Multiple myeloma is a hematologic malignancy characterized by clonal proliferation of malignant plasma cells in the bone marrow, leading to production of monoclonal immunoglobulin (M protein). The disease causes osteolytic bone lesions, renal impairment, hypercalcemia, and anemia. Key cytogenetic abnormalities include t(4;14), t(14;16), del(17p), and hyperdiploidy. Treatment includes proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, and autologous stem cell transplantation.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on the pathophysiology of Multiple Myeloma. Focus on the molecular and cellular mechanisms underlying disease progression.
Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs
Disease: Multiple Myeloma (MM) — malignant plasma cell neoplasm primarily residing in the bone marrow with systemic end-organ damage. (moscvin2023dissectingmolecularmechanisms pages 1-3, bhowmick2024pathwaystotherapy pages 1-3)
MONDO ID: Not retrieved in the provided evidence; Open Targets disease identifier returned was EFO_0001378 (“multiple myeloma”). ()
Precursor conditions: Monoclonal gammopathy of undetermined significance (MGUS) and Smoldering multiple myeloma (SMM) are clinically recognized antecedent states. (kansal2024towardprecisionmedicine pages 2-3, moscvin2023dissectingmolecularmechanisms pages 1-3, liotti2024investigationonthe pages 9-13)
Multiple myeloma is characterized by clonal expansion of malignant plasma cells in the bone marrow and is clinically defined by myeloma-defining events and/or end-organ damage (classically “CRAB”: hyperCalcemia, Renal failure, Anemia, Bone lesions). (liotti2024investigationonthe pages 9-13, moscvin2023dissectingmolecularmechanisms pages 1-3)
MM is widely described as a multi-step disease evolving from MGUS → SMM → symptomatic MM → more aggressive forms (including extramedullary disease/plasma cell leukemia), with increasing genomic complexity and microenvironmental remodeling over time. (liotti2024investigationonthe pages 9-13, gong2024novelinsightsinto pages 10-12)
Recent clinical models incorporate myeloma-defining biomarkers (SLiM-CRAB) that predict near-term progression and justify treatment initiation. * Bone marrow plasmacytosis ≥60% is associated with rapid progression. (kansal2024towardprecisionmedicine pages 2-3) * Serum free light chain (FLC) ratio thresholds (e.g., FLC >100 associated with ~79% progression) are used as high-risk markers. (kansal2024towardprecisionmedicine pages 2-3) * >1 focal lesion on whole-body MRI predicts progression. (kansal2024towardprecisionmedicine pages 2-3)
MM pathophysiology emerges from the convergence of (i) intrinsic tumor genomic/epigenomic programs and (ii) an extrinsic bone marrow niche that supplies survival cues, immune escape, and therapy resistance.
Primary initiating events often involve hyperdiploidy or IgH locus translocations (14q32) that juxtapose oncogenes to immunoglobulin enhancers; these primary events are detectable already in precursor states. (lemonakis2024factorsaffectingprognosis pages 24-28, kansal2024towardprecisionmedicine pages 2-3, liotti2024investigationonthe pages 9-13)
Progression is associated with accumulation of secondary hits (copy-number alterations, mutations, epigenetic changes) and selection of resistant subclones, especially under treatment pressure; chemotherapy can contribute a substantial fraction of nonsynonymous mutations and relapse may arise from a surviving propagating cell. (gong2024novelinsightsinto pages 10-12)
KRAS/NRAS/BRAF alterations are common, and a 2024 synthesis reports RAS mutations present in ~50% of MM patients, consistent with MAPK pathway dependence in many cases. (ram2024thegeneticand pages 25-26)
A 2024 mechanistic study demonstrates that constitutive non-canonical NF-κB signaling via p52 (NFKB2) reprograms the MM epigenome: p52 binds and activates typical enhancers/super-enhancers, reshaping 3D enhancer–promoter interactions and sustaining expression of myeloma dependency genes (e.g., BCL2, IL6ST, RGS1). (ang2024aberrantnoncanonicalnfκb pages 7-8)
In a 2024 review of genetic drivers in relapsed/refractory MM, TP53 pathway inactivation is reported in ~45% of patients in the summarized cohort(s), with complex “double-hit” contexts (e.g., 17p LOH with 1q alterations) emerging during progression. (ram2024thegeneticand pages 20-22)
Myeloma cells face extreme secretory stress; proteostasis adaptation (including heat shock programs) is implicated in relapse biology and in resistance, including links between NF-κB activation and proteasome inhibitor resistance. (ram2024thegeneticand pages 20-22)
The BMME supplies growth factors, adhesion-mediated signaling, and immune suppression.
A 2024 review explicitly frames microenvironmental “sheltering” and notes elevated stromal-derived growth factors (e.g., SCF, VEGF, IL-6) in MM marrow niches. (bhowmick2024pathwaystotherapy pages 1-3)
Environment-mediated drug resistance (EMDR) is reinforced by spatial proximity to stromal/bone compartments and bone-derived factors. A 2024 hybrid modeling + in vivo validation study supports a mechanism where bone microenvironment protection increases the probability and heterogeneity of resistant clones during therapy. (bishop2024theboneecosystem media ec296c58, bishop2024theboneecosystem media ea2ecb8d)
Immune alterations begin early and evolve toward an immune-tolerant marrow environment.
A 2023 review states that innate and adaptive effectors “show marked dysfunction and skewing towards a tolerant environment that favors disease progression,” with increased MDSCs and M2-like macrophages and lymphoid skewing toward Th17/Treg with inhibition of cytotoxic/effector T cells. (moscvin2023dissectingmolecularmechanisms pages 1-3)
Quantitative immune profiling (CyTOF/multi-omics) supports early and stage-specific shifts: * HLA-DR is reduced in CD16+ monocytes and plasmacytoid dendritic cells, with dendritic-cell stress/immune-response programs downregulated. (cheng2024multiomicsrevealimmune pages 1-2) * CyTOF-reported changes include 65% decrease of immature granulocytes in MGUS vs normal BM, 53% decrease of pDCs in SMM (and 51% in NDMM), and increases in CD16+ monocytes of 5.6-fold (MGUS), 2.0-fold (SMM), and 1.6-fold (NDMM). (cheng2024multiomicsrevealimmune pages 1-2)
In rapid-progressing MM, single-cell RNA-seq showed significantly higher enrichment of exhausted CD8+ T cells (GZMK+, TIGIT+) with P = 0.022, along with decreased cytolytic gene expression (PRF1, GZMB, GNLY), and a higher ratio of exhausted T cells (P = 0.049). (pilcher2023crosscentersinglecell pages 1-2)
Expert analysis emphasizes that immune status and spatial contexture influence outcomes of modern immunotherapies (CAR-T, bispecifics), and proposes distinct “spatial immune types” (immune depleted/permissive/excluded/suppressed/resistant) to guide patient selection. (dhodapkar2024immunestatusand pages 2-3)
Key categories supported by recent evidence include: * MAPK drivers: KRAS/NRAS/BRAF. (ram2024thegeneticand pages 25-26) * Non-canonical NF-κB chromatin drivers: NFKB2 (p52) and associated regulators (e.g., TRAF3/CYLD context in broader genomic models). (ang2024aberrantnoncanonicalnfκb pages 7-8, ram2024thegeneticand pages 22-23) * Tumor suppressor disruption: TP53 pathway inactivation enriched in advanced disease. (ram2024thegeneticand pages 20-22) * Bone disease mediators: FLT3L/STAT3/DKK1; CCL3/HMGB1/RANKL; MMP13/VSIR (PD-1H/VISTA). (shin2024elucidationofmolecular pages 1-2, anloague2024anovelccl3hmgb1 pages 13-14, fu2023thecheckpointinhibitor pages 1-2)
Supported mediators include IL-6, VEGF, CXCL12/SDF-1, RANKL, and WNT antagonists such as DKK1, plus inflammatory mediators (IL-1β, TNF-α, MIP-1α/CCL3). (bhowmick2024pathwaystotherapy pages 1-3, shin2024elucidationofmolecular pages 1-2)
Prominent involved cell types include: * Bone marrow plasma cells (malignant clone). (moscvin2023dissectingmolecularmechanisms pages 1-3, bhowmick2024pathwaystotherapy pages 1-3) * Mesenchymal stromal cells (MSCs) as niche architects with impaired osteogenic and hematopoietic support functions. (bogun2024stromalalterationsin pages 1-2, bogun2024stromalalterationsin pages 11-12) * Osteoclasts / osteocytes / osteoblast-lineage cells mediating bone remodeling imbalance. (fu2023thecheckpointinhibitor pages 1-2, anloague2024anovelccl3hmgb1 pages 13-14, shin2024elucidationofmolecular pages 1-2) * CD8+ T cells, NK cells, monocytes/DCs, and suppressor populations such as MDSCs and Tregs. (pilcher2023crosscentersinglecell pages 1-2, cheng2024multiomicsrevealimmune pages 1-2, moscvin2023dissectingmolecularmechanisms pages 1-3)
The central site is bone marrow, with major pathological consequences in bone (osteolytic disease). (moscvin2023dissectingmolecularmechanisms pages 1-3, shin2024elucidationofmolecular pages 1-2)
Evidence-supported disrupted biological processes include:
Mechanisms operate across:
MGUS and SMM are clinically defined precursor states that can progress to MM. (liotti2024investigationonthe pages 9-13, moscvin2023dissectingmolecularmechanisms pages 1-3)
Evidence-supported progression risk statistics: * MGUS: approximately ~1% annual progression risk to malignancy. (liotti2024investigationonthe pages 9-13, barakat2023investigatingtcell pages 14-17) * SMM: approximately ~10% per year for the first 5 years, then 3% for the next 5, then ~1% thereafter (reviewed summary). (liotti2024investigationonthe pages 9-13)
Stromal alterations are “already imprinted” at asymptomatic stages and become more pronounced across MGUS → SMM → MM, including BMP/TGF signaling perturbations, senescence, reduced osteogenesis, and impaired hematopoietic support. (bogun2024stromalalterationsin pages 1-2, bogun2024stromalalterationsin pages 11-12)
Immune remodeling begins early: antigen presentation defects and skewing toward immunosuppressive/exhausted states are detectable in MGUS and evolve with progression. (cheng2024multiomicsrevealimmune pages 1-2, moscvin2023dissectingmolecularmechanisms pages 11-13)
Bone disease arises from increased osteoclast activity and impaired osteoblast function. (shin2024elucidationofmolecular pages 1-2)
Recent mechanistic advances include: * FLT3L→STAT3(pY705)→DKK1, with DKK1 inhibiting WNT signaling and nuclear β-catenin translocation, suppressing osteoblast-mediated bone formation; FLT3L is higher in MM than AML/ALL and higher in MM with bone lesions. (Haematologica, Jan 2024; https://doi.org/10.3324/haematol.2023.283784). (shin2024elucidationofmolecular pages 1-2, shin2024elucidationofmolecular pages 2-3) * CCL3 induces osteocyte RANKL upregulation, and CCL3 triggers osteocyte HMGB1 release which “may act as a propagating pro-osteoclastogenic signal in neighboring osteocytes.” (Haematologica, Nov 2024; https://doi.org/10.3324/haematol.2024.286484). (anloague2024anovelccl3hmgb1 pages 13-14) * MMP-13/PD-1H (VISTA/VSIR) axis in osteoclasts: PD-1H is identified as the receptor for MMP-13, enabling enhanced osteoclast fusion and sealing-zone formation; PD-1H deficiency attenuates myeloma-induced bone destruction in vivo. (Nature Communications, Jul 2023; https://doi.org/10.1038/s41467-023-39769-8). (fu2023thecheckpointinhibitor pages 1-2)
Real-world implementation: antiresorptive agents are discussed, including bisphosphonates (pamidronate/zoledronate) and denosumab (RANKL inhibitor), with awareness of complications such as BRONJ. (shin2024elucidationofmolecular pages 9-10)
MM plasma cells produce monoclonal immunoglobulins and free light chains; excess FLC can cause renal failure, and FLC ratios are used for progression risk stratification. (liotti2024investigationonthe pages 9-13, kansal2024towardprecisionmedicine pages 2-3)
End-organ damage includes anemia, and stromal dysfunction includes reduced hematopoietic support (twofold reduction in MGUS/SMM and larger reductions in MM MSCs), providing a mechanistic link between niche failure and cytopenias. (moscvin2023dissectingmolecularmechanisms pages 1-3, bogun2024stromalalterationsin pages 11-12)
A 2024 mechanistic study shows sustained p52 (non-canonical NF-κB) remodels enhancer landscapes and 3D chromatin loops to maintain myeloma dependency transcriptional programs—moving beyond pathway “activation” to cis-regulatory architecture as a driver. (BioRxiv Jan 2024; https://doi.org/10.1101/2024.01.09.574787). (ang2024aberrantnoncanonicalnfκb pages 7-8)
Multi-omics profiling supports that immune remodeling starts in precursor states, with quantitative changes in granulocytes, pDCs, and CD16+ monocytes, and increased TIM3/TIGIT inhibitory markers during progression. (Blood Cancer Journal, Nov 2024; https://doi.org/10.1038/s41408-024-01172-x). (cheng2024multiomicsrevealimmune pages 1-2)
A 2024 Blood Advances study highlights stromal alterations already in MGUS, with BMP/TGF pathway dysregulation, senescence (e.g., CDKN2A/p16 upregulation), reduced osteogenesis, and diminished hematopoietic support; the use of a TGF-βRI inhibitor (SD208) to restore osteogenic capacity suggests a niche-targeted prevention concept. (May 2024; https://doi.org/10.1182/bloodadvances.2023011632). (bogun2024stromalalterationsin pages 1-2, bogun2024stromalalterationsin pages 11-12)
A 2024 Nature Communications study integrates a spatiotemporal model and in vivo testing to show that bone microenvironment-mediated resistance increases the heterogeneity and probability of resistant clones—supporting “ecological” strategies to delay relapse. (Mar 2024; https://doi.org/10.1038/s41467-024-46594-0). (bishop2024theboneecosystem media ec296c58, bishop2024theboneecosystem media ea2ecb8d)
Real-world MM management uses agents that target both tumor-intrinsic programs and microenvironment/immune axes.
High-risk SMM identification using SLiM biomarkers (FLC ratio, marrow plasmacytosis, imaging lesions) is a current clinical application of biology-informed progression risk. (kansal2024towardprecisionmedicine pages 2-3)
Immune dysfunction is not confined to the tumor mass: clinical malignancy “originates in the setting of systemic immune alterations that begin early in myelomagenesis and regional changes in immunity affected by spatial contexture,” and immune-status variation is “emerging as a major determinant” of immune-therapy efficacy—supporting spatially informed patient selection. (Blood Advances, May 2024; https://doi.org/10.1182/bloodadvances.2023011242). (dhodapkar2024immunestatusand pages 2-3)
A 2023 immunopathology review emphasizes that MM progression is accompanied by skewing toward an immune-tolerant environment; it highlights MDSCs, DC alterations, M2-like macrophages, and Th17/Treg shifts as a coherent immune-escape system. (May 2023; https://doi.org/10.20517/2394-4722.2022.110). (moscvin2023dissectingmolecularmechanisms pages 1-3)
| Mechanism / Pathway | Key Genes & Molecules | Cellular Context | Clinical Phenotype | Representative Evidence |
|---|---|---|---|---|
| FLT3L-STAT3-DKK1 Axis | FLT3L, STAT3 (pY705), DKK1 | Plasma Cells → Osteoblasts (Bone Marrow) | Osteolytic Bone Lesions: Inhibition of WNT-mediated bone formation; high FLT3L links to poor prognosis. | (shin2024elucidationofmolecular pages 9-10, shin2024elucidationofmolecular pages 1-2, shin2024elucidationofmolecular pages 2-3) |
| Osteocyte-Driven Osteoclastogenesis | CCL3 (MIP-1α), HMGB1, TNFSF11 (RANKL) | Plasma Cells → Osteocytes | Bone Resorption: CCL3 induces osteocyte HMGB1 release and RANKL upregulation, amplifying osteoclast activity. | (anloague2024anovelccl3hmgb1 pages 13-14, anloague2024anovelccl3hmgb1 pages 14-15) |
| Non-Canonical NF-κB Activation | NFKB2 (p52), TRAF3, CYLD, NIK | Plasma Cells | Tumor Progression: Epigenetic rewiring of enhancers drives oncogenic transcriptomes and survival. | (ang2024aberrantnoncanonicalnfκb pages 7-8, ram2024thegeneticand pages 22-23) |
| T-Cell Exhaustion & Checkpoints | TIGIT, LAG3, PDCD1 (PD-1), GZMK vs GZMB | CD8+ T Cells, NK Cells (Bone Marrow) | Immune Evasion: Rapid progression linked to TIGIT+/GZMK+ exhausted T cells and loss of cytolytic function. | (pilcher2023crosscentersinglecell pages 1-2, cheng2024multiomicsrevealimmune pages 1-2, barakat2023investigatingtcell pages 66-70) |
| Stromal Senescence & TGF-β | TGFB1, BMP2, CDKN2A (p16) | Mesenchymal Stromal Cells (MSCs) | Niche Dysfunction: Impaired osteogenesis and hematopoietic support; promotes progression from MGUS/SMM. | (bogun2024stromalalterationsin pages 1-2, bogun2024stromalalterationsin pages 11-12, bogun2024stromalalterationsin pages 6-8) |
| PD-1H (VISTA) Signaling | VSIR (PD-1H), MMP13 | Osteoclasts | Bone Destruction: PD-1H acts as a receptor for MMP-13 to drive osteoclast fusion and resorption. | (fu2023thecheckpointinhibitor pages 1-2) |
| RAS/MAPK Pathway | KRAS, NRAS, BRAF | Plasma Cells | Therapy Resistance: Mutations drive proliferation and are enriched in relapsed/refractory disease. | (ram2024thegeneticand pages 20-22, ram2024thegeneticand pages 25-26) |
| Microenvironment-Mediated Resistance | IL6, CXCL12, VEGF, Fibronectin | BM Stromal Cells, MDSCs | Drug Resistance: Stromal adhesion and soluble factors shelter tumor cells from therapy (EMDR). | (bhowmick2024pathwaystotherapy pages 1-3, bishop2024theboneecosystem media ec296c58) |
Table: A summary of key molecular pathways, cellular interactions, and genetic drivers identified in 2023-2024 literature that contribute to multiple myeloma progression, bone disease, and therapy resistance.
| Gene/Protein (HGNC) | GO Biological Process | GO Cellular Component | Cell Type (CL) | Anatomy (UBERON) | Chemical/Drug (ChEBI) | Phenotype (HPO) | Evidence |
|---|---|---|---|---|---|---|---|
| FLT3L, STAT3, DKK1 | negative regulation of ossification; Wnt signaling pathway | extracellular space | osteoblast; plasma cell | bone marrow | - | Osteolytic defects; Skeletal dysplasia | (shin2024elucidationofmolecular pages 9-10, shin2024elucidationofmolecular pages 1-2, shin2024elucidationofmolecular pages 2-3) |
| CCL3 (MIP-1α), HMGB1, TNFSF11 (RANKL) | osteoclast differentiation; positive regulation of bone resorption | extracellular space | osteocyte; plasma cell | bone | RANKL; denosumab | Osteolysis; Bone pain | (anloague2024anovelccl3hmgb1 pages 13-14, anloague2024anovelccl3hmgb1 pages 14-15) |
| NFKB2 (p52), TRAF3, CYLD | chromatin remodeling; non-canonical NF-kappaB signal transduction | nucleus; chromatin | plasma cell | bone marrow | - | Neoplasm | (ang2024aberrantnoncanonicalnfκb pages 7-8, ram2024thegeneticand pages 22-23) |
| TIGIT, LAG3, PDCD1 | T cell exhaustion; immune response-inhibiting signal transduction | plasma membrane | CD8-positive alpha-beta T cell; NK cell | bone marrow | - | Recurrent infections; Progression | (pilcher2023crosscentersinglecell pages 1-2, cheng2024multiomicsrevealimmune pages 1-2, barakat2023investigatingtcell pages 66-70) |
| TGFB1, BMP2, CXCL12 | cell differentiation; regulation of immune system process | extracellular space | mesenchymal stromal cell | bone marrow | TGF-beta; SD208 (TGFβRI inhibitor) | Anemia; Bone marrow failure | (bogun2024stromalalterationsin pages 1-2, bogun2024stromalalterationsin pages 12-13, bogun2024stromalalterationsin pages 11-12, bogun2024stromalalterationsin pages 13-14) |
| KRAS, NRAS, BRAF | cell population proliferation; MAPK cascade | cytoplasm; nucleus | plasma cell | bone marrow | bortezomib; carfilzomib | Multiple myeloma; Drug resistance | (ram2024thegeneticand pages 20-22, ram2024thegeneticand pages 25-26) |
| VSIR (PD-1H), MMP13 | cell fusion; bone resorption | plasma membrane | osteoclast | bone | - | Osteolytic defects | (fu2023thecheckpointinhibitor pages 1-2) |
| IL6, IL10 | inflammatory response; positive regulation of cell population proliferation | extracellular space | myeloid-derived suppressor cell; macrophage | bone marrow | IL-6; lenalidomide | Plasmacytosis; Inflammation | (bhowmick2024pathwaystotherapy pages 1-3, barakat2023investigatingtcell pages 17-21, radhakrishnan2024roleofimmune pages 4-5) |
Table: A structured annotation table mapping key molecular players, disrupted biological processes, involved cell types, and clinical phenotypes in Multiple Myeloma to ontology-compliant terms, supported by recent evidence.
Bishop et al. (Nature Communications, Mar 2024; https://doi.org/10.1038/s41467-024-46594-0) provide a schematic of the MM–bone “vicious cycle” and a hybrid model capturing environment-mediated drug resistance (EMDR) via spatial proximity to stroma/bone-derived factors, supporting the concept of minimal residual disease reservoirs in protective bone niches. (bishop2024theboneecosystem media ec296c58, bishop2024theboneecosystem media ea2ecb8d)
Primary claims above are mainly supported by full-text/DOI evidence in the retrieved excerpts; PMIDs were often not present in the retrieved text snippets for many 2024 papers. Where PMIDs were programmatically available from Open Targets evidence lists (and not necessarily directly tied to specific mechanistic claims above), examples include: 23480694 (CRBN association evidence) and several older FGFR3-related PMIDs (e.g., 9207791, 10568829, 11290605, 11429702, 19381019, 20439987, 22869148). ()
References
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(dhodapkar2024immunestatusand pages 2-3): Madhav V. Dhodapkar. Immune status and selection of patients for immunotherapy in myeloma: a proposal. May 2024. URL: https://doi.org/10.1182/bloodadvances.2023011242, doi:10.1182/bloodadvances.2023011242. This article has 16 citations and is from a peer-reviewed journal.
(ram2024thegeneticand pages 22-23): Meghana Ram, Molly Fraser, Junia Vieira dos Santos, Rafail Tasakis, Ariana Islam, Jannah Abo-Donia, Samir Parekh, and Alessandro Lagana. The genetic and molecular drivers of multiple myeloma: current insights, clinical implications, and the path forward. Pharmacogenomics and Personalized Medicine, 17:573-609, Dec 2024. URL: https://doi.org/10.2147/pgpm.s350238, doi:10.2147/pgpm.s350238. This article has 8 citations and is from a peer-reviewed journal.
(shin2024elucidationofmolecular pages 1-2): Dongyeop Shin, Myung-Jin Kim, Soyeon Chun, Dongchan Kim, Chansu Lee, Kwang-Sung Ahn, Eunyoung Jung, Dayeon Kim, Byung-Chul Lee, Dae-Ryong Hwang, Yonghwan Kim, and Sung-Soo Yoon. Elucidation of molecular basis of osteolytic bone lesions in advanced multiple myeloma. Haematologica, 109:2207-2218, Jan 2024. URL: https://doi.org/10.3324/haematol.2023.283784, doi:10.3324/haematol.2023.283784. This article has 8 citations.
(anloague2024anovelccl3hmgb1 pages 13-14): Aric Anloague, Hayley M. Sabol, Japneet Kaur, Sharmin Khan, Cody Ashby, Carolina Schinke, C. Lowry Barnes, Farah Alturkmani, Elena Ambrogini, Michael Tveden Gundesen, Thomas Lund, Anne Kristine Amstrup, Thomas Levin Andersen, Marta Diaz-delCastillo, G. David Roodman, Teresita Bellido, and Jesus Delgado-Calle. A novel ccl3-hmgb1 signaling axis regulating osteocyte rankl expression in multiple myeloma. Haematologica, 110:952-966, Nov 2024. URL: https://doi.org/10.3324/haematol.2024.286484, doi:10.3324/haematol.2024.286484. This article has 10 citations.
(fu2023thecheckpointinhibitor pages 1-2): Jing Fu, Shirong Li, Huihui Ma, Jun Yang, Gabriel M. Pagnotti, Lewis M. Brown, Stephen J. Weiss, Markus Y. Mapara, and Suzanne Lentzsch. The checkpoint inhibitor pd-1h/vista controls osteoclast-mediated multiple myeloma bone disease. Nature Communications, Jul 2023. URL: https://doi.org/10.1038/s41467-023-39769-8, doi:10.1038/s41467-023-39769-8. This article has 21 citations and is from a highest quality peer-reviewed journal.
(bogun2024stromalalterationsin pages 1-2): Lucienne Bogun, Annemarie Koch, Bo Scherer, Roland Fenk, Uwe Maus, Felix Bormann, Karl Köhrer, Patrick Petzsch, Thorsten Wachtmeister, Romans Zukovs, Sascha Dietrich, Rainer Haas, Thomas Schroeder, Paul Jäger, and Stefanie Geyh. Stromal alterations in patients with monoclonal gammopathy of undetermined significance, smoldering myeloma, and multiple myeloma. Blood Advances, 8:2575-2588, May 2024. URL: https://doi.org/10.1182/bloodadvances.2023011632, doi:10.1182/bloodadvances.2023011632. This article has 10 citations and is from a peer-reviewed journal.
(bogun2024stromalalterationsin pages 11-12): Lucienne Bogun, Annemarie Koch, Bo Scherer, Roland Fenk, Uwe Maus, Felix Bormann, Karl Köhrer, Patrick Petzsch, Thorsten Wachtmeister, Romans Zukovs, Sascha Dietrich, Rainer Haas, Thomas Schroeder, Paul Jäger, and Stefanie Geyh. Stromal alterations in patients with monoclonal gammopathy of undetermined significance, smoldering myeloma, and multiple myeloma. Blood Advances, 8:2575-2588, May 2024. URL: https://doi.org/10.1182/bloodadvances.2023011632, doi:10.1182/bloodadvances.2023011632. This article has 10 citations and is from a peer-reviewed journal.
(barakat2023investigatingtcell pages 14-17): Elie Barakat. Investigating t cell exhaustion in multiple myeloma. Other, Apr 2023. URL: https://doi.org/10.11575/prism/dspace/40968, doi:10.11575/prism/dspace/40968. This article has 0 citations.
(moscvin2023dissectingmolecularmechanisms pages 11-13): Maria Moscvin, Benjamin Evans, and Giada Bianchi. Dissecting molecular mechanisms of immune microenvironment dysfunction in multiple myeloma and precursor conditions. Journal of cancer metastasis and treatment, May 2023. URL: https://doi.org/10.20517/2394-4722.2022.110, doi:10.20517/2394-4722.2022.110. This article has 7 citations.
(shin2024elucidationofmolecular pages 2-3): Dongyeop Shin, Myung-Jin Kim, Soyeon Chun, Dongchan Kim, Chansu Lee, Kwang-Sung Ahn, Eunyoung Jung, Dayeon Kim, Byung-Chul Lee, Dae-Ryong Hwang, Yonghwan Kim, and Sung-Soo Yoon. Elucidation of molecular basis of osteolytic bone lesions in advanced multiple myeloma. Haematologica, 109:2207-2218, Jan 2024. URL: https://doi.org/10.3324/haematol.2023.283784, doi:10.3324/haematol.2023.283784. This article has 8 citations.
(shin2024elucidationofmolecular pages 9-10): Dongyeop Shin, Myung-Jin Kim, Soyeon Chun, Dongchan Kim, Chansu Lee, Kwang-Sung Ahn, Eunyoung Jung, Dayeon Kim, Byung-Chul Lee, Dae-Ryong Hwang, Yonghwan Kim, and Sung-Soo Yoon. Elucidation of molecular basis of osteolytic bone lesions in advanced multiple myeloma. Haematologica, 109:2207-2218, Jan 2024. URL: https://doi.org/10.3324/haematol.2023.283784, doi:10.3324/haematol.2023.283784. This article has 8 citations.
(anloague2024anovelccl3hmgb1 pages 14-15): Aric Anloague, Hayley M. Sabol, Japneet Kaur, Sharmin Khan, Cody Ashby, Carolina Schinke, C. Lowry Barnes, Farah Alturkmani, Elena Ambrogini, Michael Tveden Gundesen, Thomas Lund, Anne Kristine Amstrup, Thomas Levin Andersen, Marta Diaz-delCastillo, G. David Roodman, Teresita Bellido, and Jesus Delgado-Calle. A novel ccl3-hmgb1 signaling axis regulating osteocyte rankl expression in multiple myeloma. Haematologica, 110:952-966, Nov 2024. URL: https://doi.org/10.3324/haematol.2024.286484, doi:10.3324/haematol.2024.286484. This article has 10 citations.
(barakat2023investigatingtcell pages 66-70): Elie Barakat. Investigating t cell exhaustion in multiple myeloma. Other, Apr 2023. URL: https://doi.org/10.11575/prism/dspace/40968, doi:10.11575/prism/dspace/40968. This article has 0 citations.
(bogun2024stromalalterationsin pages 6-8): Lucienne Bogun, Annemarie Koch, Bo Scherer, Roland Fenk, Uwe Maus, Felix Bormann, Karl Köhrer, Patrick Petzsch, Thorsten Wachtmeister, Romans Zukovs, Sascha Dietrich, Rainer Haas, Thomas Schroeder, Paul Jäger, and Stefanie Geyh. Stromal alterations in patients with monoclonal gammopathy of undetermined significance, smoldering myeloma, and multiple myeloma. Blood Advances, 8:2575-2588, May 2024. URL: https://doi.org/10.1182/bloodadvances.2023011632, doi:10.1182/bloodadvances.2023011632. This article has 10 citations and is from a peer-reviewed journal.
(bogun2024stromalalterationsin pages 12-13): Lucienne Bogun, Annemarie Koch, Bo Scherer, Roland Fenk, Uwe Maus, Felix Bormann, Karl Köhrer, Patrick Petzsch, Thorsten Wachtmeister, Romans Zukovs, Sascha Dietrich, Rainer Haas, Thomas Schroeder, Paul Jäger, and Stefanie Geyh. Stromal alterations in patients with monoclonal gammopathy of undetermined significance, smoldering myeloma, and multiple myeloma. Blood Advances, 8:2575-2588, May 2024. URL: https://doi.org/10.1182/bloodadvances.2023011632, doi:10.1182/bloodadvances.2023011632. This article has 10 citations and is from a peer-reviewed journal.
(bogun2024stromalalterationsin pages 13-14): Lucienne Bogun, Annemarie Koch, Bo Scherer, Roland Fenk, Uwe Maus, Felix Bormann, Karl Köhrer, Patrick Petzsch, Thorsten Wachtmeister, Romans Zukovs, Sascha Dietrich, Rainer Haas, Thomas Schroeder, Paul Jäger, and Stefanie Geyh. Stromal alterations in patients with monoclonal gammopathy of undetermined significance, smoldering myeloma, and multiple myeloma. Blood Advances, 8:2575-2588, May 2024. URL: https://doi.org/10.1182/bloodadvances.2023011632, doi:10.1182/bloodadvances.2023011632. This article has 10 citations and is from a peer-reviewed journal.
(barakat2023investigatingtcell pages 17-21): Elie Barakat. Investigating t cell exhaustion in multiple myeloma. Other, Apr 2023. URL: https://doi.org/10.11575/prism/dspace/40968, doi:10.11575/prism/dspace/40968. This article has 0 citations.
(radhakrishnan2024roleofimmune pages 4-5): Vijay Radhakrishnan, Upendarrao Golla, and Avinash Kundadka Kudva. Role of immune cells and immunotherapy in multiple myeloma. Life, 14:461, Apr 2024. URL: https://doi.org/10.3390/life14040461, doi:10.3390/life14040461. This article has 17 citations.
name: Multiple Myeloma
creation_date: "2026-03-06T12:00:00Z"
updated_date: "2026-03-07T12:00:00Z"
category: Complex
description: >-
Multiple myeloma is a hematologic malignancy characterized by clonal proliferation
of malignant plasma cells in the bone marrow, leading to production of monoclonal
immunoglobulin (M protein). The disease causes osteolytic bone lesions, renal
impairment, hypercalcemia, and anemia. Key cytogenetic abnormalities include
t(4;14), t(14;16), del(17p), and hyperdiploidy. Treatment includes proteasome
inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, and
autologous stem cell transplantation.
categories:
- Hematologic Malignancy
- Plasma Cell Neoplasm
disease_term:
preferred_term: multiple myeloma
term:
id: MONDO:0009693
label: plasma cell myeloma
parents:
- plasma cell neoplasm
pathophysiology:
- name: Clonal Plasma Cell Proliferation
description: >-
Malignant plasma cells undergo clonal expansion in the bone marrow, driven by
genetic alterations including immunoglobulin heavy chain translocations and
hyperdiploidy. These transformed cells accumulate in the bone marrow, displacing
normal hematopoiesis and producing monoclonal immunoglobulin.
evidence:
- reference: PMID:34201396
reference_title: "Myeloma Bone Disease: A Comprehensive Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Multiple myeloma (MM) is a neoplastic clonal proliferation of plasma cells in
the bone marrow microenvironment, characterized by overproduction of heavy- and
light-chain monoclonal proteins (M-protein).
explanation: >-
Mukkamalla et al. review confirms MM as a neoplastic clonal proliferation of
plasma cells producing monoclonal proteins.
cell_types:
- preferred_term: malignant plasma cell
term:
id: CL:0000786
label: plasma cell
biological_processes:
- preferred_term: cell proliferation
term:
id: GO:0008283
label: cell population proliferation
locations:
- preferred_term: bone marrow
term:
id: UBERON:0002371
label: bone marrow
downstream:
- target: Monoclonal Immunoglobulin Production
evidence:
- reference: PMID:34201396
reference_title: "Myeloma Bone Disease: A Comprehensive Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Multiple myeloma (MM) is a neoplastic clonal proliferation of plasma cells in
the bone marrow microenvironment, characterized by overproduction of heavy- and
light-chain monoclonal proteins (M-protein).
explanation: >-
The review directly links clonal plasma cell proliferation to overproduction
of monoclonal proteins.
- target: Bone Marrow Failure
evidence:
- reference: PMID:34201396
reference_title: "Myeloma Bone Disease: A Comprehensive Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with MM usually present with hypercalcemia, anemia, renal damage,
increased risk for infections, and pathological fracture secondary to
osteolytic bone destruction
explanation: >-
Anemia from bone marrow failure is a defining feature (CRAB criteria) of
myeloma, as confirmed by this comprehensive review.
- target: Osteolytic Bone Disease
evidence:
- reference: PMID:34201396
reference_title: "Myeloma Bone Disease: A Comprehensive Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Osteolytic lesions are seen in 80% of patients with MM which are complicated
frequently by skeletal-related events (SRE) such as hypercalcemia, bone pain,
pathological fractures, vertebral collapse, and spinal cord compression.
explanation: >-
Osteolytic lesions are present in 80% of MM patients, directly linking clonal
plasma cell proliferation to bone disease.
- name: Monoclonal Immunoglobulin Production
description: >-
Malignant plasma cells secrete large quantities of monoclonal immunoglobulin
(M protein) or free light chains. These abnormal proteins can deposit in tissues,
particularly the kidneys, causing cast nephropathy and renal impairment. Serum
and urine protein electrophoresis detect the monoclonal spike.
evidence:
- reference: PMID:25439696
reference_title: "International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This International Myeloma Working Group consensus updates the disease
definition of multiple myeloma to include validated biomarkers in addition to
existing requirements of attributable CRAB features (hypercalcaemia, renal
failure, anaemia, and bone lesions).
explanation: >-
The IMWG diagnostic criteria define myeloma partly through detection of
monoclonal protein, confirming its central role in pathophysiology.
cell_types:
- preferred_term: malignant plasma cell
term:
id: CL:0000786
label: plasma cell
biological_processes:
- preferred_term: immunoglobulin production
modifier: ABNORMAL
term:
id: GO:0002377
label: immunoglobulin production
downstream:
- target: Renal Impairment
evidence:
- reference: PMID:25439696
reference_title: "International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
existing requirements of attributable CRAB features (hypercalcaemia, renal
failure, anaemia, and bone lesions).
explanation: >-
Renal failure is one of the CRAB features defining myeloma, linked to
monoclonal protein deposition causing cast nephropathy.
- name: Osteolytic Bone Disease
description: >-
Myeloma cells activate osteoclasts and suppress osteoblasts through secretion of
RANKL, MIP-1alpha, and DKK1. This uncoupled bone remodeling leads to lytic
bone lesions, pathologic fractures, hypercalcemia, and bone pain. The RANK/RANKL/OPG
axis is central to myeloma bone disease.
evidence:
- reference: PMID:34201396
reference_title: "Myeloma Bone Disease: A Comprehensive Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Elevated levels of osteoclast activating factors such as RANK/RANKL/OPG,
MIP-1-α., TNF-α, IL-3, IL-6, and IL-11 increase bone resorption by osteoclast
stimulation, differentiation, and maturation, whereas osteoblast inhibitory
factors such as the Wnt/DKK1 pathway, secreted frizzle related protein-2, and
runt-related transcription factor 2 inhibit osteoblast differentiation and
formation leading to decreased bone formation.
explanation: >-
Comprehensive review details the molecular mechanisms of myeloma bone disease
including RANKL/OPG imbalance and DKK1-mediated osteoblast inhibition.
cell_types:
- preferred_term: osteoclast
term:
id: CL:0000092
label: osteoclast
- preferred_term: osteoblast
term:
id: CL:0000062
label: osteoblast
biological_processes:
- preferred_term: osteoclast differentiation
modifier: INCREASED
term:
id: GO:0030316
label: osteoclast differentiation
- preferred_term: bone resorption
modifier: INCREASED
term:
id: GO:0045453
label: bone resorption
downstream:
- target: Hypercalcemia
evidence:
- reference: PMID:34201396
reference_title: "Myeloma Bone Disease: A Comprehensive Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Osteolytic lesions are seen in 80% of patients with MM which are complicated
frequently by skeletal-related events (SRE) such as hypercalcemia, bone pain,
pathological fractures, vertebral collapse, and spinal cord compression.
explanation: >-
Hypercalcemia is a direct consequence of osteolytic bone disease, listed as
a key skeletal-related event.
- name: Bone Marrow Failure
description: >-
Progressive infiltration of bone marrow by malignant plasma cells displaces
normal hematopoietic progenitors, leading to anemia, neutropenia, and
thrombocytopenia. Anemia is the most common cytopenia and is often the
presenting feature.
evidence:
- reference: PMID:25439696
reference_title: "International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
existing requirements of attributable CRAB features (hypercalcaemia, renal
failure, anaemia, and bone lesions).
explanation: >-
Anemia is a defining CRAB feature of myeloma, resulting from bone marrow
failure due to plasma cell infiltration.
biological_processes:
- preferred_term: hematopoiesis
modifier: DECREASED
term:
id: GO:0030097
label: hemopoiesis
locations:
- preferred_term: bone marrow
term:
id: UBERON:0002371
label: bone marrow
- name: Immune Dysregulation
description: >-
Myeloma causes profound immunodeficiency through suppression of normal
immunoglobulin production (immunoparesis), impaired T cell and NK cell function,
and alterations in the bone marrow microenvironment. This leads to increased
susceptibility to infections, which remain a major cause of morbidity and mortality.
evidence:
- reference: PMID:34201396
reference_title: "Myeloma Bone Disease: A Comprehensive Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Reduction in normal gammaglobulins (immunoparesis) leads to an increased risk
of infection.
explanation: >-
The review confirms immunoparesis as a key feature of myeloma leading to
increased infection risk.
biological_processes:
- preferred_term: immune response
modifier: DECREASED
term:
id: GO:0006955
label: immune response
- name: Renal Impairment
description: >-
Renal dysfunction in myeloma results primarily from cast nephropathy, where
monoclonal free light chains precipitate in renal tubules forming obstructing
casts. Additional mechanisms include hypercalcemia-induced nephrocalcinosis,
light chain amyloidosis, and light chain deposition disease.
evidence:
- reference: PMID:25439696
reference_title: "International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone
lesions).
explanation: >-
Renal failure is a defining CRAB feature of myeloma in the IMWG diagnostic
criteria.
locations:
- preferred_term: kidney
term:
id: UBERON:0002113
label: kidney
- name: Hypercalcemia
description: >-
Excessive osteoclast-mediated bone resorption releases calcium into the
bloodstream, leading to hypercalcemia. This is exacerbated by impaired
renal calcium excretion and contributes to renal dysfunction, confusion,
constipation, and cardiac arrhythmias.
evidence:
- reference: PMID:25439696
reference_title: "International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone
lesions).
explanation: >-
Hypercalcemia is one of the CRAB features that define symptomatic myeloma
per IMWG criteria.
phenotypes:
- category: Hematologic
name: Anemia
frequency: VERY_FREQUENT
description: >-
Normocytic normochromic anemia due to bone marrow infiltration by malignant
plasma cells, impaired erythropoiesis, and relative erythropoietin deficiency.
evidence:
- reference: PMID:34201396
reference_title: "Myeloma Bone Disease: A Comprehensive Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with MM usually present with hypercalcemia, anemia, renal damage,
increased risk for infections, and pathological fracture secondary to
osteolytic bone destruction
explanation: >-
Anemia is listed as a common presenting feature of multiple myeloma.
phenotype_term:
preferred_term: Anemia
term:
id: HP:0001903
label: Anemia
- category: Skeletal
name: Bone Pain
frequency: VERY_FREQUENT
description: >-
Bone pain, particularly in the back and ribs, is the most common presenting
symptom. Caused by osteolytic bone lesions and pathologic fractures.
evidence:
- reference: PMID:34201396
reference_title: "Myeloma Bone Disease: A Comprehensive Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Osteolytic lesions are seen in 80% of patients with MM which are complicated
frequently by skeletal-related events (SRE) such as hypercalcemia, bone pain,
pathological fractures, vertebral collapse, and spinal cord compression.
explanation: >-
Bone pain is listed as a frequent skeletal-related event complicating osteolytic
lesions in 80% of myeloma patients.
phenotype_term:
preferred_term: Bone pain
term:
id: HP:0002653
label: Bone pain
- category: Skeletal
name: Osteolytic Bone Lesions
frequency: VERY_FREQUENT
description: >-
Punched-out lytic lesions visible on skeletal survey or low-dose CT, resulting
from osteoclast activation and osteoblast suppression by myeloma cells.
evidence:
- reference: PMID:34201396
reference_title: "Myeloma Bone Disease: A Comprehensive Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Osteolytic lesions are seen in 80% of patients with MM
explanation: >-
Osteolytic lesions are present in 80% of myeloma patients at diagnosis.
phenotype_term:
preferred_term: Osteolysis
term:
id: HP:0002797
label: Osteolysis
- category: Skeletal
name: Pathologic Fractures
frequency: FREQUENT
description: >-
Fractures occurring through weakened bone at sites of lytic lesions, most
commonly vertebral compression fractures.
evidence:
- reference: PMID:34201396
reference_title: "Myeloma Bone Disease: A Comprehensive Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Osteolytic lesions are seen in 80% of patients with MM which are complicated
frequently by skeletal-related events (SRE) such as hypercalcemia, bone pain,
pathological fractures, vertebral collapse, and spinal cord compression.
explanation: >-
Pathological fractures are a frequent complication of myeloma bone disease.
phenotype_term:
preferred_term: Pathologic fracture
term:
id: HP:0002756
label: Pathologic fracture
- category: Renal
name: Renal Insufficiency
frequency: FREQUENT
description: >-
Renal impairment occurs in approximately 20-50% of patients at diagnosis,
primarily due to cast nephropathy from free light chain deposition.
evidence:
- reference: PMID:25439696
reference_title: "International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
existing requirements of attributable CRAB features (hypercalcaemia, renal
failure, anaemia, and bone lesions).
explanation: >-
Renal failure is a defining CRAB feature per IMWG diagnostic criteria.
phenotype_term:
preferred_term: Renal insufficiency
term:
id: HP:0000083
label: Renal insufficiency
- category: Metabolic
name: Hypercalcemia
frequency: FREQUENT
description: >-
Elevated serum calcium levels due to excessive bone resorption, present in
approximately 15-30% of patients at diagnosis.
evidence:
- reference: PMID:25439696
reference_title: "International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
existing requirements of attributable CRAB features (hypercalcaemia, renal
failure, anaemia, and bone lesions).
explanation: >-
Hypercalcemia is a defining CRAB feature per IMWG diagnostic criteria.
phenotype_term:
preferred_term: Hypercalcemia
term:
id: HP:0003072
label: Hypercalcemia
- category: Immunologic
name: Recurrent Infections
frequency: FREQUENT
description: >-
Increased susceptibility to bacterial infections due to immunoparesis
(suppression of uninvolved immunoglobulins) and impaired cellular immunity.
evidence:
- reference: PMID:34201396
reference_title: "Myeloma Bone Disease: A Comprehensive Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Reduction in normal gammaglobulins (immunoparesis) leads to an increased risk
of infection.
explanation: >-
Immunoparesis directly leads to increased infection risk in myeloma patients.
phenotype_term:
preferred_term: Recurrent infections
term:
id: HP:0002719
label: Recurrent infections
- category: Neurologic
name: Peripheral Neuropathy
frequency: OCCASIONAL
description: >-
Peripheral neuropathy may result from amyloid deposition, paraprotein effects
on nerves, or as a treatment side effect (bortezomib, thalidomide).
evidence:
- reference: PMID:18753647
reference_title: "Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Adverse events were consistent with established profiles of toxic events
associated with bortezomib and melphalan-prednisone.
explanation: >-
The VISTA trial documents peripheral neuropathy as a known adverse event
of bortezomib-based treatment in myeloma.
phenotype_term:
preferred_term: Peripheral neuropathy
term:
id: HP:0009830
label: Peripheral neuropathy
- category: Constitutional
name: Fatigue
frequency: VERY_FREQUENT
description: >-
Persistent fatigue and weakness due to anemia, renal dysfunction, and
the systemic effects of the malignancy.
evidence:
- reference: PMID:34201396
reference_title: "Myeloma Bone Disease: A Comprehensive Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with MM usually present with hypercalcemia, anemia, renal damage,
increased risk for infections, and pathological fracture secondary to
osteolytic bone destruction
explanation: >-
Anemia and renal damage, both presenting features of myeloma, are primary
contributors to fatigue in myeloma patients.
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
genetic:
- name: IGH Translocations
association: Somatic
gene_term:
preferred_term: IGH
term:
id: hgnc:5477
label: IGH
evidence:
- reference: PMID:25439696
reference_title: "International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These changes are based on the identification of biomarkers associated with
near inevitable development of CRAB features in patients who would otherwise
be regarded as having smouldering multiple myeloma.
explanation: >-
The IMWG criteria include cytogenetic abnormalities such as t(4;14) and t(14;16)
as myeloma-defining events, reflecting the central role of IGH translocations.
notes: >-
Translocations involving the immunoglobulin heavy chain locus (14q32) are
primary genetic events in myeloma. Key translocations include t(4;14) involving
FGFR3/MMSET, t(14;16) involving MAF, and t(11;14) involving CCND1.
- name: TP53 Deletion
association: Somatic
gene_term:
preferred_term: TP53
term:
id: hgnc:11998
label: TP53
notes: >-
Deletion of 17p13 (del(17p)) encompassing TP53 is associated with high-risk
disease and poor prognosis. Present in approximately 10% of newly diagnosed
patients and enriched at relapse.
- name: Hyperdiploidy
association: Somatic
notes: >-
Approximately 50% of myeloma cases are hyperdiploid, characterized by
trisomies of odd-numbered chromosomes (3, 5, 7, 9, 11, 15, 19, 21).
Hyperdiploid myeloma is generally associated with better prognosis
compared to non-hyperdiploid disease.
treatments:
- name: Proteasome Inhibitor Therapy
description: >-
Bortezomib, carfilzomib, and ixazomib target the ubiquitin-proteasome pathway.
Myeloma cells are particularly sensitive due to high protein production load.
Proteasome inhibitors are backbone agents in most treatment regimens.
evidence:
- reference: PMID:18753647
reference_title: "Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Bortezomib plus melphalan-prednisone was superior to melphalan-prednisone
alone in patients with newly diagnosed myeloma who were ineligible for
high-dose therapy.
explanation: >-
The VISTA trial demonstrated superiority of bortezomib-based therapy in
newly diagnosed myeloma, establishing proteasome inhibitors as backbone agents.
treatment_term:
preferred_term: proteasome inhibitor therapy
term:
id: MAXO:0000058
label: pharmacotherapy
- name: Immunomodulatory Drug Therapy
description: >-
Lenalidomide, pomalidomide, and thalidomide exert anti-myeloma effects through
cereblon-mediated degradation of IKZF1/IKZF3 transcription factors, direct
anti-proliferative effects, immune modulation, and anti-angiogenic activity.
evidence:
- reference: PMID:18032763
reference_title: "Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Lenalidomide plus dexamethasone is superior to placebo plus dexamethasone in
patients with relapsed or refractory multiple myeloma.
explanation: >-
The MM-009 trial demonstrated superiority of lenalidomide plus dexamethasone
over dexamethasone alone in relapsed myeloma.
treatment_term:
preferred_term: immunomodulatory drug therapy
term:
id: MAXO:0000058
label: pharmacotherapy
- name: Anti-CD38 Monoclonal Antibody Therapy
description: >-
Daratumumab and isatuximab target CD38, which is highly expressed on myeloma
cells. These antibodies exert anti-myeloma effects through multiple mechanisms
including ADCC, CDC, ADCP, and direct apoptosis induction.
evidence:
- reference: PMID:31141632
reference_title: "Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the risk of disease progression or death was significantly lower among those
who received daratumumab plus lenalidomide and dexamethasone than among those
who received lenalidomide and dexamethasone alone.
explanation: >-
The MAIA trial demonstrated that adding daratumumab to lenalidomide-dexamethasone
significantly reduced disease progression or death in newly diagnosed myeloma.
treatment_term:
preferred_term: anti-CD38 monoclonal antibody therapy
term:
id: MAXO:0000058
label: pharmacotherapy
- name: Autologous Stem Cell Transplantation
description: >-
High-dose melphalan followed by autologous stem cell transplant remains standard
of care for transplant-eligible patients. It deepens treatment response and
improves progression-free survival.
evidence:
- reference: PMID:12736280
reference_title: "High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
High-dose therapy with autologous stem-cell rescue is an effective first-line
treatment for patients with multiple myeloma who are younger than 65 years
of age.
explanation: >-
The MRC Myeloma VII trial established high-dose therapy with autologous stem-cell
rescue as an effective first-line treatment for transplant-eligible myeloma patients.
treatment_term:
preferred_term: autologous stem cell transplantation
term:
id: MAXO:0010039
label: organ transplantation
- name: CAR-T Cell Therapy
description: >-
BCMA-directed CAR-T cell therapies (idecabtagene vicleucel, ciltacabtagene
autoleucel) are approved for relapsed/refractory myeloma. They target B cell
maturation antigen expressed on myeloma cells.
evidence:
- reference: PMID:33626253
reference_title: "Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ide-cel induced responses in a majority of heavily pretreated patients with
refractory and relapsed myeloma; MRD-negative status was achieved in 26% of
treated patients.
explanation: >-
The KarMMa trial demonstrated that idecabtagene vicleucel induced responses
in 73% of heavily pretreated relapsed/refractory myeloma patients.
treatment_term:
preferred_term: CAR-T cell therapy
term:
id: MAXO:0000058
label: pharmacotherapy
- name: Bispecific Antibody Therapy
description: >-
Bispecific antibodies (teclistamab, elranatamab, talquetamab) redirect T cells
to myeloma cells by simultaneously binding tumor antigens (BCMA, GPRC5D) and
CD3 on T cells. Approved for relapsed/refractory disease.
evidence:
- reference: PMID:35661166
reference_title: "Teclistamab in Relapsed or Refractory Multiple Myeloma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Teclistamab resulted in a high rate of deep and durable response in patients
with triple-class-exposed relapsed or refractory multiple myeloma.
explanation: >-
The MajesTEC-1 trial demonstrated a 63% overall response rate with teclistamab
in triple-class-exposed relapsed/refractory myeloma.
treatment_term:
preferred_term: bispecific antibody therapy
term:
id: MAXO:0000058
label: pharmacotherapy
datasets: