Последние новости и достижения в области диагностики и управления клетками Плазмы.

Introduction and background

Over the past decade, the field of plasma cell dyscrasias (PCDs) has undergone several fundamental shifts that warrant an updated, integrative review. Diagnostic paradigms have expanded beyond conventional electrophoretic techniques to include mass spectrometry (MS)-based assays, next-generation flow (NGF) cytometry and sequencing for minimal residual disease (MRD) assessment, and increasingly sensitive whole-body imaging. These advances now allow detection of disease at a much lower burden, earlier identification of relapse, and more precise response evaluation than was previously possible in routine practice.

At the same time, therapeutic strategies have evolved rapidly. The introduction of immunotherapy-based approaches, including anti-CD38 monoclonal antibodies, bispecific T-cell engagers, and chimeric antigen receptor T (CAR-T) cell therapies, has reshaped treatment algorithms, delivering deeper and more durable responses across multiple disease stages. Increasing use of risk-adapted and response-guided strategies, particularly those incorporating MRD status, reflects a broader shift toward personalized care rather than uniform treatment pathways.

For clinicians, these developments translate into meaningful changes in everyday decision making: earlier confirmation of disease in diagnostically challenging cases, more accurate assessment of treatment depth, and greater flexibility in tailoring therapy intensity based on biological risk and patient-specific factors.

PCDs comprise a spectrum of disorders arising from clonal proliferation of plasma cells, ranging from asymptomatic precursor states such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), through overt multiple myeloma (MM), to aggressive and rare variants including primary plasma cell leukemia (PCL), non-secretory myeloma, and immunoglobulin isotype-defined subtypes (e.g., IgD, IgE) [ 1 , 2 ]. Rather than being isolated entities, these conditions are interconnected by shared biological features (e.g., genomic instability, monoclonal immunoglobulin production) but vary greatly in risk of progression, clinical presentation, and therapeutic needs.

In 2025, PCDs remain a major global health challenge. The global incidence and burden of MM continue to rise: a systematic analysis of the Global Burden of Disease Study (1990-2021) shows increasing age-standardized incidence, mortality, and disability-adjusted life years (DALYs), particularly in regions with high sociodemographic indices, underscoring both demographic shifts and unequal access to diagnostics and care [ 3 ]. Clinically, PCDs pose challenges in early detection (especially of rare subtypes or non-secretory disease), heterogeneity in response to treatment, and management of organ damage (bone disease, renal involvement, etc.). Economically, the cost burden is substantial: both novel diagnostics and therapies contribute to high direct medical costs, while hospitalizations, treatment of complications and relapses, and supportive care drive further expenditure [ 4 , 5 ].

Over the past decade, several paradigm shifts have transformed the diagnosis and management of PCDs. Genomic profiling has revealed increasingly better characterization of driver mutations, cytogenetic aberrations, and clonal evolution underlying not just overt MM but even in precursor states, refining risk stratification and opening the door to targetable vulnerabilities [ 6 ]. Imaging modalities have evolved: whole-body 18F-FDG PET/CT, hybrid PET/MRI, and the use of functional MRI (e.g., diffusion-weighted imaging) now allow detection of bone and extramedullary disease (EMD) with greater sensitivity, earlier than traditional skeletal surveys, and are increasingly used for response assessment. Novel tracers (e.g., 68Ga-Pentixafor) are under study for detecting MRD non-invasively [ 7 , 8 ]. Therapeutically, immunotherapies such as bispecific antibodies (BsAbs), CAR-T cell therapies, and monoclonal antibodies (e.g., anti-CD38 agents) have moved from salvage settings into earlier lines of therapy, delivering deeper, more durable responses and reshaping the treatment landscape [ 9 , 10 ].

The objective of this review is to integrate these cutting-edge diagnostic modalities and therapeutic strategies, genomics, imaging, and immunotherapy into a future-facing clinical roadmap. We aim to delineate how recent advances can inform earlier detection, individualized risk stratification, optimal therapy selection (including for rare and high-risk PCD subtypes), and sustainable healthcare delivery. Through this narrative synthesis, we hope to offer clinicians and researchers guidance on how the diagnosis and management of PCDs are likely to evolve in the coming years, and what practice changes may be most impactful in improving patient outcomes.

Review

Methodology

This narrative review was conducted to synthesize recent literature and emerging evidence related to the diagnosis and management of PCDs. A comprehensive search of PubMed, Scopus, and Google Scholar was performed for articles published between 2015 and 2025, using key terms such as “plasma cell dyscrasias,” “multiple myeloma,” “mass spectrometry,” “minimal residual disease,” “CAR-T,” “bispecific antibodies,” and “artificial intelligence.” Additional references were identified from bibliographies of relevant studies and consensus guidelines from the International Myeloma Working Group (IMWG). Only peer-reviewed English-language articles, systematic reviews, randomized clinical trials, and major observational studies were included. Editorials, commentaries, conference abstracts without full peer-reviewed publication, single case reports, and non-English-language articles were excluded from the final narrative synthesis. Data were critically analyzed to identify diagnostic innovations, therapeutic advances, and evolving management trends. The findings were qualitatively synthesized and structured thematically to provide a comprehensive and updated overview. No new patient data were collected, and ethical approval was not required. The study selection process is summarized in Figure 1 .

Revolution in diagnostics: beyond conventional electrophoresis

Recent advances in diagnostic technologies, including MS, ultrasensitive serum free light chain (sFLC) assays, NGF cytometry, and advanced imaging, enable earlier, more sensitive, and more precise detection of PCDs, particularly in low-burden, oligosecretory, or non-secretory disease, and are reshaping standards for disease assessment and monitoring. In routine practice, patients may present with clinical or radiologic features suggestive of active or relapsing disease despite negative or equivocal results on conventional serum protein electrophoresis (SPEP) or immunofixation. In such scenarios, advanced diagnostic modalities can facilitate earlier confirmation of residual or recurrent disease, improve risk stratification, and guide timely treatment decisions that would otherwise be delayed using traditional assays alone.

Limitations of Traditional Tools (SPEP, Urine Protein Electrophoresis (UPEP), and Immunofixation)

SPEP, UPEP, and immunofixation electrophoresis (IFE) have long formed the diagnostic backbone for PCDs. However, they suffer from several deficiencies. SPEP cannot reliably detect low-level monoclonal proteins (<0.5 g/dL), struggles with co-migration of proteins, and gives little qualitative detail beyond the large “M-spikes.” UPEP is cumbersome (24-hour collections), has poor patient compliance, and lower sensitivity. IFE, while qualitative, has low throughput, subjective interpretation differences across labs, and interference by therapeutic monoclonal antibodies [ 3 , 8 , 10 ]. These tools also underperform in oligosecretory, nonsecretory, or light chain only disease; in monitoring MRD, conventional electrophoretic techniques often cannot detect very low disease burdens. The diagnostic evaluation of patients presenting with multiple bone destruction, fractures, or soft tissue masses often requires an integrated approach combining imaging, histopathology, and laboratory studies to distinguish MM from other tumors (Figure 2 ).

MS-Based Assays Replacing Immunofixation

MS methods are now showing evidence that they can supplant IFE in many settings. The MASS-FIX assay (a matrix-assisted laser desorption/ionization (MALDI-TOF)-based intact light chain MS assay), when deployed in large cohorts (e.g., ~19,500 patients), proved more sensitive than IFE in confirming SPEP abnormalities, detecting small monoclonal proteins that SPEP could barely quantify, and showing greater automation and lower repeat rates. In that study, MASS-FIX detected M-proteins in samples SPEP identified as suspicious but not quantifiable, and in samples with abnormal FLC ratios, it outperformed or matched IFE [ 11 ]. The IMWG Mass Spectrometry Committee has, in its report, endorsed immune-enrichment coupled with MALDI-TOF MS (or LC-MS) as clinically equivalent or superior to IFE for diagnosis/monitoring of monoclonal proteins, differentiating therapeutic antibodies from disease, and improving detection of risk features such as light chain glycosylation [ 12 ]. Personalized MS-peptide/clonotypic assays such as “EasyM” have pushed detection limits very low (on the order of 0.0005-0.05 g/L for some peptides), and offer quantitative tracking in addition to qualitative presence/absence [ 13 ]. While MS has challenges - cost, equipment, and a need for standardization - the evidence suggests it is ready to replace or run in parallel with IFE in many diagnostic workflows.

Several of these studies represent practice-changing diagnostic advances, particularly large cohort and consensus reports demonstrating the superiority of MS over immunofixation for detecting low-level monoclonal proteins and distinguishing therapeutic antibodies from disease-related clones. In contrast, personalized peptide-based assays and novel blood-based MRD approaches currently constitute emerging evidence, with promising sensitivity but more limited real-world validation.

Advances in sFLC Assay: Ultrasensitive Quantification

Parallel to MS advances, the sFLC assay has seen refinements in reference intervals, prognostic power, and analytic performance. A large retrospective study (≈95,000 SPEP/IFE + sFLC specimens over a decade) demonstrated that the widely used manufacturer-recommended κ/λ ratio (0.26-1.65) led to a high false-positive rate among monoclonal-negative individuals; using real-world data, revised reference intervals (e.g., 0.67-2.13 for the Optilite platform) reduced false positives substantially without loss of sensitivity [ 14 ]. A Danish population study of over 13,000 patients compared SPEP + UPEP vs. SPEP + sFLC ratio in general practice; combined with SPEP, the sFLC ratio nearly matched UPEP in sensitivity, and modifying cut-offs reduced false positives [ 15 ]. Also, in MM cohorts treated with novel agents, serial sFLC measurements have shown earlier detection of response/progression than electrophoretic methods; sFLC changes often preceded urine M-protein or SPEP changes by >1 month [ 16 - 17 ]. These improvements push us toward ultrasensitive quantification, with better prognostication, more timely detection of relapse (including sFLC-only relapse), and enhanced ability to define stringent complete response (sCR).

NGF Cytometry for MRD

High-sensitivity MRD assessment using NGF cytometry, next-generation sequencing, advanced imaging, and emerging blood-based approaches provides a powerful prognostic tool that increasingly informs response assessment, treatment duration, and risk-adapted therapeutic strategies in PCDs. In patients achieving a conventional complete response, residual disease may persist at levels undetectable by standard methods, contributing to relapse risk. MRD assessment allows clinicians to identify patients with ongoing subclinical disease who may benefit from treatment intensification or prolonged maintenance, while also supporting de-escalation strategies in deeply responding, MRD-negative patients to reduce cumulative toxicity and preserve quality of life (QoL).

Real-world experience from a large reference laboratory that reflexed lower-sensitivity screening assays to high-sensitivity flow cytometry analyzed >13,000 bone marrow specimens and demonstrated that many samples negative by routine screening were MRD-positive when assessed with next-generation techniques, underscoring the clinical impact of assay sensitivity in routine practice [ 18 ]. NGF, standardized by the EuroFlow consortium, employs harmonized antibody panels and acquisition/analysis pipelines to reproducibly reach sensitivities of ~10⁻⁵-10⁻⁶ and has been widely adopted in trials and reference centers [ 19 ]. Head-to-head prospective data from contemporary trials (e.g., the FORTE program) show strong concordance between NGF and next-generation sequencing (NGS) at comparable cutoffs and confirm that sustained MRD negativity by either modality predicts markedly improved progression-free and overall survival [ 20 ]. Practically, NGF offers rapid turnaround, no requirement for a diagnostic DNA sample, and the ability to phenotype residual malignant plasma cells, though preanalytical variables (aspirate hemodilution, panel standardization) remain critical to achieving true 10⁻⁶ performance.

Hence, large prospective trials and standardized EuroFlow-based studies constitute landmark evidence establishing MRD negativity as a robust prognostic marker, while ongoing investigations are evaluating how MRD-directed strategies may be optimally integrated into routine, response-adapted clinical decision making.

Imaging Breakthroughs: Whole-Body MRI, PET/CT With Novel Tracers

International imaging recommendations now endorse sensitive whole-body techniques for staging and response assessment, recognizing that marrow heterogeneity and EMD can be missed by marrow-only testing [ 21 ]. Molecular imaging advances complement these recommendations: CXCR4-targeted 68Ga-Pentixafor PET/CT has demonstrated complementary lesion detection compared with 18F-FDG in multiple series and may identify biologically aggressive, CXCR4-positive disease amenable to theranostic approaches [ 22 ]. Standardization efforts such as MY-RADS for whole-body MRI (diffusion-weighted sequences) improve acquisition and reporting consistency, enabling WB-MRI to detect marrow involvement with high sensitivity and to serve as a noninvasive adjunct for treatment response and MRD-directed strategies [ 23 ].

Artificial Intelligence (AI) and Machine Learning in Early Diagnosis and Prognostic Prediction

AI and machine-learning tools are increasingly applied to automate and quantify imaging (e.g., volumetric metabolic tumor volume, total lesion glycolysis), flow cytometry gating, and integrative prognostic modeling. Automated AI-based volumetric segmentation of FDG PET/CT correlates with marrow infiltration and independently predicts survival outcomes, illustrating reproducible, scalable imaging biomarkers for risk stratification [ 24 ]. Larger transformer-based models that combine clinical, laboratory, and imaging data have improved prediction of progression-free and overall survival and adverse events compared with traditional staging systems, pointing toward individualized, data-driven prognostic frameworks for clinical decision making [ 25 ]. Together, NGF/NGS, advanced imaging, and AI provide a spatially and molecularly informed diagnostic ecosystem that enables MRD-driven, precision care pathways. Table 1 summarizes the emerging diagnostic modalities in PCDs, highlighting their key features, advantages, limitations, and clinical applications.

Redefining clinical spectrum: novel subtypes and overlaps

The clinical spectrum of PCDs continues to expand, with recognition and characterization of both very rare subtypes and overlapping syndromes that blur traditional boundaries. These novel entities and overlaps have implications for diagnosis, prognostication, and therapy.

Non-traditional Entities: IgE/IgD Myeloma, Biclonal Gammopathies

IgE myeloma is among the rarest isotypes (<0.1% of all MM cases), typically associated with aggressive biology. A recent genomic and immune repertoire profiling study of IgE κ MM detailed a hypermutated phenotype and heightened T cell reactivity, shedding light on its molecular distinctiveness and potential immunologic vulnerabilities [ 26 ]. Case reports also document that IgE MM can be underdiagnosed when standard immunofixation and electrophoresis miss weak bands, and that early use of novel agents combined with stem cell transplantation may improve outcomes in select cases [ 27 ]. Biclonal gammopathies, the occurrence of two distinct monoclonal immunoglobulins, are uncommon (≈1%), but series from tertiary centers (e.g., India) show presentation, heavy‐light chain combinations (e.g., IgG/IgA) similar to monoclonal disease, and comparable response to standard therapies when both clones are addressed [ 28 ].

PCDs Intersecting With Autoimmune and Paraneoplastic Syndromes

There is growing evidence for interactions between autoimmune processes and PCDs. A recent comprehensive review analyzed correlations among autoimmune diseases and conditions such as MGUS and MM; some autoimmune disorders are statistically associated with increased risk of MGUS/MM, potentially via chronic immune stimulation, cytokine milieu, or shared genetic susceptibility [ 29 ]. Clinical cases where monoclonal gammopathy (including MGUS) leads to organ damage via autoantibody‐mediated mechanisms (e.g., nephropathy, neuropathy) emphasize that “undetermined significance” is not always benign [ 30 ].

The Expanding Landscape of Amyloidosis and POEMS With New Classification Tools

The International Society of Amyloidosis (ISA) released updated nomenclature in 2024, identifying 42 distinct human amyloid fibril proteins, 19 of which cause systemic forms, refining the classification of amyloid diseases and enabling better diagnostic precision for more rare fibril types [ 31 ]. POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, Skin changes) syndrome remains rare, but recent work has delineated the “capillary‐leak phenotype” as a distinct clinical cause of morbidity and mortality in POEMS, suggesting that disease phenotyping beyond the classic criteria merits integration into prognostic stratification [ 32 ].

Concept of “Oligoclonal Reconstitution” Post-therapy

Oligoclonal reconstitution refers to the emergence of immunoglobulin bands distinct from the diagnostic clone after therapy (especially after autologous stem cell transplant or induction with novel agents). Several studies show that this phenomenon (sometimes called oligoclonal bands or immune reconstitution) is associated with deeper responses, higher rates of MRD negativity, and improved progression‐free survival [ 33 , 34 ]. For example, in a cohort of 156 patients undergoing ASCT, those with oligoclonal band formation had significantly longer PFS and OS compared to those without [ 33 ]. While not yet uniformly incorporated into response criteria, oligoclonality represents a marker of immune restoration and possibly a favorable prognosis, though it complicates sCR definitions due to effects on FLC ratios.

Management frontiers: tailoring therapy in the precision era

Immunotherapy-based strategies, including anti-CD38 monoclonal antibodies, bispecific T-cell engagers, and CAR-T cell therapies, have transformed the therapeutic landscape of PCDs by delivering deeper and more durable responses, expanding effective options across disease stages, and enabling increasingly personalized, risk-adapted treatment approaches. For patients with relapsed or refractory disease, particularly those with high-risk cytogenetics or early relapse after standard regimens, immunotherapies now offer clinically meaningful responses where conventional therapies often fail. In real-world settings, clinicians must integrate these agents thoughtfully, balancing depth of response against toxicity, infection risk, access, and cost, while considering earlier use of immunotherapy in selected high-risk or MRD-positive patients.

Induction and Early Therapy

The therapeutic backbone for newly diagnosed multiple myeloma (NDMM) has shifted decisively toward deeper, immunologically-enabled induction regimens that combine next-generation proteasome inhibition (e.g., carfilzomib), modern IMiDs, and anti-CD38 monoclonal antibodies [ 35 - 37 ]. Carfilzomib-based regimens (KRd) showed potent activity and higher complete response rates compared with older PI backbones in several studies, but clinicians must weigh efficacy against demonstrated risks (notably cardiovascular toxicity) and tailor choice on comorbidity profiles [ 35 ]. Anti-CD38 antibodies (daratumumab, isatuximab) incorporated into frontline therapy have consistently increased rates of very good partial response (VGPR), complete response (CR), and MRD negativity when added to PI-IMiD doublets/triplets [ 36 , 37 ].

A major practice evolution has been the move from triplets to quadruplet induction. Randomized and large phase 2/3 datasets (GRIFFIN, GMMG-HD7, and several contemporary trials and meta-analyses) demonstrate that quadruplets containing an anti-CD38 antibody plus a PI + IMiD + dexamethasone produce higher depth of response and improved MRD-negativity rates than historical triplets, translating into improved progression-free survival in multiple cohorts [ 38 - 40 ]. Importantly, quadruplet approaches require attention to sequencing (e.g., optimizing stem-cell collection after IMiD exposure), infection prophylaxis, and toxicity monitoring, but data from MASTER/GRIFFIN suggest that stem-cell mobilization remains feasible after modern quadruplet induction [ 41 ].

Role of Risk-Adapted Therapy

Risk-adapted approaches are increasingly formalized: comprehensive genomic/cytogenetic profiling (FISH and sequencing), baseline tumor burden, EMD, and MRD status inform escalation to intensified regimens (e.g., carfilzomib-containing quadruplets, tandem ASCT in selected centers) or de-escalation in very-low-risk patients [ 42 ]. Contemporary guidelines encourage tailoring induction intensity and post-remission consolidation to individual risk, with MRD used as an early decision pivot in many prospective frameworks.

Stem cell transplantation and beyond

Contemporary Transplant Strategies, Tandem SCT

Autologous stem cell transplantation (ASCT) remains a standard for eligible NDMM patients and continues to provide a durable PFS benefit even in the era of powerful induction regimens; however, the role of tandem ASCT is now more selective. Recent registry and randomized evaluations suggest limited incremental benefit of routine tandem ASCT in the maintenance era, though it may still be considered for selected high-risk patients who fail to achieve adequate depth of response after the first ASCT [ 43 ]. Several groups are testing strategies combining intensive quadruplet induction with either single ASCT, deferred transplant, or tandem ASCT based on MRD and cytogenetic risk. The standard therapeutic pathway for transplant-eligible patients involves triplet induction therapy, high-dose melphalan with ASCT, followed by consolidation and maintenance, tailored to disease risk and treatment response (Figure 3 ).

Maintenance Therapies and Novel Oral Regimens

Post-transplant maintenance remains a challenge to prolong remission. Lenalidomide maintenance after ASCT continues to offer PFS and OS advantage for standard-risk disease; for high-risk patients, combinations (e.g., bortezomib-based or anti-CD38 plus IMiD maintenance) are being explored to improve outcomes [ 41 , 44 ]. Recent trials indicate that anti-CD38 maintenance (daratumumab + lenalidomide) increases rates of MRD conversion and PFS vs. lenalidomide alone, albeit with increased cytopenias and infection risk that must be managed [ 44 ]. Simultaneously, convenience and adherence have improved with the evolution of oral options and targeted maintenance strategies (e.g., oral CELMoDs, selective pathways), expanding outpatient, long-term disease control possibilities.

Novel immunotherapies

CAR-T Cell Therapy: Product Evolution, Real-World Data, Challenges

CAR-T cell therapy has transformed the treatment of relapsed/refractory multiple myeloma (RRMM). Products, such as idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), demonstrate overall response rates (ORR) of 70-90% in heavily pretreated patients, with significant rates of MRD negativity [ 45 , 46 ]. Real-world data confirm efficacy but highlight variability in adverse events, including cytokine release syndrome (CRS) and neurotoxicity [ 47 ]. Emerging strategies, including dual-target CAR-T constructs, aim to mitigate antigen escape and enhance durability of responses [ 48 ].

Bispecific Antibodies and Antibody-Drug Conjugates (ADCs)

BsAbs, such as teclistamab and talquetamab, recruit T cells to malignant plasma cells, offering off-the-shelf immunotherapy with ORRs of 60-70% in RRMM [ 49 , 50 ]. BsAbs present manageable toxicity profiles and do not require personalized manufacturing. ADCs like belantamab mafodotin target BCMA-positive myeloma cells while delivering cytotoxic payloads; ocular toxicity remains a key adverse effect, requiring monitoring and dose modification [ 51 ].

Vaccines and Immune Checkpoint Inhibitors: Emerging Frontiers

Tumor-specific vaccines are under evaluation to prime adaptive immunity against myeloma cells, with early-phase trials demonstrating immunogenicity but limited clinical benefit to date [ 52 ]. Immune checkpoint inhibitors (e.g., PD-1/PD-L1 blockade) have shown modest efficacy as monotherapy; combination strategies with immunomodulatory drugs (IMiDs) or CAR-T are being explored to overcome immune evasion [ 53 ].

Management of non-myeloma PCDs

Waldenström’s Macroglobulinemia (WM): BTK and PI3K Inhibitors

WM is characterized by an IgM monoclonal protein and lymphoplasmacytic infiltration. Bruton tyrosine kinase (BTK) inhibitors, including ibrutinib and zanubrutinib, provide durable responses and are frontline therapies in symptomatic patients [ 54 ]. PI3K inhibitors target downstream survival pathways, particularly in MYD88-mutant disease, with ongoing studies evaluating efficacy and safety [ 55 ].

AL Amyloidosis: Daratumumab + CyBorD, Novel Fibril-Targeting Agents

AL amyloidosis results from misfolded light-chain deposition in organs. The combination of daratumumab with CyBorD (cyclophosphamide, bortezomib, dexamethasone) yields rapid hematologic and organ responses, becoming standard first-line therapy [ 56 ]. Novel fibril-targeting antibodies, such as CAEL-101, aim to remove deposited amyloid, showing promising early-phase results in improving cardiac and renal function [ 57 ].

Plasmacytomas and EMD

Plasmacytomas and EMD represent aggressive PCD manifestations. Management includes local radiotherapy for solitary lesions and systemic therapy for disseminated disease [ 58 ]. High-risk cytogenetics and EMD presence often necessitate incorporation of novel agents such as proteasome inhibitors, IMiDs, and anti-CD38 antibodies [ 59 ].

Special populations and supportive care: moving beyond survival

Elderly and Frail Patients: Geriatric-Adapted Scoring and Therapy De-escalation

MM predominantly affects older adults, necessitating tailored treatment approaches. The IMWG frailty score, incorporating age, functional status, comorbidities, and laboratory parameters, stratifies patients into fit, intermediate-fit, and frail categories [ 60 , 61 ]. This stratification guides therapy intensity, with frail patients often benefiting from de-escalated regimens to minimize toxicity and enhance QoL [ 60 - 62 ]. Studies have shown that frailty assessments can predict treatment-related toxicity and overall survival, emphasizing the need for individualized treatment plans [ 62 ].

Additionally, geriatric assessments, including evaluations of cognitive function, nutritional status, and social support, are crucial in managing elderly patients with MM [ 61 - 63 ]. These assessments help identify vulnerabilities and guide decisions regarding treatment intensity and supportive care. Implementing geriatric-adapted scoring systems has been associated with improved patient outcomes and reduced hospitalization rates [ 63 ].

Renal Impairment: Plasma Exchange and Novel Dialysis Filters

Renal impairment is a common complication in MM, often resulting from cast nephropathy or light chain deposition [ 64 , 65 ]. While plasma exchange has been utilized to remove FLCs, evidence supporting its efficacy is limited [ 64 ]. A study by Clark et al. found no conclusive evidence that plasma exchange substantially reduces death or dialysis dependence in patients with acute renal failure at the onset of MM [ 64 ].

Emerging therapies include high-cutoff hemodialysis membranes, which effectively remove excess light chains and may improve renal function in some patients [ 65 , 66 ]. These novel dialysis filters have shown promise in small studies, suggesting potential benefits in reversing renal impairment associated with MM [ 66 ].

Additionally, the use of anti-myeloma therapy alongside high-cutoff hemodialysis membranes has been explored as a strategy to potentially reverse renal impairment in dialysis patients [ 65 - 67 ]. However, further research is needed to establish the efficacy and safety of this combined approach [ 67 ].

Skeletal Disease: Denosumab vs. Bisphosphonates and Novel Bone-Targeted Agents

Bone disease is a common complication in MM, leading to skeletal-related events such as fractures and pain [ 68 , 69 ]. Bisphosphonates, such as zoledronic acid, have been standard in preventing these events [ 68 ]. Denosumab, a monoclonal antibody targeting RANKL, has shown superior efficacy in certain studies and is preferred in patients with renal impairment due to its non-reliance on renal clearance [ 68 - 70 ]. A meta-analysis demonstrated that denosumab was more effective than bisphosphonates in increasing bone mineral density in postmenopausal women previously treated with oral bisphosphonates [ 70 ].

Novel bone-targeted agents, such as osteoprotegerin analogs and sclerostin inhibitors, are under investigation for their potential to further mitigate bone-related complications in MM [ 71 , 72 ]. These agents aim to regulate bone metabolism pathways more precisely, offering hope for improved management of myeloma-induced bone disease [ 71 , 72 ].

Thromboprophylaxis and Infection Prevention

Patients with MM, particularly those receiving IMiDs, are at increased risk for venous thromboembolism (VTE) [ 73 , 74 ]. Risk assessment models like IMPEDE-VTE and SAVED help identify high-risk individuals [ 73 , 74 ]. Prophylactic strategies include low-molecular-weight heparin (LMWH), direct oral anticoagulants (DOACs), or aspirin, tailored to individual risk profiles [ 73 - 75 ]. The IMWG guidelines recommend primary VTE prophylaxis for all patients treated with IMiDs in combination with dexamethasone, in the absence of significant comorbidities [ 75 ].

Infection prevention is critical, especially during periods of neutropenia or following stem cell transplantation [ 76 , 77 ]. Prophylactic antibiotics, antifungals, and antiviral agents are commonly used, with adjustments based on local epidemiology and patient-specific factors [ 76 - 78 ]. Monitoring and prompt treatment of infections are essential to reduce morbidity and mortality in this patient population [ 77 , 78 ].

QoL, Survivorship, and Palliative Care

QoL considerations are paramount in MM management [ 79 , 80 ]. Patients often experience fatigue, pain, neuropathy, and psychological distress [ 79 - 81 ]. Early integration of palliative care has been shown to improve symptom management and patient satisfaction [ 79 , 80 ]. A study by Rüsing et al. highlighted that patients with MM and survivors experience substantive long-term QoL issues, underscoring the need for comprehensive symptom management, integrated palliative care, and enhancement of social and emotional support [ 82 ].

Survivorship care plans should address long-term complications, including secondary malignancies, cardiovascular health, and psychosocial support [ 82 , 83 ]. The International Myeloma Foundation's Nurse Leadership Board has developed a survivorship care plan that emphasizes the identification of unmet needs and the importance of prompt intervention to improve QoL and overall survival [ 83 , 84 ].

Despite improvements in treatment options, providing optimal care to patients with MM at the end of life remains an unmet need [ 84 ]. Patients with MM typically have high rates of emergency department visits and hospitalizations at the end of life, indicating the necessity for better palliative care integration [ 84 , 85 ]. Table 2 outlines novel therapeutic strategies in MM, including response rates, toxicity profiles, and their current clinical status.

Unmet challenges and future directions

Drug Resistance and Clonal Escape

MM is characterized by genetic heterogeneity and clonal evolution, leading to therapy resistance and disease relapse [ 86 - 87 ]. Mechanisms, such as antigen loss (e.g., BCMA or GPRC5D), epigenetic changes, and immune evasion, contribute to clonal escape and resistance to treatments like CAR-T and BsAb [ 87 - 88 ]. Recent studies have identified therapy-induced clonal evolution as a significant factor hindering long-term remission [ 88 - 89 ]. Understanding these mechanisms is crucial for developing strategies to overcome resistance and achieve durable responses [ 89 ].

Cost and Accessibility of Advanced Therapies

The high cost of MM therapies poses a significant barrier to access, particularly in low- and middle-income countries (LMICs) [ 90 - 91 ]. For instance, the cost of anti-CD38 monoclonal antibodies in combination with other agents can exceed $300,000 per year [ 90 ]. A survey of oncologists revealed that while most MM therapies are accessible in high-income countries, access is limited in LMICs due to financial constraints and insufficient regulatory approvals [ 91 - 92 ]. Efforts to reduce costs and improve accessibility are essential to ensure equitable treatment for all MM patients [ 92 ].

Need for Global Collaborative Trials (LMIC Focus)

Conducting clinical trials in LMICs is challenging due to factors like limited infrastructure, regulatory hurdles, and financial constraints [ 91 , 93 ]. A systematic review found that high-income countries enrolled patients in 100% of trials resulting in FDA approvals, while seven countries in Central and Eastern Europe had no access to MM clinical trials [ 93 ]. Collaborations between high-income and LMICs are crucial to develop global health approaches that benefit these regions [ 91 , 93 ]. Such partnerships can enhance research capacity and improve patient outcomes worldwide [ 93 ].

Integration of Multi-omics + AI-Driven Personalized Algorithms

Advancements in multi-omics technologies and AI are revolutionizing MM treatment by enabling personalized medicine [ 94 - 95 ]. The Myeloma VAE (MyeVAE) model integrates genomic, transcriptomic, and clinical data to predict patient outcomes and guide therapy decisions [ 94 ]. Machine learning approaches utilizing proteomics data have also been employed to identify personalized treatments in MM patients [ 95 - 96 ]. These innovations hold promise for optimizing treatment strategies and improving patient outcomes [ 96 ].

The “Cure vs. Control” Debate in Myeloma

The debate between aiming for a cure vs. disease control in MM treatment reflects differing philosophies in patient management [ 97 - 98 ]. While some advocate for aggressive treatment strategies to achieve long-term remission or cure, others emphasize the importance of controlling the disease to maintain QoL [ 97 ]. Recent advancements, such as the CARTITUDE-1 trial, have shown promising results in achieving deep and durable responses, suggesting that a cure may be achievable in a subset of patients [ 99 ]. However, the optimal approach remains a subject of ongoing research and discussion.

Conclusions

The diagnosis and management of PCDs are evolving rapidly, with important implications for everyday clinical practice. Advanced diagnostic tools, including MS, ultrasensitive sFLC assays, NGF or sequencing for MRD, and sensitive whole-body imaging, now enable earlier detection, improved risk stratification, and more accurate assessment of treatment response, particularly in patients with low-level or suspected residual disease.

Therapeutically, immunotherapy-based strategies such as anti-CD38 monoclonal antibodies, bispecific T-cell engagers, and CAR-T cell therapies have shifted treatment paradigms toward deeper and more durable responses across disease stages. Increasing integration of MRD status and biological risk factors is supporting individualized, response-adapted treatment decisions. Moving forward, clinicians will need to balance treatment intensity with toxicity, cost, and patient-centered outcomes, reinforcing a precision-guided and personalized approach to PCD care.

Disclosures

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:

Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.

Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.

Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Author Contributions

Concept and design: Hussein Attia Hussein Mahmoud, Anand Sunil, Ahmed Elkhider Ali Musa, Arzoo Dar, Manju Rai

Drafting of the manuscript: Hussein Attia Hussein Mahmoud, Anand Sunil, Arzoo Dar, Nafrin Kormath, Sai Lahari Sangaraju, Vinay Dontul

Critical review of the manuscript for important intellectual content: Hussein Attia Hussein Mahmoud, Ahnaf Uddin Ahmed, Ahmed Elkhider Ali Musa, Nejma Azeez, Bashir Imam, Sweta Singh, Manju Rai

Acquisition, analysis, or interpretation of data: Ahnaf Uddin Ahmed, Nafrin Kormath, Sai Lahari Sangaraju, Nejma Azeez, Bashir Imam, Vinay Dontul, Sweta Singh

Supervision: Manju Rai

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