Одиссей моноколональных гаммопатий: сосредоточен на прекурсорах и переходе от MGUS и SMM к нескольким Myeloma, с кратким обзором новых терапевтических стратегий.

Introduction

Monoclonal gammopathies are a spectrum of plasma-cell disorders defined by the presence of a monoclonal immunoglobulin, yet they vary markedly in clinical expression [ 1 ]. At one extreme lies monoclonal gammopathy of undetermined significance (MGUS), often discovered incidentally and long considered a silent precursor [ 2 ]. Progression through smoldering multiple myeloma (SMM), a transitional yet clinically quiescent stage, ultimately culminates in multiple myeloma (MM), an overt and life-threatening malignancy [ 3 ]. This stepwise evolution reflects not a sudden transformation, but rather an extended biological journey marked by accumulating genetic mutations, epigenetic dysregulation, and a progressively altered bone marrow (BM) microenvironment that sustains malignant clones [ 4 ].

Epidemiological data underscore the global burden of these disorders, with MGUS affecting nearly 4% of adults over 50 and MM accounting for ~ 2% of all cancer deaths in the United States [ 5 , 6 ]. Advances in sequencing, multi-omics, and immunological profiling have revealed the complexity of clonal plasma cell evolution, while modern therapies, including proteasome inhibitors (PIs), immunomodulatory agents, monoclonal antibodies (mAbs), and cellular therapies, have reshaped outcomes [ 7 – 10 ]. Yet, many uncertainties remain: predicting progression from MGUS or SMM to MM is imprecise, treatment resistance persists, and quality of life continues to be challenged by complications such as anemia, renal impairment, and bone disease [ 11 , 12 ].

The main goal of this review is to delineate the biological and molecular continuum that drives disease progression from MGUS and SMM to overt MM. While therapeutic and diagnostic strategies are discussed, these sections are intentionally concise and focused on recent innovations with conceptual relevance to disease control, including CAR-T cells, bispecific antibodies, circulating tumor cell (CTC) assessment, and minimal residual disease (MRD) evaluation.

Epidemiology and clinical definitions of monoclonal gammopathies

MGUS – The silent beginning of the journey

MGUS is a clonal plasma cell disorder characterized by the presence of a monoclonal (M) protein in serum or urine, produced by aberrant immunoglobulin-secreting plasma cells [ 13 ]. The paraprotein typically appears as a distinct “band” or “spike” on protein electrophoresis and may consist of intact immunoglobulins or free light chains (FLCs) [ 14 ]. MGUS is classified into three subtypes. Non-IgM MGUS (predominantly IgG, ~ 70%; IgA, ~ 12%; biclonal, ~ 3%) carries a risk of progression to MM [ 15 ]. Non-IgM MGUS is a precursor not only of MM but can also progress to AL amyloidosis and MGRS, highlighting the spectrum of potential clinical outcomes [ 16 ]; IgM MGUS (~ 15%), derived from lymphoplasmacytic clones, associated with progression to Waldenström macroglobulinemia (WM) or other B-cell lymphomas [ 17 ]; and light-chain MGUS , defined by abnormal FLC ratios without heavy-chain expression, potentially progressing to light-chain MM or AL amyloidosis [ 18 ]. Recent International Consensus Classification (ICC) refinements subdivide IgM MGUS into plasma cell–type (MYD88 wild-type, sometimes t(11;14), MM-like) and NOS type (often MYD88 L265P mutated, aligned with WM/LPL) [ 19 ].

MGUS is common in older adults, affecting ~ 3% of people > 50 years and > 8% of men > 85, with a median diagnostic age of 72 [ 20 ]. It is more frequent in men than women and in Afro-Caribbean compared with Caucasian populations [ 21 – 23 ]. Although the annual progression risk is low (~ 1% per year), nearly all MM cases arise from prior MGUS [ 24 ]. Importantly, MGUS is not entirely benign, as affected individuals face reduced survival and increased risks of infection, cardiovascular disease, renal dysfunction, and neuropathy [ 25 ]. WHO-HAEM5 recommends risk stratification incorporating FLC ratio, IgA/IgM subtype, and M-protein > 1.5 g/dL to refine progression risk [ 26 ]. Thus, MGUS is the silent precursor of MM, and its recognition is essential for risk-adapted follow-up.

SMM – The borderland state

SMM is an asymptomatic clonal plasma cell condition that bridges MGUS and overt MM [ 27 ]. It exhibits a higher clonal burden than MGUS but lacks myeloma-defining events (MDE). The International Myeloma Working Group (IMWG) defines SMM as serum monoclonal protein ≥ 3 g/dL and/or 10–59% clonal BM plasma cells, in the absence of hyperCalcemia, Renal insufficiency, Anemia, Bone lesions (CRAB) features (hypercalcemia, renal impairment, anemia, bone lesions) or other biomarkers [ 28 – 30 ]. According to SLiM-CRAB, patients with ≥ 60% plasma cells, FLC ratio ≥ 100, or > 1 focal MRI lesion are reclassified as MM rather than SMM [ 31 ]. Distinguishing SMM from symptomatic MM is essential because SMM is managed by observation rather than immediate therapy [ 30 ].

SMM is biologically heterogeneous. About 30% of patients remain stable ≥ 10 years, others progress within months, and the rest follow intermediate courses [ 32 ]. Risk of progression averages 10% annually during the first five years, then decreases to 3% and later to 1% [ 32 ]. Risk stratification models include M-protein concentration, marrow plasma cell percentage, FLC ratio, immunoparesis, circulating plasma cells, and cytogenetics [ 33 ]. The Mayo “20/2/20” model categorizes patients as low-, intermediate-, or high-risk [ 34 ]. while the 2020 IMWG system integrates cytogenetic abnormalities to define four risk tiers [ 28 ]. Therefore, SMM represents a “borderland” entity where early myeloma biology emerges, necessitating vigilant surveillance and refined prognostication.

MM – The overt malignancy

Multiple myeloma (MM; referred to as plasma-cell myeloma [PCM] in WHO-HAEM5) is the second most common hematologic malignancy and is defined by clonal plasma-cell proliferation in the marrow with monoclonal protein in serum or urine [ 35 ]. Symptomatic MM requires ≥ 10% clonal plasma cells or plasmacytoma plus ≥ 1 MDE [ 36 ]. These include CRAB features and newer biomarkers predicting imminent end-organ damage: ≥60% clonal plasma cells, FLC ratio ≥ 100, or multiple MRI lesions [ 36 , 37 ]. MM mainly affects older adults (median age 69), with higher prevalence in males and those of African descent [ 38 ]. WHO-HAEM5 adopts PCM as the official terminology, whereas ICC 2022 retains the name “MM” and further subclassifies it into NOS and groups defined by recurrent genetic abnormalities (CCND, MAF, NSD2, or hyperdiploidy) [ 19 , 26 ].

MM is clinically diverse. IgG subtype (~ 60%) predominates, followed by IgA (~ 20%), whereas IgD, IgE, and IgM forms are rare [ 39 ]. Light-chain MM (~ 15%) is marked by renal and amyloid complications and carries poor prognosis [ 40 ]. Non-secretory MM (3–5%) lacks measurable M-protein, complicating diagnosis [ 41 ]. Cytogenetically, hyperdiploidy is generally favorable, while translocations t(4;14), and t(14;16), as well as del(17p) and 1q gain, define high-risk disease [ 42 – 44 ]. In contrast, t(11;14) does not confer high-risk features but represents a distinct biological subset that may have therapeutic implications, particularly regarding sensitivity to BCL2 inhibition [ 45 , 46 ]. According to ICC 2022, cytogenetic profiling (by interphase FISH) is central to classification and risk stratification, and consensus FISH panels for MM/PCM are recommended [ 19 ].

Related disorders – Divergent roads

Other disorders overlap with MM but are distinct entities. WM is a lymphoplasmacytic lymphoma with IgM paraprotein, presenting with hyperviscosity, lymphadenopathy, and systemic symptoms but usually lacking lytic bone disease [ 47 , 48 ]. It often evolves from IgM MGUS and is characterized by MYD88 mutations (> 90%) and CXCR4 mutations (up to 40%) [ 19 ]. Systemic AL amyloidosis results from deposition of misfolded κ or λ light chains in organs such as heart, kidney, and liver, causing significant morbidity and mortality [ 49 – 51 ]. WHO-HAEM5 distinguishes systemic from localized AL (amyloidoma), the latter being indolent [ 26 ]. Importantly, AL amyloidosis may arise from MGUS or MM, while WM aligns with indolent lymphomas [ 52 , 53 ]. Table 1 summarizes the current spectrum of monoclonal gammopathies and plasma cell dyscrasias, integrating WHO-HAEM5 and ICC 2022 nomenclature, along with their diagnostic thresholds, genetic markers, and clinical implications.

Pathophysiology and molecular mechanisms

Plasma cell biology and the transition to clonality

Plasma cells represent the terminal stage of B-cell differentiation, generated in germinal centers following antigen stimulation, somatic hypermutation, and class-switch recombination, which ensure high-affinity antibody production [ 54 , 55 ]. Under physiological conditions, plasma cells account for < 1% of hematopoietic and lymphoid cells and are largely post-mitotic, with only a minority persisting as long-lived plasma cells in BM niches [ 56 ]. These long-lived cells sustain humoral memory through continuous antibody secretion, supported by stromal interactions and cytokine signaling [ 57 ]. Phenotypically, human plasma cells express CD38, CD27, and CD138, whereas in mice they are typically identified by CD138 positivity and B220 downregulation [ 58 ].

When homeostatic balance is lost, some plasma cells escape terminal differentiation checkpoints and acquire extended survival capacity [ 59 ]. These aberrant populations gradually persist within the marrow, expand clonally, and produce a monoclonal immunoglobulin that replaces the polyclonal repertoire of a healthy immune system [ 60 , 61 ]. The drivers of this transition remain incompletely understood, but chronic antigenic stimulation, environmental triggers, and genetic susceptibility are believed to contribute [ 62 , 63 ]. This shift from polyclonality to clonality marks the earliest step toward plasma cell dyscrasias [ 64 ].

Primary and secondary genetic aberrations in disease evolution

Genomic evolution in plasma-cell neoplasms begins with primary cytogenetic aberrations, which are detectable even in MGUS; these founder events persist throughout disease progression. Such lesions are present in ~ 90% of patients and define the dominant malignant clone [ 65 , 66 ]. They include numerical changes (hyperdiploidy) and structural abnormalities (IGH translocations at 14q32) [ 67 , 68 ]. Hyperdiploidy, observed in 50–60% of MM, involves trisomies of odd-numbered chromosomes (3, 5, 7, 9, 11, 15, 19, 21) [ 69 , 70 ]. It is generally considered a standard-risk event, whereas hyperhaploidy, often accompanied by monosomy 17 and TP53 mutations, confers very poor outcomes (5-year OS ~ 23%) [ 71 ]. IGH translocations, present in up to 50% of MM and already detectable in MGUS and SMM, juxtapose oncogenes with IGH enhancers, driving unchecked proliferation [ 72 , 73 ]. Partners include CCND1 [t(11;14)], FGFR3/MMSET [t(4;14)], MAF [t(14;16)], CCND3 [t(6;14)], and MAFB [t(14;20)], each with distinct prognostic implications [ 74 , 75 ].

Disease progression involves the stepwise accumulation of secondary aberrations that increase genomic complexity and confer a selective advantage [ 72 ]. Copy number alterations rise progressively from MGUS (~ 5 per patient) to SMM (7.5) and MM (~ 12) [ 76 ]. Clinically relevant examples include 1q gain, strongly associated with poor outcomes [ 77 , 78 ]. 1p deletion, more prominent in MM, and 13q14 loss, common in advanced disease [ 76 , 79 ]. Additional lesions such as 16q and 14q deletions accelerate progression in high-risk SMM [ 80 , 81 ]. The most critical abnormality is 17p deletion with TP53 inactivation, rare in MGUS, sometimes subclonal in SMM, and strongly linked to adverse prognosis and therapy resistance in MM [ 80 , 82 ]. MYC rearrangements (8q24) are late secondary events, rare in MGUS, but frequent in MM where they drive aggressive proliferation [ 83 – 85 ].

Epigenetic dysregulation in monoclonal gammopathies

Beyond genetic lesions, epigenetic dysregulation critically shapes plasma cell transformation. Global DNA hypomethylation, already present in MGUS and accentuated in MM, contributes to genomic instability, while partial re-methylation is reported in plasma cell leukemia [ 86 – 88 ]. DNMT3A downregulation and abnormal methylation patterns further implicate methyltransferase dysfunction [ 88 ]. Intriguingly, hypermethylation in MM often occurs outside CpG islands, affecting B-cell enhancers, suggesting epigenetic reprogramming that silences B-cell transcription factor networks [ 89 , 90 ]. In IgM gammopathies, methylation signatures help distinguish MGUS from WM, highlighting clinical relevance [ 91 ].

Histone modifications provide another regulatory layer. Aberrant expression of the repressor Gfi1 in the marrow microenvironment modifies histone marks at the Runx2 promoter, reducing H3K9ac and H3K4me3 and increasing H3K27me3, creating repressive chromatin that suppresses osteoblastogenesis and exacerbates bone disease. Notably, this repression can be reversed by HDAC1 or EZH2 inhibition [ 92 – 94 ]. Chromatin accessibility profiling has revealed reactivation of regulatory regions silenced during B-cell maturation, driven by IRF, FOX, and MEF2 factors [ 95 , 96 ]. Epigenomic patterns can stratify MM subgroups more precisely than expression data, reflecting integration of secondary drivers like RAS pathway alterations [ 97 ]. Distinct subtypes, such as CD2 + MM with cyclin D dysregulation, further underscore subtype-specific epigenetic programs [ 98 ]. Overall, monoclonal gammopathies exhibit a composite epigenetic landscape, global hypomethylation, enhancer-specific hypermethylation, and histone remodeling, that promotes malignant progression and represents a promising avenue for biomarker and therapeutic discovery (Table 2 ).

Signaling pathways and BM microenvironment

Intrinsic signaling pathways and BM microenvironment form an interdependent framework driving clonal expansion (Fig. 1 ). Internally, MM cells activate canonical survival pathways such as NF-κB, stimulated by IL-6 and lncRNA H19, promoting IL-8 secretion and apoptosis resistance [ 101 – 103 ]. The MAPK cascade, often driven by KRAS, NRAS, or BRAF mutations, sustains proliferation [ 104 ]. CXCR1/2 signaling, particularly in stem-like side population cells, fosters dissemination and correlates with poor outcomes in HY and MY subgroups [ 105 – 108 ]. Subsequent oncogenic events, such as MYC rearrangements, expedite the progression from precursor stages to symptomatic disease, underscoring the pivotal role of genetic drivers in disease advancement [ 109 ].

Extrinsically, BM microenvironment provides a cytokine-rich milieu. In MGUS, expansion of CD30 + and oligoclonal T cells reflects chronic immune activation, while MM is marked by CD4 + T-cell depletion, skewed CD4/CD8 ratio, and exhausted CD8 + T cells [ 105 – 108 ]. Plasma cells and stromal cells secrete pro-survival cytokines (IL-6, IL-8, HGF, IL-11) and immunosuppressive factors (TGF-β1, SDF-1α) [ 110 – 114 ]. Persistent antigenic stimulation (EBV, HCV, HSV, H. pylori) sustains monoclonal responses and alters antibody glycosylation, impairing ADCC [ 115 , 116 ]. Dysregulated chemokine signaling (CXCR1/2, CXCL2, CXCL8) drives migration, angiogenesis, and microenvironmental crosstalk [ 106 , 117 ]. Concurrently, bone remodeling is pathologically imbalanced: RANKL overexpression and OPG degradation enhance osteoclastogenesis, while Wnt inhibitors (DKK1, SOST, sFRPs) block osteoblast activity, resulting in osteolytic disease [ 118 – 121 ]. These data collectively highlight a pathogenic cycle wherein immunological dysfunction, cytokine–chemokine signaling, and alteration of the bone microenvironment collaborate with intrinsic plasma cell defects to maintain clonal survival, confer therapeutic resistance, and facilitate progression to overt plasma cell malignancy. The intricate interplay between these intrinsic and extrinsic drivers is summarized in Fig. 1 , which provides a schematic overview of the mechanisms fueling progression from MGUS to MM.

Biomarkers and risk stratification strategies

Serological markers remain the cornerstone of risk assessment in monoclonal gammopathies, particularly serum M-protein concentration and FLC ratio. These parameters not only establish the diagnosis but also provide early prognostic information by identifying patients at increased risk of progression. However, their inability to fully capture clonal heterogeneity and dynamic disease evolution has led to the exploration of novel biomarkers that more directly reflect tumor biology [ 122 , 123 ].

CTCs

CTCs, shed from BM into the peripheral blood, have gained attention as minimally invasive biomarkers that capture systemic disease biology in monoclonal gammopathies. Unlike BM biopsies, which offer only a focal “snapshot,” CTC analysis provides a dynamic “movie” of clonal evolution, resistance, and relapse [ 124 – 126 ]. Clinical studies demonstrate that elevated baseline CTC counts are strongly associated with adverse outcomes. For example, in newly diagnosed transplant-eligible MM, the presence of ≥ 0.02% CTCs predicted inferior progression-free survival (PFS) and overall survival (OS), independent of R-ISS stage [ 127 ]. Similarly, high CTC burden in relapsed/refractory settings has correlated with poor transplant outcomes and early relapse [ 128 ].

Technological advances, including single-cell sequencing (e.g., Epic platform, MinimuMM-seq), now allow precise molecular profiling of CTCs, detecting IGH translocations, copy number alterations, and subclonal heterogeneity comparable to BM plasma cells [ 125 , 129 ]. Longitudinal CTC sequencing facilitates early detection of high-risk clones, supporting adaptive therapy strategies. Importantly, combining CTC quantification with multiparametric flow cytometry (MFC) enhances prognostication, identifying ultra–high-risk patients with outcomes approximating R-ISS III [ 130 – 134 ].

Nevertheless, challenges remain: lack of standardized thresholds (reported cutoffs range from 0.01% to 2% depending on cohort), methodological differences between conventional and next-generation flow cytometry, and uncertainties regarding plasma cell egress mechanisms [ 130 , 132 , 135 ]. Lack of methodological harmonization, particularly between conventional and next-generation flow cytometry, limits cross-cohort comparisons. Moreover, uncertainties persist regarding the mechanisms of plasma cell egress and whether CTCs fully recapitulate marrow biology or reflect systemic disease burden [ 136 ]. Heterogeneity in CTC phenotypes, including CD138⁻/pS6⁺ subsets, further underscores the need for standardized detection approaches [ 125 ].

Evidence also supports the value of CTC detection in precursor stages. In a cohort of 186 patients (106 MGUS, 80 SMM), circulating tumor plasma cells (CTPCs) were identified in 15.1% of MGUS and 30.0% of SMM cases, significantly more frequent in SMM ( p = 0.019). CTPC-positive patients exhibited higher.

marrow clonal plasma cell burden (MGUS: 1.42% vs. 0.47%, p = 0.011; SMM: 2.48% vs. 1.99%, p = 0.018), reduced expression of CD28, CD38, CD56, and CD200, and a higher frequency of del(13q14) (42.9% vs. 13.9%, p = 0.002) compared with CTPC-negative counterparts [ 137 ]. These findings highlight the potential of CTCs as early markers of malignant transformation in MGUS and SMM. Moreover, serial monitoring of CTC burden can anticipate biochemical relapse before increases in M-protein or FLC ratio, providing a critical window for preemptive intervention [ 138 ].

At the molecular level, elevated CTC levels have been associated with proliferative signatures and transcriptional programs linked to cell cycle activity, along with reduced adhesion molecule expression and signs of immune activation [ 128 ]. Proof-of-concept studies further demonstrated that integrating CTC enumeration with key genomic features (e.g., IRMMa) improves prognostic discrimination, suggesting that CTCs refine traditional genomic-based risk stratification [ 139 ]. This systemic perspective complements marrow-based MRD, which captures local tumor burden but often misses spatial heterogeneity. Large-scale analyses confirmed that high CTC counts, measured by NGF and count-based approaches, stratify prognosis independently and are enriched for adverse genomic features including gain/amp1q, NSD2- or MAF/MAFB translocations, APOBEC mutagenesis, chromothripsis, and complex structural variants [ 138 ]. Collectively, these data support CTCs as a minimally invasive, reproducible biomarker that integrates with MRD to identify patients with biologically aggressive myeloma. Key findings on CTCs, their prognostic thresholds, and clinical relevance in monoclonal gammopathies are summarized in Table 3 .

MRD

MRD, the persistence of small numbers of malignant plasma cells during or after therapy, is now incorporated into IMWG response criteria to refine hematologic response assessment [ 142 ]. Following its incorporation, MRD evaluation has demonstrated enhanced prognostic stratification across several clinical contexts, encompassing newly diagnosed transplant-eligible and non-eligible patients, in addition to those with recurrent disease. Numerous retrospective and prospective studies consistently indicate that MRD negativity is significantly associated with extended PFS and OS, thereby establishing MRD negativity as a vital endpoint in current clinical trials of MM [ 143 – 145 ].

The identification of MRD in plasma cell myeloma depends on sophisticated technologies that provide unique benefits and drawbacks. MFC is the predominant method, utilizing antibody panels to differentiate between normal and cancerous plasma cells. The previous 4–6 color panels exhibited restricted specificity; however, the implementation of 8–10 color flow cytometry has significantly improved resolution, attaining sensitivities of 10⁻⁴–10⁻⁵ and establishing the foundation for the IMWG guidelines, utilizing markers such as CD38, CD138, CD45, CD19 negativity, and cytoplasmic κ/λ light chains [ 146 – 149 ]. Allele-specific oligonucleotide quantitative PCR (ASO-qPCR) provides enhanced sensitivity (10⁻⁵–10⁻⁶) and focuses on patient-specific immunoglobulin heavy or light chain rearrangements [ 150 – 152 ]. Nonetheless, its efficacy in myeloma is hindered by elevated somatic hypermutation rates and the necessity for intricate assay standardization, encompassing repetitive curve development and cloning [ 153 ]. Next-generation sequencing (NGS) now constitutes the most thorough methodology, achieving sensitivities of 10⁻⁶, which facilitates the identification of copy number variations, IGH translocations, and gene mutations through optimized focused assays [ 154 – 157 ]. Genomic analysis of asymptomatic stages has significantly indicated increased complexity, with a median of one mutation in MGUS and two in SMM patients, highlighting early clonal heterogeneity [ 158 ]. MFC yields swift real-time results, ASO-qPCR ensures accuracy in clonal monitoring, and NGS provides profound insights, collectively establishing MRD as a fundamental element for risk classification and therapy direction. As summarized in Table 4 , multiple complementary technologies are available for MRD detection, ranging from standardized BM–based assays (NGF, NGS) to emerging liquid biopsy and imaging strategies.

Risk stratification models

Risk stratification remains central to clinical decision-making in monoclonal gammopathies. For MGUS, the Mayo Clinic model (non-IgG isotype, M-protein ≥ 1.5 g/dL, abnormal FLC ratio) classifies patients into low-, intermediate-, and high-risk groups with 20-year progression rates from ~ 5% to > 50% [ 159 ]. In SMM, the Mayo 20/2/20 model (BM plasma cells ≥ 20%, M-protein ≥ 2 g/dL, FLC ratio ≥ 20) and the IMWG 2020 update incorporating cytogenetics define risk groups with 2-year progression rates ranging from < 10% to > 50% [ 28 , 160 ]. In MM, the International Staging System (ISS), based on β2-microglobulin and albumin, and its revision (R-ISS), which adds LDH and high-risk cytogenetics [t(4;14), t(14;16), del(17p)], remain globally validated frameworks [ 161 ]. The second revision (R2-ISS) further refines risk assessment by integrating the impact of 1q gain/amplification and TP53 deletion, enabling a more granular four-tier classification (R2-ISS I–IV) [ 162 – 164 ]. The recent high-risk criteria endorsed by the International Myeloma Society (IMS) and IMWG emphasize a Consensus Genomic Staging (CGS) framework that integrates both cytogenetic and molecular abnormalities [ 142 ]. Specifically, it highlights the cumulative effect of multiple high-risk lesions, including del(17p)/TP53 mutation, 1q gain/amplification, del(1p32), and IgH translocations [t(4;14), t(14;16), t(14;20)], as well as sustained MRD positivity as defining features of biological high-risk multiple myeloma (HRMM) [ 142 ].

Beyond disease-related markers, patient-related risk factors critically influence prognosis and treatment selection. These include age, frailty, performance status, renal function, comorbidities, cytopenias, and treatment tolerability, all of which guide therapy intensity and eligibility for ASCT or quadruplet regimens [ 165 ]. Incorporating frailty scores (e.g., IMWG Frailty Index, Revised Myeloma Comorbidity Index) alongside biological risk models provides a more comprehensive, individualized approach to risk-adapted therapy [ 166 ].

While traditional models rely mainly on static tumor burden measures, integrating dynamic biomarkers such as CTCs and MRD promises to refine risk stratification by capturing clonal evolution and biological aggressiveness more precisely.

Innovative therapeutic strategies

Therapeutic backbones and evolution of MM therapy

The management of MM has progressively shifted from traditional cytotoxic chemotherapy to targeted therapies that form the backbone of modern regimens. Historically, alkylating agents such as melphalan, often combined with corticosteroids, provided modest survival benefits, while high-dose melphalan followed by autologous stem cell transplantation (ASCT) established the standard first-line approach for eligible patients [ 167 , 168 ]. Corticosteroids, particularly dexamethasone, continue to serve as indispensable adjuncts, offering direct antimyeloma activity and synergistic effects with other agents [ 169 ]. Despite these advances, conventional backbones are limited by cumulative toxicity, relapse, and resistance, highlighting the need for ongoing innovation [ 170 , 171 ].

Immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, have transformed MM therapy by combining direct cytotoxicity, anti-angiogenic effects, and potent immune modulation. These agents enhance T- and NK-cell activity, suppress regulatory T cells, and influence key transcription factors, supporting durable responses in both transplant-eligible and -ineligible patients [ 172 , 173 ]. Neuropathy remains the main dose-limiting toxicity for thalidomide, while lenalidomide and pomalidomide are generally better tolerated [ 174 ]. Resistance mechanisms justify their combination with PIs, mAbs, or next-generation CELMoDs [ 175 , 176 ].

PIs such as bortezomib, carfilzomib, and ixazomib target proteostasis and NF-κB signaling, inducing apoptosis in proteasome-dependent plasma cells [ 177 , 178 ]. Second-generation agents provide enhanced potency and efficacy but carry distinct toxicities, while oral formulations improve convenience and tolerability [ 179 , 180 ]. Collectively, these therapeutic classes establish the structural framework for contemporary MM regimens, balancing efficacy, toxicity, and resistance, and laying the foundation for innovative strategies that continue to reshape patient outcomes [ 170 , 171 , 181 ].

Monoclonal antibodies and the contemporary standard of care in MM

The advent of mAbs has revolutionized the therapeutic landscape MM, introducing a new era of immune-based precision therapy. These agents exploit antibody-mediated mechanisms, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct induction of apoptosis, to selectively target and eradicate malignant plasma cells [ 182 ]. Among them, CD38-directed antibodies have had the most profound clinical impact. Daratumumab, the first-in-class anti-CD38 mAb, has shown remarkable efficacy across all disease stages, while isatuximab, recognizing a distinct CD38 epitope, has demonstrated complementary activity and robust outcomes in relapsed/refractory MM, notably in the ICARIA-MM trial [ 183 , 184 ]. Additionally, elotuzumab, targeting SLAMF7, augments natural killer (NK) cell activation and synergizes with IMiDs, though its efficacy as monotherapy remains limited [ 185 ]. Collectively, mAb-based therapies have achieved unprecedented depth and durability of response, transforming MM management from cytotoxic to immune-directed strategies [ 186 , 187 ].

The current standard-of-care for MM integrates PIs, IMiDs, corticosteroids, and CD38-directed mAbs, forming triplet or quadruplet induction backbones tailored to patient eligibility for ASCT [ 188 ]. For transplant-eligible patients, the combination of a PI, an IMiD, and dexamethasone (e.g., bortezomib–lenalidomide–dexamethasone, VRd) has long represented the preferred induction therapy, providing deep and durable responses [ 189 , 190 ]. The addition of daratumumab (D-VRd) in the GRIFFIN and PERSEUS trials has further enhanced MRD negativity rates and PFS, establishing quadruplet therapy as the new benchmark for first-line treatment [ 188 , 191 ].

For transplant-ineligible or frail patients, daratumumab–lenalidomide–dexamethasone (D-Rd) and daratumumab–bortezomib–melphalan–prednisone (D-VMP) have emerged as standard frontline options, as demonstrated in the MAIA and ALCYONE studies, respectively [ 192 , 193 ]. These regimens offer substantial survival advantages with manageable toxicity, extending therapeutic benefits to older or comorbid individuals.

ASCT remains a critical consolidative approach for eligible patients, typically following 4–6 cycles of induction therapy [ 194 ]. Post-transplant maintenance with lenalidomide, and increasingly with daratumumab–lenalidomide combinations, sustains remission and improves long-term outcomes [ 195 ]. The overarching treatment paradigm now emphasizes achieving MRD negativity through potent multi-class combinations while maintaining quality of life through risk-adapted sequencing and maintenance [ 192 ].

CAR-T cells and bispecific antibodies

Chimeric antigen receptor T-cell (CAR-T) therapy has redefined the therapeutic landscape of MM, introducing a personalized, immune-based approach that harnesses the patient’s own T cells to target malignant plasma cells [ 196 ]. These engineered T cells are modified to express an artificial receptor consisting of an extracellular single-chain variable fragment (scFv) that recognizes certain malignant plasma cell antigens, such as B-cell maturation antigen (BCMA) - a marker abundantly expressed on plasma cells - and intracellular signaling domains such as CD3ζ, along with co-stimulatory motifs (CD28 or 4-1BB) [ 197 ]. This design promotes robust T-cell activation, proliferation, and cytotoxicity, independent of major histocompatibility complex (MHC) presentation, enabling precise and potent tumor cell killing [ 198 ]. Beyond direct cytolysis, CAR-T cells may establish long-term immunologic surveillance, though durability is often challenged by antigen loss, T-cell exhaustion, and microenvironmental suppression [ 199 ].

Clinically, CAR-T therapy has produced unprecedented outcomes in relapsed or refractory MM (RRMM). In the pivotal KarMMa trial evaluating Idecabtagene Vicleucel (ide-cel), the first FDA-approved BCMA-directed CAR-T, demonstrated high overall response rates (ORR 73%), with nearly one third of patients achieving complete response (CR), even in heavily pretreated cohorts. Similarly, the CARTITUDE-1 trial of Ciltacabtagene Autoleucel (cilta-cel) achieved an unprecedented ORR of 97% with durable responses, establishing CAR-T as a transformative option in relapsed/refractory MM. modulate their expansion kinetics, persistence, and toxicity profiles. Key adverse events, including cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity (ICANS), and prolonged cytopenias, require vigilant monitoring and specialized multidisciplinary management. Ongoing studies are now moving CAR-T therapy beyond the relapsed/refractory setting, exploring its integration into earlier disease stages, including high-risk or newly diagnosed MM, where the immune system may be more intact and capable of sustaining long-term antitumor responses [ 200 ].

In parallel with CAR-T development, bispecific T-cell engagers (BiTEs) and bispecific antibodies (BsAbs) have emerged as powerful off-the-shelf immunotherapeutic platforms capable of redirecting endogenous T cells against malignant plasma cells [ 201 ]. These molecules possess dual specificity: one arm binds to a myeloma-associated antigen, most commonly BCMA, GPRC5D, or FcRH5, while the other engages CD3 on T cells, thereby forming an artificial immune synapse that triggers T-cell activation, cytokine release, and targeted cytolysis of myeloma cells [ 202 ]. Unlike CAR-T products, bispecifics do not require individualized manufacturing, allowing immediate availability and repeat dosing, features that expand access and facilitate use in both community and hospital settings [ 203 ].

Clinically, bispecifics have produced deep and durable responses in heavily pretreated MM populations. In the MajesTEC-1 trial, the BCMA/CD3 bispecific teclistamab achieved an overall response rate (ORR) of 63%, with CRs in 39% and MRD negativity in nearly half of responders, leading to its FDA approval as the first bispecific antibody for MM [ 204 ]. Similarly, talquetamab, targeting GPRC5D/CD3, demonstrated ORR 73% in the MonumenTAL-1 study, with activity maintained even in patients refractory to prior BCMA-directed therapy [ 205 ]. Compared with CAR-T, bispecifics offer easier administration, repeat dosing, and broader accessibility. Nevertheless, toxicities such as CRS, infections, and prolonged cytopenias remain relevant concerns [ 206 ]. Table 5 summarizes key clinical studies of novel therapeutic agents in MM, highlighting their mechanisms of action, efficacy outcomes, and major toxicities.

Challenges and future perspectives

Despite remarkable therapeutic advances in MM, significant challenges persist across the continuum of monoclonal gammopathies. At the earliest stages, identifying which patients with MGUS or SMM will progress to overt disease remains a major unmet clinical need. Current risk stratification models based on M-protein concentration, BM plasma cell percentage, and FLC ratios provide valuable but incomplete guidance, as they fail to capture the dynamic heterogeneity of clonal evolution. Similarly, imaging and cytogenetics improve the detection of high-risk SMM, but predicting individual trajectories toward symptomatic MM remains imprecise. This uncertainty often leads to a dilemma between overtreatment of stable cases and delayed intervention in those destined for rapid progression, underscoring the need for more refined biomarkers and integrative monitoring strategies.

Looking ahead, the future of managing monoclonal gammopathies will hinge on precision medicine guided by advanced analytics. AI and multi-omics platforms, integrating genomics, transcriptomics, proteomics, metabolomics, and epigenetics with imaging and clinical data, hold the potential to generate dynamic risk scores and real-time prognostic insights [ 91 , 209 ]. Liquid biopsy approaches such as CTCs and cell-free DNA (cfDNA) are poised to complement BM–based MRD testing, offering minimally invasive tools to track disease evolution [ 210 ]. On the therapeutic front, novel immunotherapies including CELMoDs, bispecific antibodies, and CAR-T/CAR-NK constructs are expected to be deployed in biomarker-matched regimens tailored to clonal vulnerabilities. Adaptive clinical trial designs that incorporate MRD dynamics and AI-predicted risk models may enable treatment de-escalation for indolent cases and intensification for high-risk disease. Recent studies have demonstrated that machine-learning models integrating clinical, genomic, and laboratory data can generate individualized risk scores for progression from MGUS or SMM to MM. For example, neural-network–based models trained on large cohorts (> 1,000 patients) have accurately predicted high-risk cases before symptomatic disease, allowing earlier therapeutic intervention, while identifying low-risk patients who may safely undergo treatment de-escalation [ 211 , 212 ]. Ultimately, the overarching challenge is to transform the odyssey of monoclonal gammopathies, from their silent origins in MGUS and transitional SMM to malignant MM, into a navigable journey where early detection, individualized therapy, and durable remission converge toward the prospect of cure.

Conclusion

The odyssey of monoclonal gammopathies, from the silent shadows of MGUS through the uncertain borderland of SMM to the overt malignancy of MM, reflects a multistep evolutionary journey driven by genetic, epigenetic, and microenvironmental forces. At each stage, clonal plasma cells acquire new adaptations, genomic aberrations, signaling rewiring, and microenvironmental support, that propel them further along the malignant trajectory. While current diagnostic models and therapeutic strategies have transformed outcomes, challenges such as predicting progression, overcoming drug resistance, and capturing systemic disease heterogeneity remain unresolved. The integration of multi-omics, AI, and minimally invasive biomarkers such as CTCs and cfDNA promises to refine risk stratification and enable adaptive, precision-guided care. Ultimately, the goal is to convert this odyssey from an inexorable progression to mortality into a navigable path toward durable remission and, potentially, cure driven by early detection, targeted therapy, and individualized monitoring.

Acknowledgements

None.

Abbreviations

Antibody-dependent cellular cytotoxicity

Amyloid light-chain amyloidosis

Autologous stem cell transplantation

Bone marrow

Circulating tumor cell

HyperCalcemia, Renal insufficiency, Anemia, Bone lesions

Circulating tumor plasma cell

Free light chain

International Myeloma Working Group

International Consensus Classification

Lactate dehydrogenase

Monoclonal gammopathy of clinical significance

Monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of renal significance

Multiple myeloma

Minimal residual disease

Next-generation flow cytometry

Next-generation sequencing

Plasma cell myeloma

Progression-free survival

Primary plasma cell leukemia

Revised International Staging System

Smoldering multiple myeloma

Author contributions

Concept and study supervision: H. Rahmani Seraji, Y. Huang.Manuscript conception and outline: H. Rahmani SerajiSystematic literature search and primary evidence collection: Xin Xin, Ran Sheng, Xiuchong Li, Chunhui Fan.Critical content drafting and revision (biological mechanisms, MRD and CTC sections, and therapeutic strategies): H. Rahmani Seraji, Xin Xin, Ran Sheng, X. Li, Xing Zhu, Chunhui Fan, Y. Huang.Methodologic and technical review (MRD/NGS/NGF interpretation, clinical trial evidence synthesis): Chunhui Fan, Xing Zhu, Y. Huang.English language editing, scientific polishing and manuscript formatting for submission: Y. Huang, Xin Xin, Xing Zhu.Administrative coordination, correspondence with the journal and final manuscript approval: H. Rahmani Seraji, Y. Huang.Literature search and manuscript preparation support: Dilbar Urazbaeva, Zamira Atamuratova, Abdullaeva Dilbar Ubaydullaevna.All authors reviewed and approved the final manuscript and agree to be accountable for all aspects of the work.

Funding

This research did not receive any financial support from public, commercial, or nonprofit organizations.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Yongsheng Huang, Email: paperpub198800@gmail.com.

Hamideh Rahmani Seraji, Email: rahmaniseraji63.hr@gmail.com.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.