Myeloma-defining Events Research Articles

Exploring the role of the combination of FDG-PET plus whole body MRI for staging patients with high-risk smoldering myeloma: A prospective trial.

7569 Background: According to IMWG criteria, Smoldering Multiple Myeloma (SMM) is an asymptomatic stage characterized by M-spike < 3 g/dl serum and/or bone marrow plasma cells infiltration between 10-59% in absence of myeloma-defining events and organ damage. In SMM setting, it is really important to differntiate high risk SMM (HR-SMM), in which treatment could be available thanks to clinical trials. 2016 IMWG criteria state that detection of bone lesions is mandatory for diagnosis of multiple myeloma and essential for diagnosis of SMM. It is really important to clarify in SMM the best imaging analysis in order to perform a correct diagnosis, and particularly it is necessary to define if the combination of FDG-PET/TC and WB-MRI could improve the assessment of lytic lesions and so the discrimination between high risk SMM and symptomatic MM. Methods: In our Institution we conducted a prospective trial, based on integrated new generation imaging, aiming to improve patients’ stadiation and to define its prognostic implications. From January 2021 to January 2024, we performed a prospective trial enrolling 26 consecutive newly diagnosed high risk SMM, according to IMWG, in which WB-MRI was performed according to MY-RADS criteria in combination with FDG PET-CT (median age 56; range 36-85). Results: Our comparison between WB-MRI and FDG PET-CT, showed a discordance between the two imaging modalities in 4/26 (15%) cases. In particular, in 3/26 (12%) cases WB-MRI showed bone lesions that have lead to symptomatic MM diagnosis according to IMWG criteria, while PET-CT was negative. In one case, PET-CT showed a diffuse uptake, not diagnostic for MM, while WB-MRI was negative. WB-MRI showed a 100% of accuracy in detecting SMM and MM. Therefore, WB-MRI has lead to a modification of the prognosis and treatment approach (observation in SMM vs treatment in symptomatic MM) in 3/26 patients (11%) (i.e. Figure 1, with DWI of C2 lesion). Furthermore, in 5/23 (22%) cases of confirmed SMM WB-MRI showed a slight diffuse alteration pattern of bone marrow without any overt lytic bone lesion, which could be a potential prognostic evidence. Conclusions: Our results support a fundamental role of WB-MRI in combination with FDG PET/CT in the stadiation of patients with newly diagnosed high risk SMM, which could modify prognosis and treatment, improving the differentiation with symptomatic MM. In particular, combination of WB-MRI plus FDG PET/CT could be more accurate in the detection of bone lesions than FDG PET/CT alone, being able to anticipate symptomatic MM diagnosis and consequently its treatment. Moreover, a diffuse pattern of marrow involvement could be detected in some HR-SMM patients without any overt lytic lesions: it is questionable if this group of patients is associated with a rapid progression in lytic lesions and so in symptomatic MM diagnosis. Prospective data on evolution of these patients are pending.

Prognostic value of visual IMPeTUs criteria and metabolic tumor burden at baseline [18F]FDG PET/CT in patients with newly diagnosed multiple myeloma

Background2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography combined with low-dose computed tomography (PET/CT) can be used at diagnosis to identify myeloma-defining events and also provides prognostic factors. The aim of this study was to assess the prognostic significance of baseline [18F]FDG PET/CT visual IMPeTUs (Italian myeloma criteria for PET Use)-based parameters and/or total metabolic tumor volume (TMTV) in a single-center population of patients with newly diagnosed multiple myeloma (NDMM) eligible for transplantation.MethodsPatients with MM who underwent a baseline [18F]FDG PET/CT were retrospectively selected from a large internal database of the University Hospital of Liege (Liege, Belgium). Initially, all PET/CT images were visually analyzed using IMPeTUs criteria, followed by delineation of TMTV using a semi-automatic lesion delineation workflow, including [18F]FDG-positive MM focal lesions (FL) with an absolute SUV threshold set at 4.0. In a first step, to ensure PET/CT scans accurate reporting, the agreement between two nuclear medicine physicians with distinct experience was assessed. In the second step, univariable and multivariable analyses were conducted to determine the prognostic significance of [18F]FDG PET/CT parameters on progression free survival (PFS) and overall survival (OS), respectively.ResultsA total of 40 patients with NDMM were included in the study. The observers agreement in the analysis [18F]FDG PET/CT images was substantial for the presence of spine FL, extra spine FL, at least one fracture and paramedullary disease (Cohen’s kappa 0.79, 0.87, 0.75 and 0.64, respectively). For the presence of skull FL and extramedullary disease the agreement was moderate (Cohen’s kappa 0.56 and 0.53, respectively). Among [18F]FDG PET/CT parameters, a high number of delineated volumes of interest (VOI) using the SUV4.0 threshold was the only independent prognostic factor associated with PFS [HR (95% CI): 1.03 (1.004–1.05), P = 0.019] while a high number of FL (n > 10; F group 4) was the only independent prognostic factor associated with OS [HR (95% CI): 19.10 (1.90–191.95), P = 0.01].ConclusionOur work confirms the reproducibility IMPeTUs criteria. Furthermore, it demonstrates that a high number of FL (n > 10; IMPeTUs F group 4), reflecting a high [18F]FDG-avid tumor burden, is an independent prognostic factor for OS. The prognostic value of the TMTV delineated using a SUV4.0 threshold was not significant. Nevertheless, the count of delineated [18F]FDG-avid lesions VOI using a SUV4.0 threshold was an independent prognostic factor for PFS.

Abstract 848: Influence of young age at diagnosis on the clinical presentation of disease and survival among patients with multiple myeloma

Abstract Background: Age is an important prognostic factor for multiple myeloma (MM). We evaluated the influence of age on the clinical presentation and outcomes among newly diagnosed patients with MM to optimize risk stratification. Methods: In 850 patients with first primary confirmed MM prospectively enrolled in the Integrative Molecular And Genetic Epidemiology (IMAGE) study (2009-2020), we evaluated the presence of diagnostic myeloma-defining events (MDE), progression free survival (PFS) and overall survival (OS) by young age at diagnosis (≤50 years). We evaluated the association of young age with the prevalence of diagnostic MDE, clinical features and chromosomal abnormalities using the prevalence odds ratio (OR) and corresponding 95% confidence interval (CI) calculated from multivariable logistic regression. Median PFS and OS were graphically examined using Kaplan-Meier survival curves with log-rank tests used to compare survival by diagnostic age group. Risks of disease progression and all-cause mortality were estimated using hazard ratios (HR) and corresponding 95% CI calculated from multivariable Cox proportional hazard models. Results.: Of the 850 patients, 15.4% were diagnosed at ≤50 years of age, 54% were male and 40% self-identified as Black. Compared to patients diagnosed with MM over the age of 50, young patients were more likely to self-identify as Black (59.5% vs 40.5%; P<0.0001) and to report a negative smoking history (66.2% v 56.4%; P=0.01), and less likely to present with age-dependent comorbidities including hypertension, hyperlipidemia and diabetes mellitus type II (P≤0.0001). In multivariable analyses, young patients, compared to older patients, were more likely to present at diagnosis with higher median percent bone marrow plasma cells (70% v 55%; P=0.02) and to undergo autologous stem cell transplant (ASCT) as part of their first-line treatment (82.0% v 67.6%; P=0.01) after controlling for sex, race, body mass index, smoking status and comorbidities. We did not observe significant associations of young age with the prevalence of any other MDE, clinical feature or chromosomal abnormality evaluated. The median OS was 106.9 months (range, 0.23-356.1). OS was significantly longer in young patients with MM compared to patients aged greater than 50 years (159 v 99 months, respectively; P<0.001) leading to a suggestive 1.5-fold decreased risk of mortality among younger newly diagnosed patients (HR=0.67, 95% CI 0.39-1.14; P=0.14) after adjusting for sex, International Staging System-stage, adverse cytogenetic abnormalities, and ASCT. We did not observe associations with age and PFS (P=0.81). Conclusions: Findings suggest that newly diagnosed younger patients with MM are more likely to self-identify as Black, present with more bone marrow plasma cells, have less age-dependent comorbidities, and undergo ASCT leading to a suggestive survival advantage. Citation Format: Krystle L. Ong, Kevin D. Arnold, Gayathri Ravi, Luciano J. Costa, Elizabeth E. Brown. Influence of young age at diagnosis on the clinical presentation of disease and survival among patients with multiple myeloma [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 848.

Mode of progression in smoldering multiple myeloma: a study of 406 patients

The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013–2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase (n = 71), 51 progressed by last follow-up; the MDEs included: bone lesions (37%), anemia (35%), hypercalcemia (8%), and renal failure (6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (>100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression (14%), bone pain (20%), and hospitalization/ED presentations due to MM complications/symptoms (4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing.

Bilateral Testicular Plasmacytoma Preceding Multiple Myeloma with Extramedullary Renal Involvement: A Case Report

Multiple myeloma (MM) is a clonal proliferation of plasma cells in the bone marrow, with criteria including bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma with myeloma-defining events. Solitary plasmacytoma (SP) represents a singular clonal plasma cell lesion without myeloma-defining events, while extramedullary disease (EMD) is an aggressive form of MM characterized by independent growth outside the bone marrow microenvironment. We present a unique case of a 64-year-old patient with bilateral testicular plasmacytoma anteceding the development of Immunoglobulin G (IgG) kappa-type MM, featuring extramedullary renal involvement.

Toward Precision Medicine for Patients with Multiple Myeloma

Multiple myeloma (MM), the second most common hematologic malignancy, is a plasma cell neoplasm that arises from a precursor, monoclonal gammopathy of undetermined significance (MGUS), which may or may not be previously diagnosed. Smoldering multiple myeloma (SMM), another precursor of MM, lacks myeloma-defining events and end-organ damage that are diagnostic of MM in the appropriate clinical settings. Newly diagnosed MM (NDMM) is highly heterogeneous genetically and clinically with very variable survival outcomes ranging from a few months to over a decade. Despite this heterogeneity, treatment outcomes have improved significantly in the last two decades, with overall survival improving continuously due to novel classes of drugs approved for treating MM. However, due to the immense heterogeneity, the quest for a cure will almost certainly require individualized patient evaluation and management at every level for every factor influencing patient quality of life and survival, including most importantly determining upfront the progression risks in the precursor states and prognostic risks for progression or relapse in NDMM. Toward that goal, this paper briefly describes, including a historical perspective, current concepts, and recent advances in NDMM for students, researchers, and clinical practitioners. The topics discussed include an overview of the epidemiology, current diagnostic criteria, including for distinguishing MGUS, SMM, and MM, refractory and relapsed MM, staging and prognosis of MM, treatment response criteria, including measurable residual disease evaluation, improvements in survival, current standards for treating NDMM, and disparities and inequities in receiving care in ethnic minority populations for treatment of MM, followed by progress in evaluating the risk of progression in MGUS and SMM, and finally, the genomics of MM, SMM, and MGUS since integrating disease biology in assessing and precisely managing all risk factors and achieving equity in treating all patients would help to achieve that precision medicine goal for a cure.

Bone Marrow Differential Cell Count Uncertainty In The Classification of Plasma Cell Neoplasms

Abstract Pathologic evaluation of bone marrow is diagnostically essential for many hematologic diseases, with quantification of cellular composition an important step in the pathologic work-up. Many diagnostic criteria for hematologic diseases contain precise cellular thresholds, for example 10% and 60% plasma cells in plasma cell neoplasms (PCN). Therefore, accurate cellular quantification is necessary, as it impacts treatment decisions. This process is typically performed manually and is subject to errors, including interoperator variability and heterogeneity of cellular composition within the aspirate smears. Rumke statistics were developed to predict errors in manual quantification of hematologic specimens, with resulting statistical confidence intervals. We set out to determine how statistical uncertainty of plasma cell percentages from manual differential counts could potentially affect the diagnosis and classification of PCN. Here, we extracted from the EMR a large data set containing pathologic diagnoses and laboratory data for 16,737 cases of PCN. Using the R programming language, we developed an automated method to extract plasma cell percentages from unstructured text containing manual bone marrow differential counts. Differential cell counts with plasma cell percentages were available for 4,523 cases, of which 2,445 were initial cases in the data set. Rumke statistics were calculated for each initial case using the Clopper-Pearson 95% confidence interval. Next, we identified cases where the plasma cell Rumke intervals encompassed the 10% or 60% threshold, thereby potentially changing diagnostic categorization. Of the initial cases, 228 (9.3%) encompassed a threshold (204 at 10% and 24 at 60%). To determine if diagnostic categorization would be affected, we screened for databased myeloma defining events (MDE) - hemoglobin (<10 g/dL), serum creatinine (>2 mg/dL), and total calcium (>11 mg/dL). At the 10% plasma cell threshold, 50 cases had one or more laboratory MDE and 127 had none. In cases with MDE, crossing the 10% threshold meets criteria for plasma cell myeloma (PCM) and below would likely lead to further work-up, including diagnostic imaging. In cases with no MDE, crossing the 10% threshold changes the diagnostic categorization from monoclonal gammopathy of undetermined significance to smoldering myeloma. In our data set, cases that straddled the 60% threshold all met criteria for PCM, whether they crossed the 60% threshold or not. These findings show that differential cell counts close to diagnostic thresholds fall within error ranges in a significant number of cases of PCN and potentially change diagnostic categorization. Such uncertainty must be appreciated and taken into consideration when categorizing a patient’s disease. This work also highlights the need to develop more accurate and representative methods to generate differential cell counts, such as automated methods from whole slide digital images. In addition, our methods highlight the utility of using R software to extract meaningful data from unstructured free text at large scale.

Risk Stratification Models Overestimate Progression Risk in Contemporary Patients with Smoldering Multiple Myeloma (SMM)

Introduction: SMM is an asymptomatic precursor of multiple myeloma (MM), affecting ~1 in 200 people aged >40 years. Historically, risk of progression from SMM to MM was 10% per year in the first 5 years. However, since then, the definition and characteristics of the SMM patient population have changed substantially. First, IMWG diagnostic criteria for MM in 2014 changed to include biomarker-only myeloma (SLiM), reclassifying asymptomatic patients previously considered SMM. Second, incorporation of advanced imaging (CT, PET/CT, MRI) identified bone disease with greater sensitivity. Hence, we hypothesized that in the contemporary era, the risk of progression from SMM to MM would be markedly lower than historically. Methods: We performed a retrospective cohort study of consecutive patients with SMM at Columbia University Irving Medical Center from 2014-2022 and observed without therapeutic intervention. Our primary objective was to measure cumulative incidence of progression to MM and to characterize progression events. We also calculated predicted 2-year risk of progression by different risk-stratification models (Mayo 20/2/20, PANGEA, IMWG SMM model) in our cohort. Results: 102 consecutive patients with SMM were included. Median year of diagnosis was 2019 (range, 2014-2022). Baseline clinical and demographic characteristics of the cohort are shown in Table 1. The three most common scenarios that led to SMM diagnosis were workup of anemia/cytopenias(s) (n=22; 21.8%), incidental protein gap or elevated immunoglobulin level (n=20; 19.8%), and renal dysfunction (n=16; 15.8%). The racial/ethnic makeup of our study cohort was 38% Hispanic/Latino, 38% Non-Hispanic White, 19% Black/African-American, and 5% Asian. Bone disease was ruled out by advanced imaging (whole body CT, PET/CT, WB-MRI, and/or MRI spine+ pelvis) in 81.2% of patients. The most common abnormality on FISH was hyperdiploidy (39.2%), followed by t(11;14) (22.1%), with ≥1 high-risk cytogenetic abnormality (HRCA) in 35% of patients. Median follow-up was 45 months (95% CI, 34-52). 22/102 patients (21.6%) progressed to symptomatic plasma cell dyscrasia: CRAB myeloma in 18, SLiM myeloma in 1, systemic AL amyloidosis in 3 patients. The cumulative incidence of progression to MM (CRAB/SLiM) at 1, 2, 3, and 4 years from SMM diagnosis was 3.1% (95% CI, 0.99-9.1), 7.7% (95% CI, 3.7-15.3), 13.9% (95% CI, 8.1-23.1), and 17.1% (95% CI, 10.3-27.1) respectively [Figure 1]. Notably, presence of HRCA by FISH had a dose-dependent increase in risk of progression, with the 2-year risk being 75% (95% CI, 24-97%) in patients with ≥2 HRCA vs 13.0% (95% CI, 5.9-26.3) in those with 0-1 HRCA respectively ( p=0.0049). Among 18 patients who progressed to CRAB myeloma, the myeloma-defining event/s (MDEs) were anemia in 11, anemia + bone disease in 4, and bone disease in 3 patients. Among patients with a bone disease MDE, 4/7 had >1 lytic lesions on imaging and 3 had vertebral compression fracture(s). No patient had renal insufficiency or hypercalcemia as MDE. The sole patient with SLiM had a serum free light chain ratio>100 as the only MDE. 13/102 patients (12.75%) died, with 4/13 deaths attributed to myeloma after disease progression. The predicted median 2-year risk of progression to MM with different risk-stratification models were as follows: PANGEA with Bone Marrow (BM): 5.75% (range, 1.2-42); PANGEA without BM: 4.6% (0.7-26.6); Mayo 20/2/20: 9.7% (9.7-47.4); IMWG SMM: 26% (3.8-73). Figure 2 shows Sankey diagram of predicted risk tertiles for patients at SMM diagnosis by different models. Notably, a substantial proportion of high-risk patients by 20/2/20, who are currently considered for therapeutic intervention, were re-assigned to intermediate risk (2-year risk of progression 8.1-20%) by PANGEA-BM. Conclusion: The risk of progression to MM among this cohort of contemporary patients with SMM is <5% per year for the 1 st 4 years, which is substantially lower than the historical rate of 10% per year. Morbid progression such as renal failure or fractures are very infrequent, with anemia being the most common MDE. Prospective studies testing active surveillance strategies are needed in contemporary SMM cohorts to determine the optimal approach to these patients and ensure balancing of potential risks and benefits of treatment.

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.

Trial in Progress: A Phase 2 Study of Linvoseltamab for the Treatment of High-Risk Smoldering Multiple Myeloma (LINKER-SMM1)

Background and Significance Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder that precedes the development of multiple myeloma (MM). Traditionally, patients with SMM have undergone observation until progression to MM, but this paradigm can result in poor outcomes for some patients. Phase 3 clinical trials have demonstrated that early treatment with lenalidomide with or without dexamethasone can delay the development of end-organ damage and improve overall survival among SMM patients with high-risk features. Linvoseltamab (REGN5458) is a fully human B-cell maturation antigen (BCMA)×CD3 bispecific antibody that targets BCMA on plasma cells and CD3 on T cells, resulting in targeted T-cell-mediated cytotoxicity. In the Phase 1/2 LINKER-MM1 study, linvoseltamab alone induced deep and durable responses with a generally manageable safety profile in patients with relapsed/refractory MM (Lee et al. EHA. 2023). These data highlight the potential of novel immunotherapies with promising single-agent activity to be attractive therapeutics for early intervention to prevent progression to MM. Study Design and Methods LINKER-SMM1 is an open-label, Phase 2 study (NCT05955508) designed to evaluate the safety and efficacy of linvoseltamab monotherapy in adult participants with SMM who are at a high risk of progression to MM. High-risk criteria include having both ≥95% clonal plasma cells in the bone marrow (BM) and immunoparesis and/or ≥2 of the following: serum M-protein >2 g/dL, free light chain ratio >20, and BM plasma cells >20%. Participants must have a confirmed diagnosis of SMM within 5 years of enrollment, Eastern Cooperative Oncology Group performance status ≤1, and adequate organ function to be eligible. Participants will be excluded from enrollment if they have myeloma-defining events, uncontrolled infection, history of allogeneic stem cell transplantation, or received prior treatment for SMM. The study will take place at approximately 15 sites in Spain and will include two parts: Part 1 (safety run-in) to evaluate the preliminary safety and tolerability of linvoseltamab and Part 2 (expansion) to evaluate the clinical activity of the selected dosing regimen. In Part 1, at least 6 participants will receive linvoseltamab starting with a step-up schedule before reaching the full dose. All subsequent treatment with full-dose linvoseltamab will be given over 28-day cycles until completion of 24 cycles or occurrence of a protocol-defined reason for discontinuation. Assuming that initial safety is shown to be acceptable, an additional 34 participants will be enrolled in Part 2 according to the dosing regimen established in Part 1. Post-treatment safety monitoring will continue for up to 90 days after the last dose of linvoseltamab, and participants with an ongoing response will continue routine efficacy assessments until confirmed biochemical progression, start of non-protocol cancer therapy, or death. Long-term follow-up will continue for up to 5 years after the last dose of linvoseltamab. The primary endpoints in Part 1 are frequency of adverse events (AEs) of special interest, including grade ≥2 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and frequency and severity of treatment-emergent AEs. In Part 2, the primary endpoints are complete response (assessed by International Myeloma Working Group criteria) and minimal residual disease (MRD) negativity (10 -5 sensitivity) after 12 and 24 months of treatment. Secondary endpoints include cumulative safety, overall response rate, duration of response, sustained MRD negativity, biochemical and clinical progression-free survival (PFS), time to myeloma-defining event, time to initiation of first-line treatment for MM, and overall survival as well as immunogenicity and serum concentration of linvoseltamab over time. Exploratory endpoints include PFS after the start of first-line treatment for MM, adequacy of stem cell collection, patient-reported outcomes, and various biomarker changes. As this is a proof-of-concept study, results will be analyzed using descriptive statistics and no formal hypothesis testing is planned. Study accrual is planned to begin in Q4 2023.

Survival of Patients with Multiple Myeloma Treated with Bortezomib-Based Triplets and Autologous Hematopoietic Stem Cell Transplant As First Line in Latin America

Background In transplant-eligible newly diagnosed multiple myeloma (NDMM), triplet combinations including proteasome-inhibitors and immunomodulators are the backbone of induction therapy before autologous stem cell transplant (ASCT). Post-ASCT maintenance with lenalidomide is the standard of care. This approach yields deep responses and long overall survival. In Latin America (LATAM) there is scarce data about the outcome of bortezomib-based triplets and ASCT. The aim of this study was to evaluate overall survival (OS) in Latin American transplant-eligible NDMM patients induced with bortezomib-based triplets and ASCT. Methods Retrospective international multicenter cohort study. Patients older than 18 years with MM, who received bortezomib-based triplets followed by ASCT as first line, between 2010 and 2022 were analyzed. Data were collected from clinical records in a standardized report form. We analyzed clinical characteristics at diagnosis and frontline therapy outcomes. Descriptive statistics were performed. Comparisons of characteristics between groups were made using the Chi-square test, Student´s T-test and ANOVA, as appropriate. Survival analysis was performed using Kaplan-Meier curves, comparisons between groups by Log Rank method, and calculations of the risk relationships by Cox regression. Statistical analysis was performed by using IBM SPSS version 25.0. Results A total of 279 patients with NDMM were included, 124 from Argentina, 20 from Chile, 30 from Mexico, 20 from Paraguay, 43 from Peru, 33 from Uruguay, and 9 from Venezuela. Median age was 57 years (range 29-75) with a male predominance (54.8%). Most patients (58%) were treated in private centers. 56.1% were IgG subtype, 24.8% IgA and 17.3% light chain MM. According to the ISS, 69.2% were classified as ISS II or III. Bone disease was the most frequent myeloma-defining events (75.9%), followed by anemia (61.4%), renal failure (24.2%), and hypercalcemia (20.1%). Fluorescence in situ hybridation (FISH) analysis was performed in 53.4% of patients (only 41% with plasma cell sorting), del17p was the most frequent anomaly found (17.4%), followed by t(4;14) (6%), and t(14;16) (2%). The most frequently used induction regimen was cyclophosphamide-bortezomib-dexamethasone (CyBorD) (38.7%), followed by bortezomib-thalidomide-dexamethasone (VTD) (33.7%), and bortezomib-lenalidomide-dexamethasone (VRD) (27.6%). Very good partial remission (VGPR) or better was achieved in 88.3% for VRD, 81.9% for VTD, and 76.8% for CyBorD (p=0.138). Median time from diagnosis to ASCT was 261.5 days. Only 7 patients received tandem ASCT as first-line consolidation. Maintenance treatment was administered to 88.2% of patients and was based on lenalidomide, thalidomide, bortezomib, and lenalidomide+bortezomib in 67.9%, 16.3%, 8.9% and 3.3%, respectively. Treatments and responses are shown in detail in Table 1. With a median follow-up of 45 months (range 7-140), median progression-free survival (PFS) was 33 months (95% CI, 26.7 - 39.3). Median PFS according to treatment was 21 months (95% CI, 14.3 - 27.7) for VRD, 35 months (95% CI, 22.2 - 47.8) for VTD, and 36 months (95% CI, 28 - 44) for CyBorD, p=0.004. Median OS of the whole cohort was not reached (NR), and 86% at 45 months; 75 months for VRD (95% CI, 44 - 106), and NR for CyBorD and VTD (p=0.284) (Figure 1). In the multivariate analysis hypercalcemia (p=0.01) and extramedullary disease (p=0.03) were the only independent risk factors. Discussion FISH was performed only in half of our patients, and the majority without plasma cell sorting. The main used regimen was CyBorD. Although better PFS was obtained with CyBorD, no significant differences in responses or OS were found between VRD, VTD or CyBorD. The reason why VRD PFS and OS were lower merits further study. We report a high rate of maintenance treatment.

Different Translocations of Multiple Myeloma on Fluorescent In Situ Hybridization (FISH) with Clinical Correlation.

To evaluate the association of chromosomal translocations in multiple myeloma (MM) detected by Fluorescent In Situ Hybridization (FISH) and its clinical characteristics. Cross-sectional study. Place and Duration of the Study: Department of Haematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi, Pakistan, from February to August 2022. A total of 40 cases of MM were included. All cases were diagnosed using international myeloma working group (IMWG) criteria. Clinical presentations like bone pain, backache, fatigue, pallor, and weight loss were noted. The workup for myeloma-defining events was done. FISH analysis was done for t (4;14), t (11,14), t (14;16), t (14;20), and del 17p. Data were analysed using the chi-square test. A p-value ≤0.05 was considered statistically significant. Out of 40 patients, 8 (20%) were females and 32 (80%) were males. The highest frequency of cases were noted among males in the age group >60 years and females in the age group 40-60 years. FISH for t (4;14) was positive in 22 (55%) patients, for t (11;14) was positive in 4 (10%) patients, for t (14;16) was positive in 3 (7.5%) patients, and for t (14;20) was positive in 3 (7.5%) patients, while for del17p was positive in 8 (20%) patients. Cases with t (4;14), t (11;14), and t (14;20) had bone pain, fatigue, and backache as the most common presentations. Among the various parameters studied, lytic lesions, beta-2 microglobulin, spike protein, deranged haemoglobin, TLC, ESR, albumin, and creatinine were significant risk factors in patients who were tested positive for various mutations. The FISH technique has brought an immense uprising in the genetic analysis of MM. Among translocations, t (4;14) and del17p are associated with poor clinical outcomes and prognosis. If the diagnosis of MM is delayed, then an increase in morbidity and mortality can occur. Multiple myeloma, FISH, Translocations.

Prevalence of smoldering multiple myeloma based on nationwide screening.

Smoldering multiple myeloma (SMM) is an asymptomatic precursor to multiple myeloma. Here we define the epidemiological characteristics of SMM in the general population in Iceland. The iStopMM study (ClinicalTrials.gov ID: NCT03327597 ) is a nationwide screening study for multiple myeloma precursors where all residents in Iceland 40 years or older were invited to participate. SMM was defined as 10-60% bone marrow plasma cells and/or monoclonal (M) protein concentration ≥3 g dl-1, in the absence of myeloma-defining events. Of the 80,759 who gave informed consent to participate, 75,422 (93%) were screened. The prevalence of SMM in the total population was 0.53% (95% confidence interval (CI) = 0.49-0.57%) in individuals 40 years or older. In men and women, the prevalence of SMM was 0.67% (95% CI = 0.62-0.73%) and 0.39% (95% CI = 0.35-0.43%), respectively; it increased with age in both sexes. For the 193 individuals with SMM, median age was 70 years (range 44-92 years) and 60% were males. The mean M protein concentration of individuals with SMM was 0.62 g dl-1 (range 0.01-3.5 g dl-1) and 73% had 11-20% bone marrow plasma cell infiltration. The high prevalence of SMM has implications for future treatment policies in multiple myeloma as the evidence supporting treatment initiation at the SMM stage is emerging.

Distinct phenotype of neutrophil, monocyte, and eosinophil populations indicates altered myelopoiesis in a subset of patients with multiple myeloma.

Hematologic malignancies, including multiple myeloma (MM), promote systemic immune dysregulation resulting in an alteration and increased plasticity of myeloid cell subsets. To determine the heterogeneity of the myeloid cell compartment in the peripheral blood of patients with MM, we performed a detailed investigation of the phenotype and function of myeloid subpopulations. We report that a subset of MM patients exhibits a specific myeloid cell phenotype indicative of altered myelopoiesis characterized by significant changes in the properties of circulating granulocytic, monocytic, and eosinophilic populations. The subset, referred to as MM2, is defined by a markedly elevated level of CD64 (FcγRI) on the surface of circulating neutrophils. Compared to healthy controls or MM1 patients displaying intermediate levels of CD64, neutrophils from MM2 patients exhibit a less differentiated phenotype, low levels of CD10 and CXC chemokine receptor 2 (CXCR2), increased capacity for the production of mitochondrial reactive oxygen species, and an expansion of CD16neg immature neutrophil subset. Classical and patrolling monocytes from MM2 patients express elevated levels of CD64 and activation markers. MM2 eosinophils display lower levels of C-C Chemokine receptor 3 (CCR3), Toll-like receptor 4 (TLR4, CD284), and tissue factor (TF, CD142). The MM2 (CD64high) phenotype is independent of age, race, sex, and treatment type. Characteristic features of the MM2 (CD64high) phenotype are associated with myeloma-defining events including elevated involved/uninvolved immunoglobulin free light chain (FLC) ratio at diagnosis. Detailed characterization of the altered myeloid phenotype in multiple myeloma will likely facilitate the identification of patients with an increased risk of disease progression and open new avenues for the rational design of novel therapeutic approaches.

The consultant's guide to smoldering multiple myeloma.

Smoldering multiple myeloma (SMM) is an asymptomatic precursor condition to multiple myeloma (MM). The prevalence of SMM is 0.5% in persons over 40 years old; it is higher in men than women and increases with age. When SMM is diagnosed, a thorough diagnostic workup is necessary to exclude myeloma-defining events and stratify patients according to risk of progression to MM. While close monitoring for progression remains the best management for most patients with SMM, in this article, we discuss if treatment initiation before myeloma-defining events occur might be relevant in selected high-risk cases. Two randomized clinical trials have shown a clinical benefit of initiating treatment at the SMM stage, whereof 1 showed an overall survival benefit for those receiving treatment. We discuss various risk stratification models in SMM, important treatment trials, and ongoing trials. Finally, we present how to approach the clinical management of patients with SMM.

Evidence Supporting Light Chain Cast Nephropathy As a Myeloma Defining Event

BACKGROUND In 2014, the International Myeloma Working Group (IMWG) revised the Renal involvement of the CRAB (hyperCalcemia, Renal, Anemia, Bone lesions) criteria for the diagnosis of multiple myeloma (MM) as an acute decline in kidney function represented by either a serum creatinine (Scr) > 2 mg/dl or an estimated glomerular filtration rate of < 40 ml/min/1.73 m2 secondary to light chain cast nephropathy (LCCN) biopsy proven or suspected. Since LCCN occurs only in patients with high serum free light chain (FLC) levels, a high tumor burden is presumed but how often it occurs with other myeloma defining events (MDE) is unknown. METHODS Patients were selected from 2 cohorts. The first cohort came from a multicenter study on LCCN who were all diagnosed with MM between 2000 and 2018. Only newly diagnosed patients were included in this study. A second cohort was identified from the Mayo Clinic Kidney Biopsy database from 2003 to 2013. Inclusion criteria of this cohort were: the LCCN must be the dominate pathology on the kidney biopsy and it is secondary to a plasma cell proliferative disorder. Laboratory and radiologic data were collected to assess for CRAB criteria. Bone lesions were assessed by standard skeletal X-ray, MRI or CT/PET. Most had skeletal X-ray. The new SLiM CRAB criteria which have the addition 3 biomarkers: (S) >60% bone marrow plasma cells, (Li) an involved to uninvolved free light chain (FLC) ratio > 100 and (M) >1 bone lesion on MRI were also assessed. RESULTS From the multicenter study, 28 patients were excluded for having relapsed MM and 27 were from Mayo who were included in the second cohort leaving 123 patients. In the Mayo cohort, 52 patients were identified who met criteria. Both cohorts were comparable in age, sex, bone marrow plasma cells and hemoglobin at diagnosis (Table 1). Interestingly, 3.3% of the multicenter cohort and 3.9% of the Mayo cohort did not meet the R criterion due to a presenting creatinine of ≤ 2.0 mg/dl. In the multicenter cohort 2/99 (2.0%) and 4/52 (7.7%) of the Mayo cohort had < 10% bone marrow plasma cells. The presenting involved FLC was higher in the multicenter group (p = 0.001). In the multicenter cohort, 99.1% met at least one of the SLiM criteria and 84.7% met one the C,A,B criteria. In the Mayo cohort, fewer patients met at least one of the SLiM criteria (86.5%, p < 0.001) but more patients met one or more of the C,A,B criteria (98.1%, p = 0.01). All but 1 patient from the multicenter cohort met one or more of the SliM C,A,B criteria. The most common SLiM criteria met in the multicenter cohort was Li while it was M in the Mayo cohort. The most common C,A,B criteria in the multicenter cohort was A while it was B in the Mayo cohort. DISCUSSION This study provides the first evidence that nearly all patients who present with biopsy proven LCCN have at least one other MDE. Bone marrow burden was met in 98.0% of the multicenter cohort where all patients were diagnosed with MM, 92.3% of the Mayo cohort where the diagnosis of MM was not a prerequisite. More importantly, 84.7% and 98.1% of patients from the 2 cohorts respectively had another MDE besides LCCN confirming that LCCN is associated with high tumor burden. All but 1 patient would have been diagnosed with MM based on the SLiM CRAB criteria. In comparison to patients with other kidney lesions associated with monoclonal immunoglobulin, generally only 20-30% met the CRAB criteria for MM. This is why it is more appropriate to classify those patients as having monoclonal gammopathy of renal significance while patients with LCCN should be diagnosed with MM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effect of a 6-Week Cycle of Nordic Walking Training on Vitamin 25(OH)D3, Calcium-Phosphate Metabolism and Muscle Damage in Multiple Myeloma Patients-Randomized Controlled Trial.

Multiple myeloma (MM) is a hematological malignancy affecting older adults. One of the most common myeloma-defining events is the development of symptomatic lytic bone disease. The serum concentrations of calcium (Ca), inorganic phosphorus (P), and vitamin 25(OH)D3 in the serum reflect bone metabolism. An enzyme lactate dehydrogenase (LDH) is a marker of muscle damage, but its serum activity also has an important prognostic value in MM. Myoglobin (Mb) is a small protein present in muscles; its serum level increases when myocytes are damaged. In this study, the impact of a 6-week Nordic walking (NW) exercise program on blood parameters related to calcium-phosphate metabolism and damage of skeletal muscles was assessed. A total of 33 patients with MM in the remission stage, without cytostatic treatment, were allocated and randomly assigned to one of two groups: 17 in the training group (NW) and 16 in the control group (CG). All patients were supplemented per os with vitamin D3 and calcium carbonate daily and received zoledronic acid every 4 weeks (intravenous). Nordic walking training sessions took place 3 times a week for 6 weeks, 1 h each. Blood samples were drawn before and after the 6 weeks of training sessions to assess the serum concentrations of vitamin 25(OH)D3, P, Ca, Mb, and LDH. Patients from the NW group showed a statistically significant decrease in mean serum myoglobin concentration (p = 0.018) and an increase in 25(OH)D3 (p &lt; 0.001) and total Ca (p = 0.001) concentrations. There were no statistically significant changes in the results obtained in CG. Between groups, after 6 weeks, Mb serum concentration was significantly lower in NW (p = 0.041), and 25(OH)D3 was higher (p &lt; 0.001) compared to CG. There was a correlation between the changes in myoglobin, phosphorus, 25(OH)D3, and Ca concentrations after 6 weeks. NW training is a safe and beneficial form of physical exercise for patients with MM without inducing muscle damage. NW performed outside improves serum vitamin 25(OH)D3 concentration.

How I approach smoldering multiple myeloma

AbstractThe current standard of care in smoldering multiple myeloma (SMM) is close surveillance, outside of clinical trials. Efforts are being made to understand the pathobiologic process that leads to the progression of SMM to active MM. This review provides a critical description of available data, including risk factors and risk models of progression, as well as clinical trials investigating interventions for this patient population. We describe 2 cases in which patients were seen before the concept of a myeloma-defining event was established. Today, based on the International Myeloma Working Group criteria, both patients would have been identified as experiencing myeloma-defining events, and therapy would have been initiated. These cases show that occasionally, patients can undergo observation only, even when they exceed criteria for high-risk SMM.

Curative Strategy (GEM-CESAR) for High-Risk Smoldering Myeloma (SMM): Carfilzomib, Lenalidomide and Dexamethasone (KRd) As Induction Followed By HDT-ASCT, Consolidation with Krd and Maintenance with Rd

Curative Strategy (GEM-CESAR) for High-Risk Smoldering Myeloma (SMM): Carfilzomib, Lenalidomide and Dexamethasone (KRd) As Induction Followed By HDT-ASCT, Consolidation with Krd and Maintenance with Rd

BRAF Mutations and Inflammatory Gene Expression in Myeloma Cells from Patients with Renal Dysfunction

BRAF Mutations and Inflammatory Gene Expression in Myeloma Cells from Patients with Renal Dysfunction