion. Encore Abstract - previously submitted to EHA 2023 The research was funded by: This investigation was supported by the International Cooperation Projects of National Natural Science Foundation (grants 81920108006), CAMS Innovation Fund for Medical Sciences (CIFMS) (grants 2022-I2M-1-022), the National Natural Science Foundation (grants 81630007; grants 82270218, 81670202; grants 81900214), and the Atlas of Blood Cell Alliance. Keywords: genomics, epigenomics, and other -omics, microenvironment, multiple myeloma No conflicts of interests pertinent to the abstract.

Alternative splicing in multiple myeloma is associated with the non-homologous end joining pathway

Alternative splicing plays a pivotal role in tumorigenesis and proliferation. However, its pattern and pathogenic role has not been systematically analyzed in multiple myeloma or its subtypes. Alternative splicing profiles for 598 newly diagnosed myeloma patients with comprehensive genomic annotation identified primary translocations, 1q amplification, and DIS3 events to have more differentially spliced events than those without. Splicing levels were correlated with expression of splicing factors. Moreover, the non-homologous end joining pathway was an independent factor that was highly associated with splicing frequency as well as an increased number of structural variants. We therefore identify an axis of high-risk disease encompassing expression of the non-homologous end joining pathway, increase structural variants, and increased alternative splicing that are linked together. This indicates a joint pathogenic role for DNA damage response and alternative RNA processing in myeloma.

Bortezomib Maintenance After Allogeneic Transplantation in Newly Diagnosed Myeloma Patients Results in Decreased Incidence and Severity of Chronic GVHD

Allogeneic hematopoietic cell transplantation (HCT) has curative potential in myeloma but remains hampered by high rates of relapse and chronic graft-versus-host disease (GVHD). We hypothesized that bortezomib (BTZ) as maintenance therapy after allo HCT could not only decrease the incidence of relapse but also the incidence and severity of chronic GVHD. The primary endpoint of this study was to determine whether BTZ maintenance decreases the incidence and severity of chronic GVHD using National Institutes of Health (NIH) criteria. The secondary endpoints were to determine the immunosuppression burden, organ involvement and survival (overall survival, progression-free survival) in patients either receiving or not receiving BTZ. In this retrospective study, we compared the outcome of 46 myeloma patients who received BTZ after upfront tandem auto-allo HCT between 2008 and 2020 to 61 patients without maintenance. We explored the impact of BTZ maintenance on incidence and severity of chronic GVHD using the 2014 NIH criteria. At 2 years, incidences of overall (61.2% versus 83.6%; P=.001), and moderate/severe chronic GVHD (44.5% versus 77.0%; P=.001) were significantly lower in BTZ recipients who had less mouth (43% versus 67%; P=.018) and eyes (9% versus 41%; P=.001) involvement at initial diagnosis. We report a lower use of systemic steroids (45.1% versus 76.4%; P < .001), mycophenolate mofetil (15.5% versus 28.2%; P=.031) and tacrolimus (34.5% versus 70.6%; P < .001) in BTZ recipients. Probability of being alive and off systemic immunosuppressants at 3 years was 77% in BTZ recipients and 56% in controls (P=.046). To date, there is no difference in survival between both groups. In summary, BTZ maintenance improved incidence and severity of chronic GVHD and should be considered as a valid option in myeloma patients receiving upfront tandem auto-allo HCT.

High serum IL-17A is associated with bone destruction in newly diagnosed multiple myeloma patients.

BackgroundMultiple myeloma (MM) is a malignant proliferative disease of the blood system, characterized by the abnormal growth of clonal plasma cells in the bone marrow. The bone marrow microenvironment (BMM) is highly critical in the pathological process of MM. Many studies have shown that serum interleukin-17A (IL-17A) plays a key role in various infectious diseases, autoimmune diseases, and cancers. However, more clinical studies need to be performed to further prove the influence of serum IL-17A levels on multiple myeloma patients.MethodsAmong a total of 357 participants in our institution’s MM cohort, 175 were eligible for the retrospective study. Multivariate regression models adjusted by potential confounding factors, the violin plots, the generalized additive model and smooth curve fittings, receiver operating characteristic (ROC) curve, and Kaplan–Meier (K-M) curve analysis were applied to the research.ResultsA total of 175 patients with newly diagnosed MM were enrolled in this study. The multivariate linear regression analysis showed that serum IL-17A level in MM patients correlated with the degree of bone lesions and fracture incidence (fully adjusted model, pbone lesion < 0.0001, pfracture < 0.0001). The violin plot showed that MM patients with higher serum IL-17A levels had more severe bone lesions and higher fracture incidence than those with lower serum IL-17A levels. A total of 171 patients were included in the study of the relationship between serum IL-17A and best overall effect (BOE). We found that serum IL-17A levels were independently related to the best inductive therapeutic efficacy (fully adjusted model, p = 0.037), and the relationship was especially obvious in the light chain group (fully adjusted model, p = 0.009) and IgA group (fully adjusted model, p = 0.0456). It could be deduced from the smooth curve that the higher the serum IL-17A level, the worse the BOE (p = 0.0163). The ROC prediction curve suggested that serum IL-17A could predict the BOE to a certain extent (area under the curve (AUC) = 0.717, p = 0.0327). A total of 148 MM patients were observed in the longitudinal study of the relationship between serum IL-17A and progression-free survival/overall survival (PFS/OS). The K-M curve analysis indicated that serum IL-17A levels in MM patients were not significantly correlated with PFS and OS. However, in the light chain subgroup, MM patients with high serum IL-17A had worse PFS (p = 0.015) and OS (p = 0.0076) compared to those with low serum IL-17A. In the IgA type subgroup, the higher IL-17A level was related to worse OS (p = 0.0061).ConclusionThis retrospective study found that higher levels of serum IL-17A were independently correlated with higher severity of bone disease and fracture incidence in newly diagnosed MM patients. High serum IL-17A level was related to poor best overall efficacy in the light chain type. High serum IL-17A was also associated with poor PFS and OS in the light chain type and OS in the IgA type subgroup.

Impact of the changing landscape of induction therapy prior to autologous stem cell transplantation in 540 newly diagnosed myeloma patients: a retrospective real-world study

IntroductionAutologous stem cell transplantation (ASCT) is the standard treatment for younger patients with newly diagnosed multiple myeloma (MM). However, due to restrictive exclusion criteria, more than half of eligible patients are usually excluded from transplant studies.MethodsThis retrospective monocentric analysis included 540 patients with MM who received an ASCT between 1996 and 2019.ResultsUp to 2005, induction therapy consisted mainly of conventional chemotherapies, e.g. vincristine/doxorubicin/dexamethasone (VAD). In the following years, the triple-combinations based on bortezomib coupled with doxorubicin/dexamethasone (PAD), melphalan/prednisolone (VMP), cyclophposphamide/dexamethasone (VCD) or bendamustine/prednisolone (BPV) became the most popular treatment options. A progressive improvement in PFS was observed in patients treated with the two current induction therapies BPV (47 months) or VCD (54 months) compared to VAD (35 months, p < 0.03), PAD (39 months, p < 0.01 and VMP (36 months, p < 0.01). However, there was no significant difference in median OS (VAD 78, PAD 74, VMP 72, BPV 80 months and VCD not reached). In our analysis, we also included 139 patients who do fulfill at least one of the exclusion criteria for most phase 3 transplant studies (POEMS/amyloidosis/plasma cell leukemia, eGFR < 40 mL/min, severe cardiac dysfunction or poor general condition). Outcome for these patients was not significantly inferior compared to patients who met the inclusion criteria for most of the transplant studies with PFS of 36 vs 41 months (p = 0.78) and OS of 78 vs 79 months (p = 0.34).ConclusionsOur real-world data in unselected pts also stress the substantial value of ASCT during the first-line treatment of younger MM pts.

OAB-041: Daratumumab carfilzomib lenalidomide and dexamethasone as induction therapy in high-risk transplant eligible newly diagnosed myeloma patients: results of the phase 2 study IFM 2018-04

OAB-041: Daratumumab carfilzomib lenalidomide and dexamethasone as induction therapy in high-risk transplant eligible newly diagnosed myeloma patients: results of the phase 2 study IFM 2018-04

Prognostic Stratification of Multiple Myeloma Using Clinicogenomic Models: Validation and Performance Analysis of the IAC-50 Model.

A growing need to evaluate risk-adapted treatments in multiple myeloma (MM) exists. Several clinical and molecular scores have been developed in the last decades, which individually explain some of the variability in the heterogeneous clinical behavior of this neoplasm. Recently, we presented Iacobus-50 (IAC-50), which is a machine learning-based survival model based on clinical, biochemical, and genomic data capable of risk-stratifying newly diagnosed MM patients and predicting the optimal upfront treatment scheme. In the present study, we evaluated the prognostic value of the IAC-50 gene expression signature in an external cohort composed of patients from the Total Therapy trials 3, 4, and 5. The prognostic value of IAC-50 was validated, and additionally we observed a better performance in terms of progression-free survival and overall survival prediction compared with the UAMS70 gene expression signature. The combination of the IAC-50 gene expression signature with traditional prognostic variables (International Staging System [ISS] score, baseline B2-microglobulin, and age) improved the performance well above the predictability of the ISS score. IAC-50 emerges as a powerful risk stratification model which might be considered for risk stratification in newly diagnosed myeloma patients, in the context of clinical trials but also in real life.