While observation is the current standard of care for smoldering multiple myeloma (sMM), emerging evidence suggests that early therapeutic intervention may delay progression and improve outcomes especially for high-risk patients. A systematic review and meta-analysis of randomized clinical trials was performed according to the PRISMA guidelines in order to evaluate the effect of treatment compared to observation in outcomes of patients with sMM. Five studies (7 articles) involving 844 patients with intermediate or high risk sMM and comparing treatment to observation or placebo were deemed eligible. All studies reported progression-free survival results, with progression defined as time to active myeloma (without high heterogeneity, I2 = 42%, p = 0.14). A statistically significant 60% reduced pooled risk for disease progression or death (HR = 0.40, 95%CI:0.29-0.55) was revealed for patients who underwent treatment compared to those who did not. An exploratory sensitivity analysis involving 3 trials with only observation in the control group, revealed a 66% lower risk for disease progression or death (HR = 0.34, 95%CI: 0.21-0.56) for patients in the treatment group compared to the control group. Furthermore, time-to-progression was reported in 3 studies; the pooled effect estimate revealed a statistically significant 58% reduced risk for progression to symptomatic MM (HR = 0.42, 95%CI: 0.29-0.61) for patients who underwent treatment compared to those who did not. Only 2 trials reported mature overall survival outcomes, and the pooled effect estimate showed a 45% lower risk for death (HR = 0.55, 95%CI: 0.37-0.82) for sMM patients who received treatment compared to those on observation. Regarding safety, the odds for serious adverse events for those on treatment was as 3.5 times as high (OR = 3.53, 95%CI: 1.14-10.91) compared to those on observation or placebo. In conclusion, this meta-analysis highlights the significant benefits of early treatment in selected patients with sMM, across key clinical outcomes. However, close monitoring is essential for the management of treatment-related toxicities.

Reliable strategies to capture patients at risk of progression from precursor stages of multiple myeloma (MM) to overt disease are still missing. We assembled a comprehensive collection of MM genomic data comprising 1,030 patients (218 with precursor conditions) that we used to identify recurrent coding and non-coding candidate drivers as well as significant hotspots of structural variation. We used those drivers to define and validate a simple 'MM-like' score, which we could use to place patients' tumors on a gradual axis of progression toward active disease. Our MM precursor genomic map provides insights into the time of initiation and cell-of-origin of the disease, order of acquisition of genomic alterations and mutational processes found across the stages of transformation. Taken together, we highlight here the potential of genome sequencing to better inform risk assessment and monitoring of MM precursor conditions.

The signaling lymphocytic activation molecule family (SLAMF) consists of nine distinct cell surface receptors predominantly expressed on immune cells, each characterized by unique structural features, expression patterns, downstream signaling pathways, and biological functions. These receptors play critical roles in modulating various immune cell activities within the tumor microenvironment, thereby shaping immune responses in cancer. Although accumulating evidence demonstrates their value as therapeutic targets for developing cancer immunotherapies, the full spectrum of SLAMF receptors in cancer remains incompletely understood. This review aims to provide a comprehensive overview of the molecular characteristics and immunomodulatory functions of each SLAMF receptor, underscoring their pivotal contributions to cancer progression. Furthermore, we also highlight their potential as promising targets for advancing cancer immunotherapeutic strategies. Finally, we discuss clinical trials evaluating the efficacy and safety of SLAMF receptor-based immunotherapies, emphasizing their translational relevance in the development of cancer treatments.

Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved.

In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria.

Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified.

Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.).

Serum-free light-chain assays are important in the diagnosis and in monitoring therapeutic responses of plasma cell disorders and are complementary to serum protein electrophoresis. The serum-free light-chain assay detects the light-chain portion of immunoglobulin in its free form with high sensitivity. In combination with serum protein electrophoresis and serum immunofixation electrophoresis, the free light-chain assay serves an important role in predicting disease progression in monoclonal gammopathy. Here, we compare the performance of a cartridge-based system Mispa i3 using Diazyme reagent in comparison to Roche Cobas using Freelite reagent. Both of these reagents use polyclonal antibodies for the detection of serum-free light chains. Mispa i3 is a cartridge-based protein analyzer and has a unique channel shifting technology with both turbidimetric and nephelometric principles for immuno assays. Samples of 196 patients were included in this study, and very good agreement was observed between these two assays. Our data show that even though discrepancies were observed for high concentration samples, they are clinically correlated by the free light-chain ratios. We observed a very good concordance of 89% between these two assays for free light-chain ratios.

To establish an advanced automated bone marrow (BM) segmentation model on whole-body (WB-)MRI in monoclonal plasma cell disorders (MPCD), and to demonstrate its robust performance on multicenter datasets with severe myeloma-related pathologies.

The study cohort comprised multi-vendor, multi-protocol imaging data acquired with varying field strength across 8 different centers. In total, 210 WB-MRIs of 207 MPCD patients were included. An nnU-Net algorithm was established for segmenting the individual bone marrow spaces (BMS) of the spine, pelvis, humeri and femora (advanced segmentation model). For this task, 186 T1-weighted (T1w) WB-MRIs from center 1 were used in the training set. Test sets included 12 T1w WB-MRIs from center 2 (I) and 9 T1w WB-MRIs from centers 3-8 (II). Example cases were included to showcase segmentation performance on T1w WB-MRIs with extensive tumor load. The segmentation accuracy of the advanced segmentation model was compared to a prior established basic segmentation model by calculating Dice scores and using the Wilcoxon signed-rank test.

The mean Dice score on the individual BMS was 0.89±0.13 (test set I) and 0.88±0.11 (test set II), significantly higher than the Dice scores of a prior basic model (p<0.05). Dice scores for the BMS of the individual bones ranged from 0.77 to 0.96 (test set I), and 0.81 to 0.95 (test set II). BM altered by myeloma-relevant pathologies, artifacts or low imaging quality was precisely segmented.

The advanced model performed reliable, automated segmentations, even on heterogeneously acquired multicenter WB-MRIs with severe pathologies.

Early intervention in smoldering multiple myeloma (SMM) may delay progression to MM. Here, we present the final analysis of the phase 2 CENTAURUS study. In total, 123 patients with intermediate/high-risk SMM were randomized to IV daratumumab 16 mg/kg after a long-intense (n = 41), intermediate (n = 41), or short-intense (n = 41) dosing schedule. At a combined median follow-up of 85.2 months, in the long-intense, intermediate, and short-intense arms complete response or better rates were 4.9%, 9.8%, and 0%; overall response rates were 58.5%, 53.7%, and 37.5%; progressive disease/death rates were 0.096, 0.102, and 0.109 (P < .0001 for all arms); and median progression-free survival was not reached, 84.4, and 74.1 months, respectively. Median overall survival was not reached in any arm. Thirty-six patients in the long-intense or intermediate arms continued daratumumab in an optional extension phase after completing 20 cycles of per-protocol treatment. The median duration of study treatment was 44.0 (range, 1.0-91.6), 35.2 (range, 1.9-90.6), and 1.6 (range, 0.1-1.9) months in the long-intense, intermediate, and short-intense arms, respectively. No new safety signals were observed. With extended follow-up (median, ∼7 years), these data highlight the tolerability of daratumumab and support ongoing trials investigating daratumumab as an early intervention for SMM. This trial was registered at www.ClinicalTrials.gov as #NCT02316106.

Smoldering multiple myeloma (SMM) represents an intermediate stage between monoclonal gammopathy of undetermined significance and symptomatic multiple myeloma (MM), with a significant risk of progression. Bone disease is a key feature of MM, often marking the transition to symptomatic disease. Whole-body low-dose computed tomography (WBLDCT) is an easily accessible and highly sensitive imaging modality for detecting osteolytic lesions, providing an advantage over conventional skeletal surveys. In our real-world cohort, we prospectively evaluated the role of WBLDCT in the early identification of bone progression in patients with SMM based on the recommendations by the International Myeloma Working Group. A total of 113 patients were monitored with annual WBLDCT assessments; 36.3% progressed to symptomatic MM, with 9.7% progressing solely with bone lesions, highlighting the importance of early detection. Therefore, integrating annual WBLDCT assessments into clinical practice for SMM patients is essential to facilitate treatment strategies and prevent disease-related complications. This is even more important in the upcoming era of early treatment initiation for patients with SMM at high risk for progression.

Monoclonal gammopathy of undetermined significance (MGUS) is the most common type of plasma cell disorder, characterized by clonal proliferation of plasma cells in the bone marrow, a mild increase in monoclonal protein (M protein), and no organ damage. Smoldering multiple myeloma (SMM) is a plasma cell disease that lies between MGUS and active multiple myeloma (AMM), featuring elevated levels of M protein in the plasma and increased plasma cell infiltration in the bone marrow, but without typical clinical manifestations. SMM is considered as a precursor state to AMM. This consensus was jointly developed by the Plasma Cell Disease Group, Chinese Society of Hematology, Chinese Medical Association and the Chinese Myeloma Committee-Chinese Hematology Association, covering the epidemiological characteristics, clinical manifestations, testing and examination, diagnostic criteria, differential diagnosis, prognosis assessment, and patient management strategies for MGUS and SMM. The consensus aims to provide standardized guidance for the comprehensive management of MGUS and SMM, ensuring timely monitoring of disease progression and intervention at the appropriate time to improve the quality of life and survival rates of patients.

The management of multiple myeloma (MM) is becoming increasingly more complex. The approval of novel treatment approaches provides much-needed opportunities but also raises questions and controversies about how to optimally sequence therapies and select treatments for individual patients.

A panel of experts assembled to discuss current controversies in the care of patients with MM across the disease continuum. Workshop topics included: management of smoldering MM; treatment selection for transplant-eligible and transplant-ineligible patients; risk assessment and the possibility of risk-adapted treatment; use of measurable residual disease (MRD) as a clinical trial end point and to guide treatment decisions; management of early relapse; management of triple class-refractory MM; treatment sequencing; and novel therapies.

Many controversies remain regarding the management of patients with MM related to risk assessment, treatment selection and sequencing, and the optimal use of current therapies while balancing efficacy, toxicity, patient considerations, and treatment logistics. Ongoing research efforts are needed to further define the optimal use of current therapies and to develop more efficacious therapies for all patients and for particular subset populations with unmet need.

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are premalignant stages in the development of multiple myeloma (MM). Advances in detection, risk stratification, and therapeutic intervention have transformed our understanding of disease progression. Sensitive techniques like mass spectrometry have identified smaller monoclonal gammopathies, such as monoclonal gammopathy of indeterminate potential (MGIP), which may precede MGUS. Risk stratification models for MGUS and SMM, including the Mayo Clinic, PETHEMA, 2/20/20, IMWG, and PANGEA models, leverage tumor burden markers and cytogenetic abnormalities to predict prognosis. Genomic studies have revealed mutations, structural changes, and mutational signatures that predict progression. Immune microenvironmental alterations underscore the multifactorial nature of disease evolution, while epigenetics is emerging as a source of tumoral and microenvironmental changes. Therapies for high-risk SMM, including lenalidomide, daratumumab, and next-generation immunotherapies, demonstrate efficacy in delaying progression to MM but raise concerns regarding safety in asymptomatic patients. Future research must refine prognostic models, integrate genomic and immunophenotypic data, and establish consensus on optimal strategies for early intervention. This comprehensive review highlights the biological, clinical, and therapeutic advancements in MM and its precursors, emphasizing the importance of early risk assessment and targeted treatment to improve outcomes.

Detection of light chain (LC) monoclonal gammopathies (MGs) traditionally relies on serum free LC (FLC) κ, λ, and their ratio (κ/λ) reference ranges based on a mostly White population. We investigated FLC values in a racially diverse population by screening 10 035 individuals for heavy chain MG, identifying 9028 negative cases whose FLC were measured. Participants included 4149 from the PROMISE study (United States, n = 2383; South Africa, n = 1766) and 4879 from the Mass General Brigham Biobank, with 44% self-identifying as Black. Using standard FLC reference ranges, 1074 of 10 035 individuals (10.7%) were diagnosed with LC monoclonal gammopathy of undetermined significance (MGUS), with 99% being κ-restricted. In the United States, 14.8% of Black and 4% of White individuals were diagnosed (P < .01). Among US participants of African (AFR) and European (EUR) genetic ancestry, 14.4% AFR and 2.9% EUR were diagnosed (P < .01). Among South Africans (100% Black), 27.8% were diagnosed using standard ranges. To avoid overdiagnosis, we propose a new κ/λ ratio reference range (0.686 to 2.10) for populations of AFR descent with normal renal function, with standard values for κ and λ being 7.97 to 77.50 mg/L and 6.20 to 49.20 mg/L, respectively. This reduces LC-MGUS overdiagnosis by 91% (10.7% vs 0.97%). Using the new reference, LC-MGUS accounts for 8.8% of MGUS cases, with 74% being κ-restricted, consistent with LC myeloma rates. These findings highlight the importance of basing disease definitions, such as MGUS, on diverse populations. Adopting our proposed FLC reference values would reduce MGUS overdiagnosis among Black individuals, avoiding unnecessary financial, psychological, and medical consequences. This study includes data from NCT03689595.

Fatty infiltration of skeletal muscle (Myosteatosis) is associated with increased frailty, decreased muscle and mobility function, which seems fairly prevalent in multiple myeloma (MM) patients. This study aimed to determine the prognostic value of myosteatosis assessed by CT for progression-free survival (PFS) and overall survival (OS).

This IRB-approved cohort study included patients with newly diagnosed MM who were treated at a single university hospital and received CT at baseline. Geriatric assessment was performed via International Myeloma Working Group frailty score and Revised Myeloma Comorbidity Index. Myosteatosis was determined through measurement of paravertebral muscle radiodensity. Statistical analyses included uni- and multivariable Cox proportional hazard models and the Kaplan-Meier-method.

A total of 226 newly diagnosed MM patients (median age: 65 years [range: 29-89], 63% males, mean BMI: 25 [14-42]) were analyzed. The prevalence of myosteatosis was 51%. Muscle radiodensity was significantly decreased in individuals with International Staging System stage III vs. I (p < 0.001), indicating higher fatty muscle infiltration in patients with advanced disease. Both PFS and OS were significantly decreased in patients with myosteatosis (PFS: median 32.0 months (95% CI 20.5.5-42.2) vs. 66.4 months without myosteatosis (95% CI 42.5-not reached), p < .001); OS: median 58.6 (95% CI 51.3-90.2) vs. not reached, p < .001). Myosteatosis remained an independent predictor of OS in multivariable analyses (HR: 1.98; 95%-CI: 1.20-3.27).

Myosteatosis seems fairly prevalent in patients with newly diagnosed MM and associated with impaired overall survival. Prospective clinical trials are required to better understand the role of myosteatosis in MM patients.

Paraproteinemic neuropathies represent an important subset of peripheral neuropathies. Once identified, further evaluation into the paraproteinemic subtype, clinical exam pattern, and electrodiagnostic phenotype helps clarify if the paraproteinemia is coincidental or causal of the neuropathy, as not all paraproteinemias cause neuropathy. Of all paraproteinemias, immunoglobulin M (IgM)-associated peripheral neuropathy, or IgM neuropathy, is of particular importance as half of IgM neuropathies also harbor anti-myelin-associated glycoprotein antibodies, which produce a characteristic demyelinating pattern on nerve conduction testing. Immunoglobulin G and immunoglobulin A paraproteinemias are less strongly associated with peripheral neuropathy, except in the setting of multiple myeloma or osteosclerotic myeloma (POEMS syndrome), which have characteristic systemic features. In multiple myeloma, chemotherapy is more likely to result in neuropathy than the myeloma itself. Finally, the presence of systemic features (e.g., cardiomyopathy, nephropathy, recurrent carpal tunnel syndrome, and autonomic insufficiency) should raise concern for hereditary or acquired light (AL) chain amyloidosis. AL amyloidosis can occur in the setting of any light or heavy chain paraproteinemia. Central to the proper evaluation of paraproteinemic neuropathy is electrodiagnostic testing, which helps delineate axonal versus demyelinating paraproteinemic neuropathy, the latter often misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy.

Smoldering multiple myeloma (SMM) was first described over 40 years ago yet much is still unknown including which patients will ultimately progress to symptomatic multiple myeloma (MM). The genetics of the premalignant clone and the immune microenvironment in which it exists is now well understood to both play a role in disease progression. However, the clinical risk models available to help identify patients at most risk of progression still rely primarily on data reflecting volume of disease rather than underlying biology. While it is of upmost importance to accurately diagnose patients with SMM to avoid over or under treatment, efforts are ongoing to tease out if early intervention is indeed warranted for a subgroup of patients with SMM. This article will review the history and biology of SMM, discuss the utility of existing risk models, and examine the efforts to date which have challenged standard management.

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), the asymptomatic precursors to multiple myeloma, affect up to 5% of the population over the age of 40. Bone involvement, a myeloma-defining event, represents a major source of morbidity for patients. Key goals for the management of myeloma precursor conditions include (1) identifying patients at the highest risk for progression to MM with bone involvement and (2) differentiating precursor states from active myeloma requiring treatment. Computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET)-CT with [18F]fluorodeoxyglucose (FDG) have improved sensitivity for the detection of myeloma bone disease compared to traditional skeletal surveys, and such advanced imaging also provides this field with better tools for detecting early signs of progression. Herein, we review the data supporting the use of advanced imaging for both diagnostics and prognostication in myeloma precursor conditions.

Early therapeutic intervention in high-risk smoldering multiple myeloma (HR-SMM) has shown benefits, however, no studies have assessed whether biochemical progression or response depth predicts long-term outcomes. The single-arm I-PRISM phase II trial (NCT02916771) evaluated ixazomib, lenalidomide, and dexamethasone in 55 patients with HR-SMM. The primary endpoint, median progression-free survival (PFS), was not reached (NR) (95% CI: 57.7-NR, median follow-up 50 months). The secondary endpoint, biochemical PFS, was 48.6 months (95% CI: 39.9-NR) and coincided with or preceded SLiM-CRAB in eight patients. For additional secondary objectives, the overall response rate was 93% with 31% achieving complete response (CR) and 45% very good partial response (VGPR) or better. CR correlated strongly with the absence of SLiM-CRAB and biochemical progression. MRD-negativity (10-5 sensitivity) predicted a 5-year biochemical PFS of 100% versus 40% in MRD-positive patients (p = 0.051), demonstrating that deep responses significantly improve time to progression. Exploratory single-cell RNA sequencing linked tumor MHC class I expression to proteasome inhibitor response, and a lower proportion of GZMB+ T cells within clonally expanded CD8+ T cells associated with suboptimal outcomes.

Light-chain (LC) monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and related conditions. LC-MGUS is characterized by free light-chain (FLC) levels outside defined reference intervals, indirectly indicating underlying plasma cell (PC) monoclonality. Next-generation flow cytometry (NGF) was used to evaluate clonal PC presence in bone marrow (BM) samples from individuals with LC-MGUS in the iStopMM study, aiming to assess the predictive value of the FLC ratio for clonal PC presence and its prognostic implications. BM samples from 61 individuals with LC monoclonal gammopathy were analyzed. Clonal plasma cells were detected in 53.6% of LC-MGUS samples (n = 28) and in all samples from individuals with more advanced conditions (n = 33). The FLC ratio was predictive of clonal PC presence for kappa-involved FLC ratios (p < 0.05; n = 42), with an optimal cutoff of 3.15 (96.7% sensitivity, 91.7% specificity). Of 195 individuals with kappa-involved LC-MGUS in follow-up within the iStopMM study, none with FLC ratios >1.65 to 3.15 progressed to MM (n = 124), whereas 4/71 (5.6%) with FLC ratios >3.15 progressed over median follow-up of 55 months. These findings support using a kappa-involved FLC ratio cutoff of >3.15 to more accurately identify individuals at increased risk of developing symptomatic PC disorders.

Smoldering multiple myeloma (SMM) patients are a heterogeneous group with variable prognosis. A subset of SMM patients have a higher risk of progressing to multiple myeloma (MM) within 2 years. The definition of high-risk patients is not consistent among different risk models, and the combination of various biomarkers and new technologies improves the predictive performance of risk models. In clinical research, different risk models are often combined and applied. New drugs for treating MM are gradually being applied in the treatment of high-risk SMM. Single or dual drug therapy prolongs the progression free survival of patients, but most studies have not yet shown an overall survival benefit for patients. Multi drug combination and intensive treatment can achieve deep relief in high-risk SMM, but most of the studies are single arm studies, which are not yet sufficient to prove that multi drug treatment is more effective than lower intensity treatment. Further exploration of treatment plans for high-risk SMM patients is still needed. This article reviews the progress in risk stratification and treatment of high-risk SMM.

Significant progress has been made in the treatment of multiple myeloma (MM), with the introduction of several new drugs with different mechanisms of action. The treatment of newly diagnosed MM has evolved dramatically with the development of highly effective combinations that include 1 or more of the new drugs. Despite the continuing improvement in the overall survival of patients with MM, nearly a quarter of the patients have significantly inferior survival, often driven by a combination of factors, including tumor genetics and host frailty. The focus of initial therapy remains rapid control of the disease with reversal of the symptoms and complications related to the disease with minimal toxicity and a reduction in early mortality. The selection of the specific regimen, to some extent, depends on the ability of the patient to tolerate the treatment and the underlying disease risk. It is typically guided by results of randomized clinical trials demonstrating improvements in progression-free and/or overall survival. While increasing risk calls for escalating the intensity of therapy by using quadruplet combinations that can provide the deepest possible response and the use of autologous stem cell transplant, increasing frailty calls for a reduction in the intensity and selective use of triplet or doublet regimens. The choice of subsequent consolidation treatments and maintenance approaches, including duration of treatment, also depends on these factors, particularly the underlying disease risk. The treatment approaches for newly diagnosed myeloma continue to evolve, with ongoing trials exploring bispecific antibodies as part of initial therapy and CAR T cells for consolidation.

This study aimed to provide real-world evidence on progression risk in patients with high-risk smoldering multiple myeloma (SMM). This retrospective, observational study leveraged data from the Flatiron Health database. Eligible patients had SMM and relevant measures to apply Mayo 2018, International Myeloma Working Group (IMWG) 2020, and AQUILA trial risk criteria. Time to progression to active MM (TTP), progression or death (PFS), and death or progression on first-line MM therapy (PFS2) were evaluated using Kaplan-Meier methods and multivariate Cox regression models adjusted for age, Charlson Comorbidity Index, and time from SMM diagnosis to risk classification date. Across the three risk models (Mayo 2018, IMWG 2020, and AQUILA trial), high-risk patients with SMM had 3.0-4.0 times the risk of TTP, 2.1-3.5 times the risk of PFS, and 1.7-3.2 times the risk of PFS2 versus non-high-risk patients (p < 0.001 for all comparisons). Similar results were observed when patients with early treatment, early progression, and/or bone disease were excluded. This study demonstrates that high-risk patients with SMM have worse prognoses than non-high-risk patients, regardless of the criteria used, and highlights a need for early intervention testing.

Multiple myeloma is an incurable plasma cell malignancy that evolves over decades through the selection and malignant transformation of monoclonal plasma cells. The evolution from precursor states to symptomatic disease is characterized by an increasing complexity of genomic alterations within the plasma cells and a remodelling of the microenvironment towards an immunosuppressive state. Notably, in patients with advanced disease, similar mechanisms of tumour escape and immune dysfunction mediate resistance to modern T cell-based therapies, such as T cell-engaging bispecific antibodies and chimeric antigen receptor (CAR)-T cells. Thus, an increasing number of clinical trials are assessing the efficiency and safety of these therapies in individuals with newly diagnosed multiple myeloma and high-risk smoldering multiple myeloma. In this Review, we summarize the current knowledge about tumour intrinsic and extrinsic processes underlying progression from precursor states to symptomatic myeloma and discuss the rationale for early interception including the use of T cell-redirecting therapies.

It elucidates advancements in identifying and managing high-risk smoldering multiple myeloma (SMM), moving from observation strategies to intervention approaches. It highlights the significance of differentiating high-risk SMM from its less aggressive counterparts to prevent progression to multiple myeloma (MM).

Recent developments have improved SMM risk-stratification, integrating clinical, molecular and biological markers to identify high-risk individuals accurately. The advent of dynamic risk models that incorporate disease evolution and the application of novel diagnostic technologies are enhancing the understanding of SMM. Clinical trials exploring low to high intensity interventions, have shown promise in delaying MM onset and improving patient prognosis. There is a significant change in high-risk SMM management, leaning towards early intervention and precision medicine. The focus now is on refining these approaches, exploring new treatments, and proving the sustained benefits of early interventions to ultimately improve SMM patient care and outcomes.

The basic idea of modulating the immune system to better recognize and fight tumor cells has led to the successful introduction of adoptive cellular immunotherapy (ACT). ACT-based treatment regimens, in which the patient's own immune cells are isolated and subsequently expanded (ex vivo) and reinfused, have also contributed significantly to the development of a personalized treatment strategy. Complementing this, the unprecedented advances in ACTs as chimeric antigen receptor (CAR)-T cell therapies and their derivatives such as CAR-NK, CAR-macrophages, CAR-γδT and CAR-NKT have further maximized the therapeutic outcomes. Herein, we provide a comprehensive overview of the development of ACTs in multiple myeloma (MM) and outline how they have evolved from an experimental form to a mainstay of standard clinical settings. Besides, we provide insights into cytokine-induced killer cell (CIK) therapy, an alternative form of ACT that (as CIK or CAR-CIK) has enormous potential in the clinical spectrum of MM. We also summarize the results of the major preclinical and clinical studies of adoptive cell therapy in MM and address the current challenges (such as cytokine release syndrome (CRS) and neurotoxicity) that limit its complete success in the cancer landscape.

Monoclonal proteins are common, with a prevalence in the United States around 5% and the incidence increases with age. Although most patients are asymptomatic, the vast majority of cases are caused by a clonal plasma cell disorder. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions with variable risk of progression to multiple myeloma (MM). In recent years, significant progress has been made to better understand the factors that lead to the development of symptoms and progression to myeloma. In this review, we summarize the current diagnosis treatment guidelines for MGUS and SMM and highlight recent advances that underscore a shifting paradigm in the evaluation and management of plasma cell precursor conditions.

Early intervention trials have been initiated for the precursor disease smoldering myeloma (SMM). A recent study showed that genomic complexity varies widely among patients treated for high-risk SMM and is associated with response to triplet therapy, suggesting that established clinical risk scores often fail to discriminate between stable and aggressive disease. See related article by Kazandjian et al., p. 4482.

Multiple myeloma (MM) is a heterogeneous and complex disease, both in mutational biology as well as in the clinical presentation of patients. While tailored and biomarker-targeted therapy remains the direct goal for patient-centric management, existing therapies in MM remain largely uniform. Translocation t(14;16) is a rare primary genetic event found in less than 5% of patients with newly diagnosed MM. Here, we present an overview of the biology of t(14;16), epidemiology, clinical presentation, prognostic impact, and discuss the future clinical and therapeutic strategies for targeting this rare yet high-risk group in MM to optimize patient outcomes.

Risk of progression of monoclonal gammopathy of undetermined significance (MGUS) into multiple myeloma and related plasma cell disorders can be determined by three major risk stratification models, namely Mayo2005, Sweden2014, and NCI2019. This retrospective study of 427 patients with MGUS diagnosed according to the 2014 International Myeloma Working Group criteria aimed to describe and analyze the longitudinal applicability of these risk models. In all three models, the majority of patients remained at their baseline risk group, whereas small numbers of patients migrated to a different risk group. Proportions of patients among risk groups remained stable over time (e.g. Mayo2005 model, low-risk group, at baseline: 43%, after 1, 2, 3, 4, 5, and 8 years: 40%, 37%, 37%, 43%, 44%, and 43%). All three risk models reliably distinguished risk of progression at baseline, upon yearly reassessment (e.g. 1 year from diagnosis) and in time-dependent analyses. Upstaging to a high-risk category was associated with an increased risk of progression in all three models (Mayo2005: hazard ratio [HR] = 5.43, 95% confidence interval [95% CI] 1.21-24.39, p = 0.027; Sweden2014: HR = 13.02, 95% CI 5.25-32.28, p < 0.001; NCI2019: HR = 5.85, 95% CI 2.49-13.74, p < 0.001). Our study shows that MGUS risk stratification models can be applied longitudinally to repeatedly determine and improve individual risk of progression. Patient migration to higher risk categories during follow up should prompt more frequent monitoring in clinical routine.

Precursor diseases of multiple myeloma (MM) are monoclonal gammopathy of uncertain significance and smoldering MM. While it is well known that a percentage of those affected by these conditions will progress to MM, it is difficult to predict who will progress and when, and guidelines for screening for these conditions are lacking. Moreover, there are various models for risk stratification, though there are ongoing efforts to improve these models in order to predict who may benefit from treatment. Finally, there are various clinical trials, both past and ongoing, expanding the scope of possible treatment options for precursor diseases.