Active Multiple Myeloma Research Articles

Active Multiple Myeloma in β-Thalassemia: A Case Report

Active Multiple Myeloma in β-Thalassemia: A Case Report

Abstract 6170: Risk stratification of smoldering multiple myeloma using fourier transform infrared spectroscopy of serum

Abstract Background: Smoldering multiple myeloma (SMM) is a state where patients have more than 10% clonal plasma cells or a serum monoclonal protein > 3g/dl but no evidence of end organ damage. Patients with SMM are at risk of developing active multiple myeloma (defined by the CRAB criteria). The best stratification system with respect to the risk of progression to active myeloma is the 20/2/20 (20% plasma cells, M protein >2.0 g/dl, and involved to uninvolved immunoglobulin free light chain ratio >20). The presence of ≥2 criteria predicts a 50 - 60% risk of progression within 2 years. Thus, many patients considered ‘high-risk’ may not progress in this time frame, and patients with ≤1 risk factor can progress to active myeloma. Therefore, improved risk stratification methods are needed to correctly identify patients at high risk of progression. We hypothesized that Fourier Transform InfraRed (FTIR) spectroscopic analysis of serum combined with artificial intelligence (AI) can correctly risk stratify patients with SMM. Methods: We identified 192 SMM patients: 96 who progressed and 96 who did not progress within 2 years of diagnosis. We used stored sera from the time of diagnosis to perform FTIR to determine differences in the spectra of patients who did/did not progress and train an AI algorithm. A randomized 10-fold cross-validation analysis was performed using 172 samples (86 from each group) for training and the remaining 20 for testing to assess the model across 10 independent iterations. Subsequently, we blindly tested the trained model against an independent set of serum samples (N=24) from patients who progressed ≤3 years of diagnosis. Receiver operator characteristic (ROC) analysis was used to assess the FTIR AI algorithm output compared to the clinical outcome data. Results: From the 96 patients who progressed, 48 had complete data for the 20/2/20 risk stratification. 11 patients (23%) had ≤1 of the criteria and so would have been considered at low likelihood to progress. Of the 96 who did not progress within 2 years, 49 had complete data for risk stratification. Of these, 27 (55.1%) met the high-risk criteria of the 20/2/20 classification and would have been predicted to progress within 2 years. FTIR/AI model correctly identified the patients at risk of progression (95% accuracy) with AUC of 0.96. Similarly, it was able to classify patients who did not progress within 2 years of diagnosis (94% accuracy) with an AUC of 0.96. FTIR/AI correctly predicted the patients at risk of progression within 2 years (90%) and 3 years (87.5%) in the blinded validation group with an AUC of 0.89 and 0.82, respectively. Conclusion: Analysis of serum in patients with newly diagnosed SMM with FTIR is able to correctly identify those at risk of progression within 2 or 3 years of diagnosis with an accuracy of ~90% in a blinded external validation study. FTIR may, therefore, be used to assess SMM patient risk before committing to potentially toxic therapy. Citation Format: David Dingli, Darlyna Khonkhammy, Caden Gunnarson, Grant Schlauderaff, Dan Q. Pham, Ali Khammanivong. Risk stratification of smoldering multiple myeloma using fourier transform infrared spectroscopy of serum [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6170.

The Involvement of LAG-3positive Plasma Cells in the Development of Multiple Myeloma.

The Lymphocyte-Activation Protein 3 (LAG-3) inhibitory receptor is expressed on regulatory plasma cells (PCs). Micro-environmental cells that express LAG-3 were found to be increased during the progression of smoldering multiple myeloma (SMM). To assess the possible role of LAG-3 expression on regulatory PCs in patients with plasma cell dyscrasia. Purified Cluster of Differentiation 138 (CD138+) PCs from patients with premalignant conditions, active multiple myeloma (MM), and controls were analyzed for the expression of LAG-3 by flow cytometry. Autologous CD8+T cells were incubated with sorted LAG-3pos or LAG-3neg PCs for 24 h. The expression of granzyme (Grz) in CD8+T cells was assessed by flow cytometry. LAG-3 expression on PCs in active MM (newly diagnosed and relapse refractory MM) was significantly increased compared to monoclonal gammopathy of undetermined significance (MGUS)/ SMM. Grz expression was significantly decreased in CD8+T cells incubated with CD138+LAG-3pos PCs, compared to CD138+LAG-3neg PCs in patients with plasma cell dyscrasia, n = 31, p = 0.0041. LAG-3 expression on malignant PCs can be involved in the development of MM from MGUS by decreasing the expression of Grz in CD8+T cells.

Smoldering Multiple Myeloma Progressing to Active Multiple Myeloma Vs De-Novo Active Multiple Myeloma - a Comparison of Disease Characteristics, Organ Involvement and Outcomes in a Real-Life Multicenter Retrospective Cohort Study

Background Smoldering Multiple Myeloma (SMM) is an intermediate precursor phase in Multiple Myeloma (MM) evolution. SMM patients are monitored for progression to active disease, supposing such surveillance will identify myeloma-defining events (MDEs) early and consequently hasten treatment, prevent complications and improve outcomes. To what extent this approach is successful is not well established. We aimed to compare disease characteristics, end organ involvement and outcomes between SMM patients who progressed to active MM vs newly diagnosed MM (NDMM) patients. Methods We performed a two-center real-world case-control retrospective cohort study. Consecutive patients receiving first line treatment for MM after progressing from SMM were identified; each was matched by age and year of diagnosis (±2 years) to a patient first presenting as NDMM. SMM, MM, MDEs and response were defined by the International Myeloma Working Group (IMWG) criteria (2014, 2016); progression-free survival (PFS) and overall survival (OS) were calculated from active MM diagnosis. Data was extracted in 07/2023. Results We identified two cohorts of newly diagnosed MM patients, presented between 09/2008and 02/2023: Post SMM (P-SMM, N=57) and De novo MM patients (D-MM, N=57). Median follow up time was 38.6 months (IQR 23.3 - 72.7). There were no differences in baseline demographics between gender (p=.19), and median age: 73.4 (range 42 - 88) in the P-SMM group and 72.9 (range 42 - 92) in the D-MM (p=.75). Comparing MDEs using SLiM-CRAB criteria between groups, more patients in the D-MM group presented with hypercalcemia (p=.02) and lytic lesions (p=.03). Other domains were similar between groups: anemia (p=.68), renal failure (p=.59), FLC ≥100 (p=.76), % bone marrow plasma cells (BMPC) ≥ 60 (p=.11). D-MM patients had higher ISS/R-ISS at presentation: ISS ≥ II (30 vs 11, p=.004) and R-ISS ≥ II (31 vs 13, p=.002). Additional disease characteristics were balanced at diagnosis of active MM: heavy chain (p=.53), light chain type (p=.69), M-Protein level (p=.23), extra medullary disease (p=.14), Al amyloidosis (p=.13), and high-risk cytogenetics (p=.65). Bone involvement was more frequent in D-MM vs P-SMM patients, with significantly more pathological fractures (p=.006), bone pain (p=.001), and a detrimental bone disease (p=.001) (defined as combination of pathological fracture and/or ≥ 3 lytic lesions) (Figure 1B). Significantly higher rates of hospital admissions for upfront therapy initiation were seen in the D-MM group compared with P-SMM, 18 vs 7 (p=.008), as well as more potentially irreversible MDEs (pathological fractures and/or renal injury): 43 (p=.009) vs 31 (41.9%) respectively. Treatment patterns were balanced excluding bortezomib used more often in the D-MM (p=.009) and daratumumab in the P-SMM group (p=.03). Best response rates to upfront therapy were comparable between groups, (p=.71) as well as ≥ very good partial response (VGPR) rates (p=.88), 52.4% vs 47.6% in P-SMM and D-MM respectively. Frequency of skeletal imaging tests up-to 2-year period prior to active MM diagnosis were associated with lower rates of detrimental bone disease (p=.006). Despite the similar ≥ VGPR rates between cohorts, PFS was longer in the P-SMM group vs D-MM group, 39.6 vs 21.6 months, respectively (log-rank 0.01). A superior PFS in P-SMM group vs D-MM remained after correction for % BMPC at diagnosis (46.2% vs 58.8%, p=.03). OS was also longer, not reached vs 93.7 months (log-rank=.047) (Figure 1A). Conclusions Patients who develop active MM post SMM clinic surveillance presented with a lower disease burden, as well as reduced rates of detrimental bone disease and potentially irreversible MDEs. P-SMM patients had favorable PFS and OS rates. This may reflect effectiveness of SMM monitoring resulting in lower disease burden at time of treatment onset; favorable long-term outcomes may also be affected by variability in treatment patterns between groups. Another possible explanation is that patients with more indolent MM biology may have extended periods of precursor condition, hence increasing their likelihood to be diagnosed by incidental laboratory tests during their SMM phase.

Assessing a New Paradigm in Defining High Risk Precursor Disease State for Patients with Plasma Cell Dyscrasia: Fluctuating Monoclonal Protein

Multiple Myeloma (MM) is a malignancy originating from mature plasma cells in the bone marrow, typically preceded by clinically asymptomatic precursor conditions. Early identification of the risk of progression from these precursor states, like Monoclonal Gammopathy of Undetermined Significance (MGUS) or Smoldering Myeloma, to full-blown MM is critical for improving patient outcomes. The current risk models for MM rely on limited clinical and laboratory parameters, unable to fully encompass the complex nature of the disease continuum. To overcome these challenges, developing and validating a more comprehensive risk model is imperative, incorporating a wider array of clinical, genetic, and immune-related factors. This approach will enhance predictive accuracy and clinical applicability significantly. Notably, changes in serum monoclonal protein spike (M-spike) levels can reflect dynamic fluctuations in the net clonal mass, representing the ongoing battle between the plasma cell clone and the anti-myeloma immune response within patients. However, the impact of this highly dynamic state on the risk of progression to MM remains largely unexplored. Our study aims to bridge this knowledge gap by investigating the association between the dynamic M-spike pattern and the risk of progression from a precursor clone to MM, offering valuable insights into a potential novel prognostic marker for disease advancement. Methods: This study aimed to redefine high-risk precursor states in patients with plasma cell dyscrasias, focusing on positive serum electrophoresis (SPEP) results recorded between January 2011 and January 2021. We categorized precursor states as patients with positive SPEP, excluding those who had received active multiple myeloma (MM) treatment within 90 days of their first positive SPEP, showed M-spike values exceeding 3g/l, or displayed evident signs of disease progression. To assess M-spike patterns, we classified them as stable or fluctuating, using a 20% difference criterion to differentiate between the two (i.e., fluctuations less than 20% from baseline were labeled as stable). The time-to-treatment (TTT) was calculated from the first positive SPEP to the initiation of treatment, with death considered a competing risk. Results: The study included 565 patients, among whom 372 showed a stable M-spike pattern, while 193 exhibited a fluctuating pattern. The racial composition of the study population was predominantly white (75.58%), followed by black (21.77%) and other races (2.65%). The distribution of races was virtually identical in both the fluctuation and stable groups (p=0.977). The fluctuation group had a slightly lower proportion of females (49.7%) than the stable group (53.2%), but this difference was not statistically significant (p=0.432). Univariate analysis revealed that patients in the fluctuating group had a significantly higher odds ratio (OR) of requiring treatment (OR: 4.5, 95% CI: 1.37 - 14.18, p = 0.013) than those in the stable group. Interestingly, the prevalence of autoimmune conditions differed significantly between the groups. While 11.86% of the whole group had an autoimmune disorder, the proportion was lower in the fluctuation group (9.8%) than in the stable group (16.7%) (p=0.028).Confirming these findings, the multivariate time-to-event analysis further demonstrated that patients with fluctuating M-spike patterns had a greater likelihood of needing therapy (Hazard Ratio: 3.73, 95% CI: 1.19 - 11.66, p = 0.024) compared to those with stable patterns. Conclusion: Our study introduces a novel approach to defining high-risk precursor states in patients with plasma cell dyscrasias, emphasizing the significance of undulating monoclonal protein patterns. The dynamic nature of these fluctuations, representing the delicate interplay between pro-growth myeloma clones and anti-tumor immunity, emerges as a strong predictor of progression to MM. Further investigation and validation of these findings in more extensive studies hold promise for advancing personalized risk assessment and the development of targeted therapeutic strategies to prevent or delay the onset of multiple myeloma.

Prothrombotic Profile in Patients with Active Multiple Myeloma and the Impact of Immunomodulators: The Roadmap-MM Study

Backround: Thromboembolism occurs in about 10% of patients with multiple myeloma (MM). The incidence of VTE is higher in newly diagnosed MM patients as compared to those with relapsed or refractory disease and it is higher during the first 3 to 6 months after the initial diagnosis and treatment initiation. Some of the treatments administered to patients with MM are independent risk factors for VTE. Immunomodulatory agents (IMiDs) among anti-myeloma treatments stand out as having a considerable prothrombotic effect. Recognizing the significant risk associated with the use of immunomodulatory agents (the International Myeloma Working Group (IMWG) 2014 statement, and the European Myeloma Network Guidelines in 2015 both included guidance on the prevention of VTE in MM patients who receive IMiDs. The prospective, longitudinal observational study ROADMAP-MM CAT was designed to explore alternative strategies for the development of risk stratification tools in patients with multiple myeloma. To this target we evaluated the baseline profile of hypercoagulability in multiple myeloma patients with various disease status. Blood borne hypercoagulabity partly consisted of enhanced thrombin generation, a common phenomenon in patients with malignancies . It remains to be seen whether this phenomenon appears for multiple myeloma patients during the physical course of the disease. Aim: We conducted a study to explore the relationship between stages of MM and alterations of various thrombosis-related biomarkers in patients with MM and their relationship with MM therapy. Materials and Methods Patients with MM (n=162) were recruited and stratified to the following groups: 59 newly diagnosed treatment-naïve patients (ND), 49 patients receiving IMiDs (IM), 52 in complete remission (CR) and 12 patients in partial remission on IMiDs (PR/IM). Patients on anticoagulant treatment were excluded from the study. The control group (CG) consisted of 30 healthy age and sex-matched individuals. Samples of platelet-poor plasma (PPP) were assessed for thrombin generation (TG) with the TF 5pM PPP-Reagent® on Calibrated Automated Thrombogram (Diagnostica Stago, France). Plasminogen activator inhibitor-1 (PAI-1), soluble endothelial protein C receptor (sEPCR), and soluble vascular cell adhesion molecule-1 (sVCAM-1), Procoag-PPL were measured using antibody-based ELISA kits (Invitrogen International Inc., CA, USA, and Diagnostica Stago, France ). TF expression MPC-derived microparticles (MPC-dMPs) were detected using a Zymuphen MP-TF activity kit (Hyphen BioMed, Neuville sur Oise, France). The upper and lower normal limits (LNL and UNL) were calculated by the mean±2 SD. Results A total of 162 patients were enrolled (age 66.0±12.0 yrs; 53% male). Distribution of disease stage was as follows: 32% ISS I, 23% ISS II, 45% ISS III. Bone disease was present in 71% of patients and 19% of patients had high risk cytogenetic lesions. Patients with ongoing MM (ND, IM, PR/IM) had significantly lower Peak, ETP and MRI as compared to the CG. In contrast, patients in CR had Peak, ETP, MRI values similar to the CG. Patients with PR had lower ETP and MRI values as compared to the CR group. In ND 9% had TG >UNL and 22% had TG<LNL. In IM 10% had TG>UNL and 67% had TG<LNL. None in PR/IM had TG>UNL and 35% had TG<LNL. In CR, 23% had TG>UNL and 12% had TG<LNL. MP-TF levels and PPL were higher in untreated MM (CR) patients compared to control. MP-TF and PPL levels decreased significantly after chemotherapy in PR/IM but MP-TF remained high at CR. The plasma concentrations, PAI-1, sEPCR, and sVCAM-1 were higher in MM patients than controls. , Treatment with IMDs reduced all biomarker levels gradually from PR/IM to CR (Table 1). Conclusion Patients with active MM showed attenuated TG which was enhanced in the presence of IMiDs treatment. Complete remission was associated with normalization of TG. The plasma concentrations, TF-MP , PAI-1, sEPCR, and sVCAM-1 were increased in MM patients suggesting vascular aggression which is followed by release of these markers that could contribute to the procoagulant environment. Attention should be paid to therapy-related thrombosis indeed the effect the suggested role of IMiDs in hypercoagulability does not seem to be confirmed and requires further studies .

Evaluating the Effect of Evolving Changes in Serum Biomarkers on the Risk of Progression in Smoldering Multiple Myeloma

Introduction Smoldering multiple myeloma (SMM) is a heterogeneous condition which includes patients with varying risk of progression to active multiple myeloma (MM). The current risk stratification model is based on biomarkers reflecting disease burden at the time of diagnosis, without regard to evolution of biomarkers over time. In this study, we evaluated the dynamic changes in the monoclonal protein (MP) concentration and the free light chain ratio (FLCr), and their relation to risk of progression from SMM to MM. Methods We included all SMM patients managed at Memorial Sloan Kettering Cancer Center between 2002 and 2019, with follow up until end of 2022. Date of diagnosis and progression, as well as baseline laboratory, pathology and imaging data were manually reviewed. Serial FLC and MP were obtained through computerized data extraction. Diagnoses of SMM and MM were defined according to IMWG 2014 criteria and/or starting MM directed therapy. Time to progression (TTP) was assessed using the Kaplan-Meier method, with log-rank tests for comparison between groups. We used multivariate Cox regression to estimate the risk of progression with hazard ratios (HRs) and 95% confidence intervals (CIs). Results A total of 398 patients were included in the study; the median age was 64 years and 55% were men. At baseline, the median M-protein was 1.3 g/dL, and the median FLCr was 9.8. The overall median TTP for the cohort was 94 months during a median follow up time of 65 months. First, we stratified patients into quintiles (Q1-Q5) based on baseline M-protein and FLCr, with the highest risk of progression seen in Q5 for M-protein (defined as MP ≥2.2 g/dL, median TTP 29 months [95% CI: 24-64]) and Q5 FLCr (defined as FLCr ≥26, median TTP 36 months [29-62]), respectively (p<0.001). We compared patient trajectories during the first year of follow up based on the baseline quintiles. Interestingly, among patients who progressed from SMM to MM during the first year (11%, n=42/369), only 43% had a baseline M-protein ≥2.2 g/dL (Q5) and 43% had a FLCr ≥26 (Q5). In fact, among those who progressed, 29% had a baseline M-protein <1.6 g/dL (Q1-Q3), and 26% had baseline FLCr <11.3 (Q1-Q3). The patient trajectories during the first year of follow up based on the M-protein level are characterized in Figure 1. We then analyzed changes in M-protein and FLCr during the first year, and stratified patients into quintiles based on the rate of change. We defined evolving M-protein (eMP) and evolving FLCr (eFLCr) based on the levels of the top quintile for each group, which was an increase in ≥0.3 g/dL for eMP and ≥50% increase for eFCLr. Patients with eMP had an increased risk of progression with a median TTP of 22 months (17-not reached [NR]) after the first year (p<0.001). Patients with eFLCr had a median TTP of 48 months (21-116) after the first year (p<0.001). Recognizing that patients with high baseline M-protein level and FLCr also may have a greater increase, we developed a multivariate model adjusting for baseline levels of M-protein and FLCr. In the multivariate model, we included age, gender, and baseline M-protein ≥2g/dL and FLCr ≥20 from the Mayo 2018 risk score, as well as eMP and eFLCr. Adjusting for baseline risk, patients with eMP (Q5) had a HR of 1.8 (0.98-3.16) of progression and patients with eFLCr (Q5) had a HR of 2.9 (1.4-6) of progression using patients with little to no change in M-protein or FLCr as reference (Table 1). Finally, we did a subgroup analysis evaluating eMP and eFLCr in each baseline risk group separately. Patients with no serum risk markers per Mayo-2018 at baseline (i.e. MP <2g/dL, FLCr <20, n=127) who had both eMP (≥0.3 g/dL increase) and eFLCr (≥50% increase), had a median TTP of 25 months (0.42-NR), patients who had either eMP or eFLCr had a median TTP of 100 months (42-NR), whilst patients with neither eMP nor eFLCr had a median TTP of 201 months (130-NR), (p<0.001). Conclusion In summary, we found that when adjusting for baseline M-protein level and FLCr, evolving changes in M-protein and FLCr were associated with a higher risk of progression from SMM to MM. Interestingly, for patients with low risk by baseline stratification (M-protein <2g/dL and FLCr <20), the presence of eMP (≥0.3 g/dL increase) and eFLCr (≥50% increase) was associated with a median TTP of 25 months, similar to those with a baseline high risk. Thus, in addition to baseline disease burden, dynamic disease evolution should be considered in the risk stratification for patients with SMM.

Tracking the cellular immune response from early premalignancy to active multiple myeloma in a new model.

To calibrate a murine model to study premalignant to malignant multiple myeloma, mice were inoculated with different amounts of myeloma cells, and changes in the immune profile were tracked for over 200 days. The model highlights the development of T-cell exhaustion and suppressor before the appearance of clinical symptoms.

Clinical characteristics and outcomes in risk-stratified patients with smoldering multiple myeloma: data from the Czech Republic Registry of Monoclonal Gammopathies

Smoldering multiple myeloma (SMM) is an asymptomatic precursor to active multiple myeloma (MM). The aim of this study was to report clinical characteristics and outcomes of patients with SMM stratified based on their risk of progression to MM using the Mayo 20/2/20 criteria. Data were leveraged from the Czech Myeloma Group Registry of Monoclonal Gammopathies (RMG). Key outcomes included progression-free survival from SMM diagnosis to active MM diagnosis or death (PFS), progression-free survival from SMM diagnosis to progression on first line (1 L) MM treatment or death (PFS2), and overall survival (OS). Of 498 patients, 174 (34.9%) were classified as high risk and 324 (65.1%) as non–high risk. Median follow-up was approximately 65 months. During follow-up, more patients in the high-risk vs non–high-risk group received 1 L MM treatment (76.4% vs 46.6%, p < 0.001). PFS, PFS2, and OS were significantly shorter in high-risk vs non–high-risk patients (13.2 vs 56.6 months, p < 0.001; 49.9 vs 84.9 months, p < 0.001; 93.2 vs 131.1 months, p = 0.012, respectively). The results of this study add to the growing body of evidence that patients with high-risk vs non–high-risk SMM have significantly worse outcomes, including OS.

Long term follow-up of humoral and cellular response to mRNA-based vaccines for SARS-CoV-2 in patients with active multiple myeloma.

Long-term kinetics of antibody (Ab) and cell-mediated immune (CMI) response to full anti-SARS-CoV-2 vaccine schedule and booster doses in Multiple Myeloma (MM) patients remain unclear. We prospectively evaluated Ab and CMI response to mRNA vaccines in 103 SARS-CoV-2-naïve MM patients (median age 66, 1 median prior line of therapy) and 63 health-workers. Anti-S-RBD IgG (Elecsys®assay) were measured before vaccination and after 1 (T1), 3 (T3), 6 (T6), 9 (T9) and 12 (T12) months from second dose (D2) and 1 month after the introduction of the booster dose (T1D3). CMI response (IGRA test) was evaluated at T3 and T12. Fully vaccinated MM patients displayed high seropositivity rate (88.2%), but low CMI response (36.2%). At T6 the median serological titer was halved (p=0.0391) in MM patients and 35% reduced (p=0.0026) in controls. D3 (94 patients) increased the seroconversion rate to 99% in MM patients and the median IgG titer in both groups (up to 2500 U/mL), maintained at T12. 47% of MM patients displayed a positive CMI at T12 and double-negativity for humoral and CMI (9.6% at T3) decreased to 1%. Anti-S-RBD IgG level ≥346 U/mL showed 20-times higher probability of positive CMI response (OR 20.6, p<0.0001). Hematological response ≥CR and ongoing lenalidomide maintenance enhanced response to vaccination, hindered by proteasome inhibitors/anti-CD38 monoclonal antibodies. In conclusion, MM elicited excellent humoral, but insufficient cellular responses to anti-SARS-CoV-2 mRNA vaccines. Third dose improved immunogenicity renewal, even when undetectable after D2. Hematological response and ongoing treatment at vaccination were the main predictive factors of vaccine immunogenicity, emphasizing the role of vaccine response assessment to identify patients requiring salvage approaches.

P62 USE OF ANTIVIRAL FOR PAUCISINTOMATIC COVID-19 INFECTION IN MULTIPLE MYELOMA PATIENTS UNDERGOING TREATMENT

Patients with multiple myeloma are at increased risk of mortality from COVID-19 infection and show a lower rate of sieroconversion after vaccination and usually late negativization. In this regard, some studies have shown slight changes in mortality during the post-vaccine era. COVID-19 infection, during treatment creates several issues such as discontinuation of active treatment for the disease and a rapid negativization is useful to allow early resumption of therapy. From February 2022, it is possible to set up antiviral treatment with Nirmatrelvir or Molnupiravir in paucisymptomatic patients by reducing hospitalization and evolution in more severe infection. In this study, we collect data on 75 patients with active Multiple Myeloma and COVID-19 infection from Center District (Lazio, Umbria, Marche, Abruzzo) to evaluate the efficacy of this treatment. Of 75 pts, 57 (76%) were in first line of treatment and 18 (24%) in different lines; 62 (82.6%) were treated with antivirals, specifically 49 (65%) with oral antivirals (Nirmartelvir or molnupinavir) and 14 (18.6%) with intravenous antivirals (remdesivir); the remaining 13 (17.4%) patients had no treatment. Of the 62 patients treated with antivirals, 14 (22.6%) were hospitalized for worsening general condition, and 5 (8%) died. This group of patients resolved the infection with swab negativization with a median of 10 days (range 4-72) while the 13 patients who did not undergo any antiviral treatment presented a median of negativization of 15 days. (range 5-20). The majority of patients (67/75 subjects; 89%) had been vaccinated with at least two doses of mRNA vaccine; of these, 54 patients were treated with antivirals presenting a median time to negativization of 9 days compared with 16 days for the unvaccinated and antiviral-treated (P=NS). No difference in hospitalization and mortality. Mortality from COVID-19 infection in the sample was 8% (6/75). In conclusion despite the limitations of the sample size, the use of antivirals in patients with multiple myeloma under active treatment seems to offer a more rapid negativization of the infection promoting a rapid resumption of chemotherapy treatment despite an important effect on mortality and hospitalization. A larger sample will be useful in providing further information on mortality and hospitalization in this patient setting

Secondary extramedullary plasmacytoma in the absence of active multiple myeloma: a rare cause of small bowel obstruction

A 75-year-old woman with a history of multiple myeloma in remission presented with signs, symptoms and imaging findings consistent with a small bowel obstruction secondary to an intussusception. She underwent operative management, and intraoperative findings were consistent with an intussusception of mid small bowel as the cause of the small bowel obstruction. The offending portion of small bowel was resected, and histopathology confirmed a plasmacytoma deposit in the small bowel at the lead point of the intussusception. Secondary extramedullary plasmacytomas in the gastrointestinal system are rare but can have significant consequences like small bowel obstruction requiring operative management. We present a rare case that emphasizes the need to be highly suspicious for uncommon sequelae of multiple myeloma like secondary extramedullary plasmacytomas when managing patients with history of multiple myeloma in remission with concerning abdominal symptoms.

Immune dysregulation in multiple myeloma: the current and future role of cell-based immunotherapy.

Immune dysregulation is a hallmark of clinically active multiple myeloma (MM). Interactions between malignant clonal cells and immune cells within the bone marrow microenvironment are associated with the formation of a milieu favorable to tumor progression. IL-10, TGF-β and other immunoregulatory pathways are upregulated, promoting angiogenesis, tumor cell survival and inhibition ofthenative immune response. Transcriptomic evaluation of the bone marrow microenvironment reveals polarization of the T cell repertoire towards exhaustion and predominance of accessory cells with immunosuppressive qualities. These changes facilitate the immune escape of tumor cells and functional deficiencies that manifest as an increased risk of infection and a reduction in response to vaccinations. Immunotherapy with Chimeric Antigen Receptor (CAR) T cells and other cellular-based approaches have transformed outcomes for patients with advanced MM. Characterization of the immune milieu and identification of biomarkers predictive of treatment response are essential to increasing durability and allowing for the incorporation of novel strategies such as cancer vaccines. This paper will review the current use of cancer vaccines and CAR T cell therapy in MM as well as potential opportunities to expand and improve the application of these platforms.

Characteristics of 6 Cases of Overlapping Plasma Cell Disorders

BACKGROUND: Plasma cell disorders (PCD) are a group of diseases in which monoclonal plasma cells overproliferate and produce monoclonal immunoglobulins, including monoclonal gammopathy of undetermined significance, multiple myeloma, primary systemic light chain amyloidosis, extramedullary plasmacytoma, POEMS syndrome and so on. These groups of diseases are diagnosed according to signs, symptoms, laboratory examination and pathological manifestations, based on corresponding diagnostic criteria. It is generally believed that all kinds of plasma cell disorders exist independently and will not occur together. However, in clinic, we found that few patients can meet the diagnostic criteria of more than one kind of plasma cell diseases at the same time, and we named the diagnosis of such patients overlapping plasma cell disease. Methods: This study retrospectively analyzed the characteristics of 6 cases of overlapping plasma cell disorders which were diagnosed in First Affiliated Hospital, Sun Yat-sen University. Results: All 6 cases of overlapping plasma cell disorders were diagnosed with two plasma cell disorders at the same time at the onset. Among them, 5 cases were POEMS syndrome overlapping other plasma cell diseases, including 4 cases of POEMS syndrome overlapping solitary plasmacytoma and 1 case of POEMS syndrome overlapping active multiple myeloma (AMM). Another case was smoldering multiple myeloma (SMM) overlapping primary systemic light chain amyloidosis (pAL). All 6 patients were diagnosed strictly according to the diagnostic criteria, and they all met the diagnostic criteria of two plasma cell diseases. There are 3 males and 3 females, and the median age is 57 years old. Among them, the median plasma cells in bone marrow of 4 cases of POEMS syndrome overlapping solitary plasmacytoma were 2%, and no clonal plasma cells were found by flow cytometry. Plasma cells in bone marrow of patients with POEMS syndrome overlapping AMM and SMM overlapping pAL were 22% and 12%. The median level of VEGF of 5 cases of POEMS overlapping other plasma cell diseases was 441.38pg/ml. Of the 5 patients with POMES overlapping other PCDs, 3 received lenalidomide-based treatment, 2 received bortezomib-based treatment, and the patient with SMM overlapping pAL received Dara+Rd. The median follow-up time of these patients was 24 months. The median progression-free survival and median overall survival were not achieved. Conclusion: Overlapping plasma cell disorders are a group of rare plasma cell diseases, which requires careful screening of various clinical manifestations, laboratory tests and pathological features for diagnosis. At present, it is difficult to diagnose this kind of disease, and we need to accumulate cases and experience.

The NSG-hIL6 Mouse As a Novel Murine Patient Derived Xenograft Model of Plasma Cell Dyscrasias for Study of Disease Biology and Therapeutic Development

Background Plasma cell dyscrasias include pre-malignant and malignant conditions spanning the spectrum from monoclonal gammopathy of undetermined significance (MGUS) to smoldering multiple myeloma (SMM) to active multiple myeloma (aMM) and include the disorders AL amyloidosis and plasma cell leukemia (PCL). Though the last 2 decades has yielded effective therapies against these disorders, there remain no reliably curative treatments, and complications due to multiple myeloma are most often the cause of death. A major reason for the lack of curative therapies is the dearth of relevant research models in which to study these diseases and test new drug candidates. Cell lines that do not reflect the biology of mainstream myeloma are currently the mainstay of disease modeling. Plasma cells do not survive well outside the bone marrow and to this point, little success has been made using primary tumors from patients to model disease. Thus, there is a significant need for more relevant models to build the next, hopefully curative, generation of therapeutics for these diseases. Research Significance We present a novel immunodeficient murine model able to engraft plasma cell dyscrasias from primary patient tumors and the ability to study basic biology and test efficacy of cellular therapies, representing a significant advance in this field. Methods The NSG-h(IL6) mouse, developed by Dr. Shultz, builds on the background NSG mouse that lacks adaptive immunity and has limited innate immunity. It expresses a BAC with a piece of human chromosome 7, containing the human IL-6 gene and all associated local promoter and enhancer elements. With the expertise of the stem cell and xenograft core facility (SCXC), mice were preconditioned with busulfan, and 1e6 mononuclear cells (MNCs) isolated from human myeloma patient marrow aspirate were injected into the murine femur. Blood and urine were sampled every 4-5 weeks and analyzed for the presence of human antibodies by ELISA. Deceased mice were sent for histology and their spleens and marrow analyzed for the presence of clonal plasma cells by flow cytometry. Serum protein electrophoresis (SPEP) and complete blood counts (CBC) were noted as hallmarks of disease. Samples from patients with MGUS, SMM, aMM (both newly diagnosed and relapsed/refractory), PCL and AL amyloidosis were engrafted into mice as above. Mice were treated with untraduced T-cells (UTD) or BCMA-directed CARTs 10 weeks after engraftment of active myeloma and blood was assayed for level of immunoglobulins to follow response. Results Analysis of murine serum and urine by ELISA revealed the presence of rising titers of human antibodies in all engrafted mice and the presence of an M-spike on SPEP. NSG-hIL6 mice conditioned with busulfan showed greater engraftment than non-IL6 containing mice and non-conditioned mice (7 vs 2 vs 0, p<0.005). Light chain specific ELISA showed a clear predominance of one light chain, congruent with the patient sample that was engrafted. Flow cytometric analysis of engrafted murine bone marrow showed the presence of light chain restricted plasma cells. Histology showed the presence of plasma cells in the marrow, spleen and liver of engrafted animals with IHC positivity for specific light chain and CD138. CBC showed pancytopenia (p<0.005) with anemia being most significant in engrafted vs. unengrafted animals. All fresh samples and nearly all frozen samples of MGUS, SMM, aMM, PCL and AL amyloidosis were able to be engrafted at high rates (>50% of mice). Mice injected with column separated CD138+ cells alone showed no engraftment vs. mice injected with total MNCs from the marrow of the same myeloma (3 vs 0, p<0.005 ). BCMA directed CARTs significantly decreased circulating antibody compared to UTD controls (p<0.005). Conclusion Using the NSG-hIL6 mouse, busulfan conditioning and intrafemur injections, we have been able to engraft all the major plasma cell dyscrasias as denoted by the presence of monoclonal human antibody in these mice and presence of light chain restricted plasma cells congruent with the patient's paraprotein. We have preliminarily shown that the ability to engraft disease is dependent on human supporting cells. Additionally, treatment with BCMA directed CARTs is showing a response. This simple model will allow for further preclinical testing of new agents against multiple myeloma and associated plasma cell neoplasms and allow for study of basic biology of these diseases. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-world variability in use of bone-modifying drugs for multiple myeloma by payer type.

129 Background: The use of bone-modifying agents (BMAs) in multiple myeloma is gold standard. Benefits include prevention of skeletal-related events, reduction in bone pain, and improved progression-free survival. Guidelines recommend that patients with active multiple myeloma receive a BMA for up to two years. Unfortunately, real-world data has shown undertreatment with delays in initiation, interruptions in dosing, and premature discontinuation. These gaps are more pronounced for Black patients. The objective of this study was to describe real-world BMA treatment patterns across different payer types: Medicaid, Medicare, and Commercial/Exchange. Methods: This was a retrospective observational study using oncology prior authorization data from multiple payers in the New Century Health (NCH) database. NCH is specialty risk management company who supported over 107,000 oncology patients in 2021. All patients with a diagnosis of multiple myeloma, as indicated by the treating provider’s office, were included who had a prior authorization request for anti-cancer therapy between January 1, 2021, and December 31, 2021. Use of BMA was defined as having ≥1 authorization request for zoledronic acid or denosumab any time in the prior 24 months. BMA use was also evaluated by payer: Medicaid, Medicare, or Commercial/Exchange. Results: A total of 4774 patients were identified as having active multiple myeloma from January 1, 2021, to December 31, 2021. Fifty-nine percent (59.6%) of patients had at least one authorization request for a BMA submitted by their treating provider any time in the preceding 24 months. While most of the identified patients had Medicare, when request for BMA was disaggregated by payer, meaningful differences were found. For patients with commercial or exchange coverage, 64.6% (281/435) had a BMA requested; for patients with Medicare coverage, 60.1% (2339/3890) had a BMA requested. However, for patients with Medicaid, only 51% (229/449) had a BMA requested. Conclusions: Like other studies, our findings highlight underuse of BMAs in multiple myeloma. Differences in request for BMA across payer types suggests variability in adherence to guidelines may be based on patient insurance. To achieve equitable outcomes, including for patients of lower socioeconomic status, targeted efforts must be put in place to ensure receipt of guideline-directed therapy. A strength of this study is the large population and diversity of patients from practices in 41 states with multiple payer types. However, our analysis is limited by several unknown factors such as patient contraindication to or declination of BMA in past that are not captured in the NCH database. This retrospective study, using a large real-world oncology database, highlights that many patients with multiple myeloma may not be receiving guideline-based BMA therapy and that there are meaningful differences depending on patient insurance type.

PB2000: LESSONS LEARNED FROM CERBA RESEARCH CHIMERIC ANTIGEN RECEPTOR T-CELL (CAR T) MULTIPLE MYELOMA RUNNING TRIALS

Background: The pipeline has 359 liquid tumor trials that are CAR T driven where Cerba Research (CR) understands that there is a demand to provide innovative specialty testing, such as flow cytometry, sequencing and downstream biomarker analysis. Herein, CR examined 38 of our active multiple myeloma (MM) trials since 2016 with a focus on CAR T therapy. We identified 15 of those trials where CR participated as a central laboratory. Aims: The aim of this evaluation is to identify gaps within current CAR T MM trial endpoints and to improve for the future of our liquid tumor trials. Methods: We analyzed internal trial matrix database and examined other documents such as laboratory specification documents, trial design, protocol, and schedule of activities. We used descriptive statistics to illustrate our specialty testing involvement and to identify gaps in our offerings. Results: CR currently has 38 running MM trials, in which 15 (39%) have a CAR T therapy. Sixteen (42%) of our MM trials are phase I/first-in-human (FIH), whereas 14 (37%) and 7 (18%) are phase II and III, respectively. Within our MM CAR T trials, we perform flow cytometry (FCM) in 87% of cases. Our involvement in FCM is exploratory in nature, and the design of the panels is performed with continued scientific discussions with sponsors. Some of the flow cytometry panels performed in our CAR T trials are: - Enumeration of CAR T cells in whole blood and bone marrow aspirates, including PK evaluation - Immunophenotyping of CAR T cells (memory, regulatory, activation status, exhaustion status) - Minimal residual disease (MRD) CR is often involved across full CAR T programs starting at FIH up to registration trials. We have robust upstream capabilities where we perform peripheral blood mononuclear cell (PBMC) isolation (60%), bone marrow mononuclear cell (BMMC) isolation (53%), DNA extraction (47%), cell sorting (53%), serum and urine protein electrophoresis/immunofixation (47%), and histopathology (decalcification, embedding, sectioning) (53%). We are also involved in routine testing such as hematology (27%), biochemistry (33%) and coagulation (27%). However, except for FCM (87%), immunohistochemistry (IHC 47%) and FISH (47%), we identified a gap in requests for sequencing within MM CAR T trials (0%.) Next generation sequencing (NGS), which was mostly for MRD assessment, was performed by referral labs. We also identified up to 11 referral labs participating in MM trials which significantly adds to a trial operation complexity. Summary/Conclusion: CR currently has strong FCM fit-for-purpose design and execution capabilities as demonstrated by our participation in CAR T programs as a central laboratory. Using FCM in CAR T trials is important as it can aid in determining effectiveness of therapy, any potential side effects, and general health of the immune system by performing longitudinal monitoring of the immune system. We also frequently isolate PBMCs/BMMCs, extract DNA and perform histopathology on a global scale for clinical trial purposes. Herein, we determined that we have good downstream efforts with FCM, IHC and FISH and plan on growing NGS offerings by creating a new MRD NGS oncopanel and compare it with FCM for validation and concordance in multiple myeloma.

P332 ACUTE HEART FAILURE IN AN ELDERLY, DIABETIC, HYPERTENSIVE PATIENT. A NEVER BANAL CASE UNDERLINES THE ROLE OF EMERGENCY ECHOCARDIOGRAPHY AND AND THE RELIABILITY OF THE ANAMNESIS COLLECTED IN URGENCY

Abstract We describe the case of a 78–year old male who acceded to high intensity medicine ward for acute heart failure after some days management in the emergency room, with acuity stabilization. In his history all atherosclerosis‘ risk factors were present (diabetes mellitus type 2, arterial hypertension, dyslipidemia and kidney chronic disease) together with no active IgGk multiple myeloma, diagnosed the month before. A previous echocardiogram demonstrated aortic valve calcifications, preserved ejection fraction and mild mitral valve failure. the emergency echocardiography service was activated and the patient received echocardiography on first day. Echocardiography revealed severe aortic insufficiency secondary to erosive endocarditis of 15 mm in diameter, increased left ventricular filling pressures, and increased estimated right ventricular pressures. empirical antibiotic therapy was immediately undertaken and were carried out blood cultures.from the emergency echocardiography service the cardiology service was activated for a trans–esophageal echocardio execution which confirmed the findings Streptococcus gallolyticus was isolated. only after performing the echocardiogram did the patient remember having had fever for a few days, more than a month before the first symptoms of heart failure. In the next days, colon adenocarcinoma‘s diagnosis was made. Notably Streptococcus gallolyticus‘s infections are frequent in immunocompromised patients and its most common clinical manifestation is infective endocarditis.This kind of infection is usually connected with colon rectum cancer, mostly in patients that have already started chemotherapy. When endocarditis regards people who don‘t make use of intravenous drugs or that haven‘t congenital or acquired valves defects, the most involved one is the aortic valve. This is especially true in elderly patients.That could be explained by aortic valve damage caused by shear stress and atherosclerotic process, that always involves aortic valve‘s endothelium. This damage manifests itselves as calcium endothelium overload and aortic valve stenosis. All of these factors transform the aortic valve into the perfect target for bacteremia.The patient underwent aortic replacement surgery, because of acute massive aortic valve failure, that impaired patient‘s hemodynamic, and proper antibiotics therapy was started, with benefit. Finally, the colon cancer was treated with surgery, no chemotherapy was needed.

Adhesion molecules in multiple myeloma oncogenesis and targeted therapy.

Every day we march closer to finding the cure for multiple myeloma. The myeloma cells inflict their damage through specialized cellular meshwork and cytokines system. Implicit in these interactions are cellular adhesion molecules and their regulators which include but are not limited to integrins and syndecan-1/CD138, immunoglobulin superfamily cell adhesion molecules, such as CD44, cadherins such as N-cadherin, and selectins, such as E-selectin. Several adhesion molecules are respectively involved in myelomagenesis such as in the transition from the precursor disorder monoclonal gammopathy of undetermined significance to indolent asymptomatic multiple myeloma (smoldering myeloma) then to active multiple myeloma or primary plasma cell leukemia, and in the pathological manifestations of multiple myeloma.

Using Administrative Health Care Databases to Identify Patients With End-Stage Kidney Disease With No Recorded Contraindication to Receiving a Kidney Transplant.

Background:Administrative health care databases can be efficiently analyzed to describe the degree to which patients with end-stage kidney disease (ESKD) have access to kidney transplantation. Measures of access to transplantation are better represented when restricting to only those patients eligible to receive a kidney transplant. The way administrative data can be used to assess kidney transplant eligibility in the absence of clinical data has not been well described.Objective:To demonstrate a method that uses administrative health care databases to identify patients with ESKD who have no recorded contraindication to receiving a kidney transplant.Design and setting:Population-based cohort study using linked administrative health care databases in Ontario, Canada.Patients:Adult patients with ESKD approaching the need for dialysis (predialysis) or receiving maintenance dialysis between January 1, 2013 and March 31, 2015 in Ontario, Canada.Measurements:Recipient of a kidney-only or kidney-pancreas transplant.Methods:We assessed more than 80 baseline characteristics, including demographic information, comorbidities, kidney-specific characteristics, and referral and listing criteria for kidney transplantation. We compared these characteristics between patients who did and did not receive a kidney transplant.Results:We included 23 642 patients with ESKD (11 195 who were predialysis and 12 447 receiving maintenance dialysis). Over a median follow-up of 3.2 years (25th, 75th percentile: 1.3, 5.6), 3215 (13.6%) received a kidney-only or kidney-pancreas transplant. Of the studied characteristics available in administrative databases, >97% of patients with one or more of these characteristics did not receive a kidney transplant during follow-up: ESKD-modified Charlson Comorbidity Index score ≥7 (a higher score represents greater comorbidity), home oxygen use, age above 75 years, dementia, living in a long-term care facility, receiving at least one physician house call in the past year, and a combination of select malignancies (ie, lung, lymphoma, cervical, colorectal, liver, active multiple myeloma, and bladder cancer). Using these combined criteria reduced the total number of patients from 23 642 to 12 539 with no recorded contraindications to transplant (a 47% reduction), while the proportion who received a kidney transplant changed from 13.6% (denominator of 23 642) to 24.9% (denominator of 12 539).Limitations:Administrative databases are unable to capture all the complexities of determining transplant eligibility.Conclusion:We identified several criteria available within administrative health care databases that can be used to identify patients with ESKD who have no recorded contraindications to kidney transplant. These criteria could be applied when reporting measures of access to kidney transplantation that require knowledge of transplant eligibility.