Animedix

Multiple Myeloma (C90.00)

Multiple myeloma (MM) has evolved from a disease defined by paraprotein production to one understood as a genetically and microenvironmentally orchestrated plasma cell malignancy characterized by clonal evolution, immune escape, and bone marrow niche dependence. Foundational genomic insights—hyperdiploidy; IgH translocations such as t(11;14), t(4;14), and t(14;16); and recurrent mutations in KRAS, NRAS, BRAF, TP53, and DIS3—have clarified dysregulated signaling through MAPK, PI3K/AKT/mTOR, and NF-κB pathways, while epigenetic reprogramming and MYC activation drive proliferative fitness. The proteasome dependency of plasma cells established ubiquitin–proteasome system inhibition as a therapeutic pillar, and deeper understanding of cereblon biology refined immunomodulatory drug (IMiD) and CELMoD targeting of IKZF1/3. Microenvironmental crosstalk via IL-6, BAFF/APRIL, CXCR4–CXCL12, and RANKL signaling has illuminated stromal support and osteolytic disease as druggable axes. The immune landscape—T-cell exhaustion, impaired antigen presentation, and checkpoint dysregulation—has enabled BCMA-directed therapies (CAR-T cells, bispecific T-cell engagers, and antibody–drug conjugates) to transform relapsed/refractory disease, while additional targets such as GPRC5D and FcRH5 expand the antigenic repertoire. Precision subsets are emerging, including BCL-2 dependency in t(11;14) disease, MAPK-driven clones responsive to targeted inhibition, and strategies addressing minimal residual disease through multi-omic profiling. The therapeutic landscape is now defined by rational combinations that integrate proteostasis disruption, immune redirection, apoptosis priming, and microenvironmental modulation—moving the field toward adaptive, state-dependent precision medicine aligned with clonal dynamics and temporal disease biology.

Causes

The etiology of multiple myeloma reflects a multistep progression from premalignant clonal plasma cell expansion—most commonly monoclonal gammopathy of undetermined significance (MGUS)—to overt malignancy, driven by cumulative genetic lesions and permissive microenvironmental pressures. Early events frequently include hyperdiploidy or immunoglobulin heavy chain (IgH) translocations that juxtapose oncogenes such as CCND1, FGFR3/MMSET, or MAF to strong enhancer elements, establishing proliferative and survival advantages. Secondary mutations affecting RAS–MAPK signaling (KRAS, NRAS, BRAF), DNA damage response pathways (TP53, ATM), and MYC dysregulation promote clonal evolution and genomic instability. Etiologic risk factors include advancing age, male sex, African ancestry, family history of plasma cell disorders, obesity, chronic antigenic stimulation, and certain environmental exposures (e.g., ionizing radiation, agricultural chemicals). At a systems level, chronic inflammatory signaling within the bone marrow niche—mediated by IL-6, BAFF/APRIL, and stromal adhesion pathways—creates a survival-permissive environment that supports the expansion of genetically primed clones. Thus, multiple myeloma arises not from a single causative event, but from the convergence of inherited susceptibility, somatic genomic alterations, and sustained microenvironmental selection pressures that progressively favor malignant plasma cell dominance.

Pathophysiology

The pathophysiology of multiple myeloma is defined by clonal expansion of malignant plasma cells within the bone marrow, driven by constitutive survival signaling, immune evasion, and progressive disruption of normal hematopoiesis and bone remodeling. Oncogenic activation of MAPK (KRAS/NRAS/BRAF), PI3K/AKT/mTOR, NF-κB, and MYC pathways enhances proliferation and resistance to apoptosis, while epigenetic reprogramming reinforces plasma cell identity and metabolic fitness. Myeloma cells exhibit heightened proteasome dependency due to excessive immunoglobulin synthesis, creating vulnerability to proteostasis stress but also contributing to unfolded protein response activation and adaptive survival signaling. The bone marrow microenvironment plays a central mechanistic role: adhesion to stromal cells activates IL-6 and JAK/STAT signaling, promotes angiogenesis via VEGF, and induces drug resistance through cell-adhesion–mediated mechanisms. Osteolytic bone disease arises from RANKL-driven osteoclast activation coupled with suppression of osteoblast differentiation (e.g., via DKK1 and sclerostin), leading to net bone resorption. Immunologically, T-cell exhaustion, impaired dendritic cell function, and altered checkpoint signaling enable immune escape. The cumulative effect is a self-reinforcing malignant ecosystem characterized by monoclonal immunoglobulin production, marrow failure (anemia, thrombocytopenia), skeletal destruction, and progressive clonal evolution under therapeutic and microenvironmental selection pressure.

Clinical features

The clinical presentation of multiple myeloma reflects the cumulative effects of marrow infiltration, monoclonal immunoglobulin production, and osteolytic bone destruction. The classic features are summarized by the “CRAB” criteria—hyperCalcemia, Renal dysfunction, Anemia, and Bone lesions. Patients commonly present with persistent bone pain (particularly in the spine, ribs, or pelvis) due to lytic lesions or pathologic fractures; vertebral compression fractures may lead to height loss or neurologic compromise. Normocytic anemia results from marrow replacement and inflammatory cytokine signaling, producing fatigue and dyspnea. Hypercalcemia, driven by osteoclast activation, may cause confusion, constipation, polyuria, and dehydration. Renal impairment arises from light-chain cast nephropathy, hypercalcemia, and amyloid deposition. Recurrent infections are frequent due to impaired humoral immunity and hypogammaglobulinemia. Additional features may include peripheral neuropathy (either disease-related or treatment-induced), hyperviscosity in cases of high paraprotein burden, and constitutional symptoms such as weight loss. Increasingly, earlier disease is identified through laboratory abnormalities before end-organ damage, reflecting shifts toward earlier detection and intervention in high-risk smoldering disease.

Diagnosis

The diagnosis of multiple myeloma is established through integration of laboratory, pathologic, and imaging criteria as defined by the International Myeloma Working Group (IMWG). Evaluation begins with detection of a monoclonal protein via serum protein electrophoresis (SPEP), immunofixation, and serum free light chain assay, alongside 24-hour urine protein studies when indicated. Definitive diagnosis requires clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma plus evidence of myeloma-defining events: classic CRAB features (hypercalcemia, renal insufficiency, anemia, bone lesions) or specific biomarkers of malignancy such as ≥60% clonal plasma cells in marrow, a serum free light chain ratio ≥100 (involved/uninvolved), or more than one focal lesion on advanced imaging. Cross-sectional imaging with low-dose whole-body CT, PET-CT, or MRI is preferred over conventional skeletal survey to detect lytic disease and extramedullary involvement. Bone marrow biopsy enables cytogenetic and molecular risk stratification using FISH and next-generation sequencing to identify high-risk features (e.g., del(17p), t(4;14), t(14;16), 1q gain). Increasingly, measurable residual disease (MRD) assessment by multiparameter flow cytometry or next-generation sequencing provides highly sensitive disease quantification, reflecting the shift toward precision staging and response-adapted therapeutic strategies.

Mechanism of action videos

Biological pathways

  • t(4;14) translocations of FGFR3
  • Calcium signaling pathway
  • p53 signaling pathway
  • Ubiquitin mediated proteolysis
  • Toll-like receptor signaling pathway
  • Regulation of actin cytoskeleton
  • Protein processing in endoplasmic reticulum
  • Proteasome
  • Phosphatidylinositol signaling system
  • Osteoclast differentiation
  • Natural killer cell mediated cytotoxicity
  • NF-kappa B signaling pathway
  • B cell receptor signaling pathway
  • JAK-STAT signaling pathway
  • Insulin signaling pathway
  • Hematopoietic cell lineage
  • Glycolysis / Gluconeogenesis
  • Apoptosis
  • FoxO signaling pathway
  • Focal adhesion
  • FGFR3 mutant receptor activation
  • ErbB signaling pathway
  • DNA replication
  • Cytokine-cytokine receptor interaction
  • Complement and coagulation cascades
  • Chemokine signaling pathway
  • Cellular senescence
  • Cell cycle
  • Notch-HLH transcription pathway
  • NOTCH1 Intracellular Domain Regulates Transcription
  • Diseases of signal transduction by growth factor receptors and second messengers
  • Signaling by NOTCH1 in Cancer
  • Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer
  • Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
  • Signaling by NOTCH1
  • Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane
  • Transport of connexons to the plasma membrane
  • Cell Cycle, Mitotic
  • Post NMDA receptor activation events
  • The role of GTSE1 in G2/M progression after G2 checkpoint

Clinical trials

  • A Phase II Study of CART-ddBCMA for the Treatment of Patients With Relapsed or Refractory Multiple Myeloma
  • A Phase 3 Randomized Study Comparing JNJ-79635322 and an Anti-BCMAxCD3 Bispecific Antibody in Participants With Relapsed or Refractory Multiple Myeloma Who Have Received at Least 3 Prior Lines of Therapy Including a PI, an IMiD, and an Anti CD38 Antibody
  • MATCH Treatment Subprotocol H: Phase II Study of Dabrafenib and Trametinib in Patients With Tumors With BRAF V600E or V600K Mutations (Excluding Melanoma, Thyroid Cancer, Colorectal Adenocarcinoma, and Non-Small Cell Lung Cancer)
  • A Randomized Phase 2 Study of Daratumumab-Selinexor-Velcade-Dexamethasone (Dara-SVD) for High-Risk Newly Diagnosed Multiple Myeloma
  • SENTI-202-101: A Phase 1, Multicenter, Open-Label Study of SENTI-202, a Selective Off-the-Shelf Logic Gated CAR NK Cell Therapy, in Subjects With CD33 and/or FLT3 Expressing Malignancies
  • A Multicenter, Phase 1b, Open-label Study to Evaluate Dose Optimization Measures and Safety of Etentamig (ABBV-383) in Subjects With Relapsed or Refractory Multiple Myeloma
  • Cancer Moonshot Biobank Research Protocol
  • A Phase 3, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of CAEL-101 and Plasma Cell Dyscrasia Treatment Versus Placebo and Plasma Cell Dyscrasia Treatment in Plasma Cell Dyscrasia Treatment Naïve Patients With Mayo Stage IIIb AL Amyloidosis
  • Randomized Phase 2 Study of Iberdomide Maintenance Therapy Following Idecabtagene Vicleucel CAR-T in Multiple Myeloma Patients
  • A Randomized Phase II Trial for High-Risk Multiple Myeloma That is Refractory or in First Relapse With Daratumumab, Teclistamab (DT) Versus Daratumumab, Pomalidomide, Dexamethasone (DPd) or Daratumumab, Carfilzomib, Dexamethasone (DKd)
  • A Phase 2, Randomized, Open-Label Study to Assess the Safety and Efficacy of GPC 100 and Propranolol With and Without G-CSF for the Mobilization of Stem Cells in Patients With Multiple Myeloma Undergoing Autologous Stem Cell Transplant
  • Study of Precursor Hematological Malignancies to Assess the Relationship Between Molecular Events of Progression and Clinical Outcome
  • A Phase 3, Two-stage, Randomized, Multicenter, Open-label Study Comparing Mezigdomide (CC-92480/BMS-986348), Carfilzomib, and Dexamethasone (MeziKD) Versus Carfilzomib and Dexamethasone (Kd) in Participants With Relapsed or Refractory Multiple Myeloma (RRMM): SUCCESSOR-2
  • Molecular Analysis for Therapy Choice (MATCH)
  • Phase I Dose-Escalation and Dose-Expansion Trial of a Novel Glutaminase Inhibitor (CB-839 HCl) in Combination With Carfilzomib and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma
  • National Longitudinal Cohort of Hematological Diseases (NICHE)
  • A Phase 3, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of CAEL-101 and Plasma Cell Dyscrasia Treatment Versus Placebo and Plasma Cell Dyscrasia Treatment in Plasma Cell Dyscrasia Treatment Naïve Patients With Mayo Stage IIIa AL Amyloidosis
  • Individualized Dynamic Frailty-tailored Therapy (DynaFiT) in Elderly Patients With Newly Diagnosed Multiple Myeloma: a Prospective and Multi-center Study
  • A Prospective Single-Arm, Single-Center Study of BCMA/CD3 Bispecific Antibody as Bridging Therapy Before CAR-T Cell Infusion in Relapsed or Refractory Multiple Myeloma
  • A Phase III, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Single Agent Belantamab Mafodotin Compared to Pomalidomide Plus Lowdose Dexamethasone (Pom/Dex) in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (DREAMM 3)
  • Master Protocol for the Phase 1 Study of Cell Therapies for the Treatment of Patients With Relapsed Refractory Multiple Myeloma, Including Long-term Safety Follow-up
  • Phase 1/2 FIH Study of REGN5458 (Anti-BCMA x Anti-CD3 Bispecific Antibody) in Patients With Relapsed or Refractory Multiple Myeloma
  • INTEGRATIVE "MULTI-OMICS" AND FUNCTIONAL PLATFORM FOR THE COMPLETE DIAGNOSTIC CHARACTERIZATION OF TUMORS: THE ITALIAN TUMOR CHEMOGENOMIC PROFILER (IT-TCP)
  • A Study Combining Big Data Mining With Experimental and Clinical Research to Validate the Alleviating Effect of Fish Oil on Bortezomib-Induced Peripheral Neuropathy
  • A Phase Ⅰ Study Evaluating Safety and Efficacy of C-CAR088 Treatment in Subjects With Relapsed or Refractory Multiple Myeloma
  • GammaGA: Study of the Prevalence of Acid Sphingomyelinase Deficiency Disease (ASMD) and Gaucher Disease in Patients With Monoclonal Gammopathies and/or Multiple Myeloma
  • A Phase 2 Randomized, Multi-center Study of GEO-CMO4S1 (SARS-CoV-2 Vaccine) Versus mRNA SARS-CoV-2 Vaccine in Patients Post Cellular Therapy for Hematological Malignancies
  • A Multicenter Access and Distribution Protocol for Unlicensed Cryopreserved Cord Blood Units (CBUs) for Transplantation in Pediatric and Adult Patients With Hematologic Malignancies and Other Indications
  • A Phase II Study of CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone) Plus Daratumumab for Patients With Monoclonal Gammopathy of Renal Significance (MGRS)
  • ALTITUDE - ALTernating Induction Therapies to Achieve Undetectable Disease Endpoints: A Phase 1/2 Alternating Dara-RVd/Teclistamab-RVd in Transplant Eligible Standard-risk Newly Diagnosed Multiple Myeloma
  • An Open Label, Multicenter, Phase II Study of Belantamab Mafodotin in Combination With VRd for the Treatment of Newly Diagnosed Transplant Eligible Multiple Myeloma Patients
  • A Phase 1b/2 Dose-Escalation and Cohort-Expansion Study to Determine the Safety and Efficacy of BGB-11417as Monotherapy, in Combination With Dexamethasone, Dexamethasone/Carfilzomib, Dexamethasone/Daratumumab, and Dexamethasone/Pomalidomide in Patients With Relapsed/Refractory Multiple Myeloma and t(11;14)
  • Multicenter Open Label Phase 3 Study of Isatuximab Plus Lenalidomide and Dexamethasone With/Without Bortezomib in the Treatment of Newly Diagnosed Non Frail Transplant Ineligible Multiple Myeloma Elderly Patients (≥ 65; < 80 Years).
  • Prevent Allergic Reactions to Aphexda With Dexamethasone (PARADE)
  • A Phase 3, Randomized, Open-Label, Multicenter Study to Compare the Efficacy and Safety of Arlocabtagene Autoleucel (BMS-986393), a GPRC5D-directed CAR-T Cell Therapy, Versus Standard Regimens in Adult Participants With Relapsed or Refractory and Lenalidomide-exposed Multiple Myeloma
  • A Phase 3, Two-stage, Randomized, Multi-center, Controlled, Open-label Study Comparing Iberdomide Maintenance to Lenalidomide Maintenance Therapy After Autologous Stem Cell Transplantation (ASCT) in Participants With Newly Diagnosed Multiple Myeloma (NDMM) (EXCALIBER-Maintenance)
  • A PHASE 1/2, OPEN-LABEL, MULTICENTER STUDY TO EVALUATE A DOSING REGIMEN WITH TWO STEP-UP PRIMING DOSES AND LONGER DOSING INTERVALS OF ELRANATAMAB (PF-06863135) MONOTHERAPY IN PARTICIPANTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA
  • Self-administration of Subcutaneous Elranatamab in the Patients' Homes. An Open Label, Phase Two, Prospective, Multi-center, Non-randomized, Sponsor-initiated Explorative Trial
  • A Single-Arm, Prospective Study of Maintenance Therapy Cessation for Patients With Multiple Myeloma in Sustained MRD-Negative Remissions
  • A Phase 2, Open-Label, Multicenter Study of Arlocabtagene Autoleucel (BMS-986393), a GPRC5D-directed CAR T Cell Therapy in Adult Participants With Relapsed or Refractory Multiple Myeloma (QUINTESSENTIAL)

Therapeutic area: Oncology