17:I[462708,["/_next/static/chunks/3yo3kiro3bmlp.js","/_next/static/chunks/3vr2wvd8f2efb.js","/_next/static/chunks/2vtmb68_vu-9t.js","/_next/static/chunks/2s8mt6_8wrpfo.js","/_next/static/chunks/3vkulz2i3l61y.js","/_next/static/chunks/1cqw2i1silz0i.js","/_next/static/chunks/14dbm3lm_t629.js","/_next/static/chunks/335_v2mb569ld.js","/_next/static/chunks/1jvnwmb7jnkpz.js","/_next/static/chunks/3cmavum774kjt.js","/_next/static/chunks/3th-0-a2xf9qs.js","/_next/static/chunks/0p0xpwde6kzmv.js","/_next/static/chunks/401-sxxnzbtf_.js","/_next/static/chunks/0wywtv698a1v0.js","/_next/static/chunks/2botzqwpnrzyj.js"],"ArticleReader"] 18:T67cd,## Summary Multiple myeloma (MM) is a clonal plasma-cell malignancy diagnosed when there are **≥10% clonal bone-marrow plasma cells or a biopsy-proven plasmacytoma plus at least one myeloma-defining event**. Defining events include attributable CRAB organ injury—hypercalcemia, renal impairment, anemia, or osteolytic bone disease—or one of three biomarker criteria: **≥60% clonal marrow plasma cells; involved:uninvolved serum free-light-chain (FLC) ratio ≥100 with involved FLC ≥100 mg/L; or >1 focal MRI lesion, each ≥5 mm**.[1] An M-protein alone is not sufficient for diagnosis. Initial workup should define the plasma-cell disorder, quantify measurable disease, identify emergencies, establish cytogenetic risk, and determine treatment fitness. Core studies include CBC, creatinine/eGFR, calcium, albumin, total protein, LDH, beta-2 microglobulin, SPEP with immunofixation, serum FLCs, quantitative immunoglobulins, urine protein studies when indicated, bone-marrow aspirate/biopsy with flow cytometry and FISH, and modern whole-body imaging.[1,2] **Renal injury, severe hypercalcemia, spinal cord compression, hyperviscosity, sepsis, unstable fracture, and major cytopenia are time-critical.** Suspected cast nephropathy requires rapid light-chain reduction, avoidance of nephrotoxins, correction of dehydration/hypercalcemia, and urgent hematology-nephrology coordination. Bortezomib-based therapy remains a cornerstone when myeloma causes renal impairment; mechanical light-chain removal has not shown an overall-survival benefit and must not delay effective systemic treatment.[2] Frontline therapy is selected by physiologic fitness, frailty, renal function, neuropathy, cytogenetic risk, and autologous stem-cell transplant (ASCT) candidacy. Anti-CD38–based quadruplets have become central in many U.S. frontline pathways. In January 2026, the U.S. FDA expanded daratumumab plus bortezomib, lenalidomide, and dexamethasone to adults with newly diagnosed MM who are ineligible for ASCT, after a randomized trial showed higher minimal-residual-disease (MRD) negativity and improved progression-free survival.[8] Relapse treatment is sequence-dependent. Prior exposure and refractoriness to lenalidomide, anti-CD38 therapy, proteasome inhibitors, BCMA-directed therapy, and GPRC5D-directed therapy are more useful than counting lines alone. Major 2025-2026 U.S. changes include daratumumab for selected **high-risk smoldering MM**, belantamab mafodotin with bortezomib/dexamethasone after at least two prior lines, teclistamab with daratumumab after at least one prior line containing a proteasome inhibitor and immunomodulatory agent, and accelerated approval of **iberdomide plus daratumumab and dexamethasone** after at least one such prior line.[7-10] Supportive care is part of antimyeloma treatment: prevent kidney injury, use bone-modifying therapy when indicated, assess venous-thromboembolism risk with immunomodulatory agents, vaccinate, plan infection prophylaxis, monitor neuropathy, and coordinate transfusion testing before anti-CD38 therapy because these antibodies can interfere with indirect antiglobulin testing.[3,4] ## Disease spectrum ### Monoclonal gammopathy of undetermined significance Typical non-IgM MGUS has a serum monoclonal protein <3 g/dL, clonal marrow plasma cells <10%, and no myeloma-defining event attributable to the clone.[1] It is monitored rather than treated. ### Smoldering multiple myeloma Smoldering MM generally has clonal marrow plasma cells **10-59%** and/or higher monoclonal-protein burden without a myeloma-defining event.[1] Risk is heterogeneous. A commonly used “20/2/20” framework identifies higher risk with: - marrow plasma cells >20%; - M-protein >2 g/dL; - FLC ratio >20. Cytogenetics and evolving biomarkers can further refine risk. ### U.S. 2025 change: high-risk smoldering MM In November 2025, the U.S. FDA approved subcutaneous daratumumab-hyaluronidase for **adults with high-risk smoldering MM** based on a randomized trial in which treatment reduced progression to active MM or death compared with active monitoring (HR 0.49, 95% CI 0.36-0.67).[7] This is a jurisdiction-specific option, not a reason to treat every patient with smoldering disease. Confirm the risk definition used by the applicable label/guideline and discuss long treatment duration, toxicity, competing risks, and patient preference. ## Diagnostic criteria: SLiM-CRAB Diagnosis requires clonal marrow plasma cells ≥10% or biopsy-proven plasmacytoma plus at least one defining event.[1] | Domain | Defining event | Interpretation | |---|---|---| | **C — Calcium** | Serum calcium >1 mg/dL above upper limit of normal or >11 mg/dL | Must be attributable to the plasma-cell disorder | | **R — Renal** | Creatinine clearance <40 mL/min or serum creatinine >2 mg/dL | Cast nephropathy is classic; other renal causes remain possible | | **A — Anemia** | Hemoglobin >2 g/dL below lower limit of normal or <10 g/dL | Exclude bleeding, nutrient deficiency, hemolysis, CKD, other marrow disease | | **B — Bone** | ≥1 osteolytic lesion on CT, PET/CT, or radiography | Osteoporosis alone is not a defining lytic lesion | | **S — Sixty** | Clonal marrow plasma cells ≥60% | Biomarker defining active MM | | **Li — Light chain** | Involved:uninvolved FLC ratio ≥100 **and involved FLC ≥100 mg/L** | Confirm context and renal function | | **M — MRI** | >1 focal lesion, each ≥5 mm | One focal lesion does not meet this biomarker criterion | CRAB injury must be attributable to the clone. Do not classify anemia from iron deficiency or renal failure from sepsis as myeloma-defining solely because an M-protein is present. ## Pathophysiology and clinical consequences Clonal plasma cells alter marrow, bone, kidney, and immune physiology. Common consequences include: | Mechanism | Clinical effect | |---|---| | Marrow infiltration and inflammatory signaling | Anemia; later thrombocytopenia/neutropenia | | Immunoparesis | Recurrent bacterial and viral infection | | Free-light-chain filtration and tubular injury | Cast nephropathy and acute kidney injury | | Monoclonal deposition/amyloid | Proteinuria, cardiomyopathy, neuropathy, systemic organ injury | | Osteoclast activation + osteoblast suppression | Lytic lesions, fractures, hypercalcemia | | High circulating paraprotein | Hyperviscosity in selected cases | | Clonal evolution under therapy | Drug resistance and relapse | ## Presentation Common presentations include persistent back or rib pain, pathologic fracture, fatigue, anemia, recurrent infection, renal dysfunction, hypercalcemia, or an incidentally detected monoclonal protein. Some patients present through elevated total protein, proteinuria, neuropathy, or unexplained high ESR. ### Emergencies | Problem | Recognition | Immediate action | |---|---|---| | **Suspected cast nephropathy** | AKI/oliguria, high involved FLC, compatible urine pattern | Stop nephrotoxins, correct reversible factors, urgent FLC characterization and rapid antimyeloma treatment with hematology/nephrology | | **Spinal cord/cauda equina compression** | New weakness, sensory level, sphincter dysfunction, severe focal spine pain | Emergency spinal MRI; glucocorticoid and radiation/surgical pathway according to local protocol | | **Severe hypercalcemia** | Confusion, dehydration, AKI, arrhythmia | Isotonic fluid when appropriate, calcitonin for rapid effect, antiresorptive therapy, treat MM | | **Neutropenic sepsis** | Fever or instability with neutropenia | Cultures and immediate empiric antipseudomonal antibiotics | | **Hyperviscosity** | Headache, visual change, mucosal bleeding, confusion, dyspnea | Urgent hematology; plasma exchange when clinically indicated plus disease therapy | | **Unstable fracture** | Severe focal pain, deformity, mechanical instability | Protect limb/spine; urgent orthopedic/spine input | ## Diagnostic workup ### Laboratory studies Obtain: - CBC with differential and blood film; - creatinine/eGFR, electrolytes, corrected or ionized calcium, albumin, liver tests; - LDH and beta-2 microglobulin; - SPEP and serum immunofixation; - serum FLCs; - quantitative immunoglobulins; - urine total protein, electrophoresis, and immunofixation when light-chain disease or renal injury is suspected; - baseline type and screen before anti-CD38 therapy when possible. SPEP quantifies many intact immunoglobulin M-proteins; immunofixation identifies isotype; FLC testing increases sensitivity for light-chain and oligosecretory disease. Renal impairment raises polyclonal FLC levels and alters interpretation. ### Bone marrow Bone-marrow aspirate/biopsy establishes plasma-cell percentage and clonality and provides material for flow cytometry and FISH. Contemporary risk panels commonly include: - del(17p); - t(4;14); - t(14;16); - 1q gain/amplification; - additional abnormalities according to laboratory and current specialist guideline. ### Imaging Whole-body low-dose CT, FDG PET/CT, and MRI have complementary roles. CT is sensitive for lytic cortical disease; PET/CT adds metabolic and extramedullary assessment; MRI is especially useful for marrow infiltration and spinal/neurologic questions. A normal conventional skeletal survey does not exclude clinically important myeloma bone disease when suspicion remains high. ## Differential diagnosis | Disorder | Distinguishing feature | |---|---| | MGUS | Low clonal burden and no myeloma-defining event | | Smoldering MM | Higher clonal burden but no myeloma-defining event | | Solitary plasmacytoma | One biopsy-proven lesion without systemic MM criteria | | Waldenström macroglobulinemia | IgM paraprotein with lymphoplasmacytic lymphoma biology; lytic lesions uncommon | | AL amyloidosis | Amyloid-mediated organ injury; can coexist with MM | | Monoclonal gammopathy of renal significance | Kidney injury from a small clone that may not meet MM criteria | | Metastatic solid tumor | Bone lesions without a plasma-cell clone explaining disease | | Primary hyperparathyroidism | Hypercalcemia with elevated/inappropriately normal PTH | ## Staging and risk ### International Staging System | Stage | Criteria | |---|---| | I | beta-2 microglobulin <3.5 mg/L **and** albumin ≥3.5 g/dL | | II | Neither stage I nor III | | III | beta-2 microglobulin ≥5.5 mg/L | ### R2-ISS The Second Revision of the International Staging System improves risk discrimination by integrating ISS stage, LDH, del(17p), t(4;14), and 1q gain/amplification.[5] | Feature | Points | |---|---:| | ISS II | 1 | | ISS III | 1.5 | | del(17p) | 1 | | t(4;14) | 1 | | Elevated LDH | 1 | | 1q gain/amplification | 0.5 | Score groups: **I = 0; II = 0.5-1; III = 1.5-2.5; IV = 3-5**.[5] Extramedullary disease, circulating plasma cells, TP53 abnormalities, early relapse, and multiple high-risk lesions can confer additional risk beyond a staging score. ## Initial treatment ### Decide whether therapy is indicated Treat **active MM**. MGUS is observed. Smoldering MM is monitored with risk-adapted intervals except where a jurisdiction-specific high-risk treatment pathway is selected.[1,7] ### Transplant-intended patients For fit adults, contemporary pathways commonly use an anti-CD38 antibody plus **bortezomib, lenalidomide, and dexamethasone**, followed by stem-cell collection and ASCT when appropriate, then risk-adapted maintenance. ASCT candidacy depends on physiologic fitness, organ function, frailty, goals, and center criteria—not chronological age alone. A common component-dose framework in protocolized quadruplet therapy is: | Drug | Reference dose used in common regimens | Key monitoring | |---|---|---| | Daratumumab-hyaluronidase | **1,800 mg/30,000 units SC** on regimen-specific schedule | Administration reaction, infection, cytopenias, transfusion-test interference | | Bortezomib | Commonly **1.3 mg/m² SC** on protocol-defined days | Peripheral neuropathy, thrombocytopenia, zoster reactivation | | Lenalidomide | Commonly **25 mg PO daily** on protocol-defined treatment days when renal function permits | Cytopenias, thrombosis, rash, embryo-fetal toxicity; renal dose adjustment | | Dexamethasone | Commonly **40 mg weekly** in fit adults; lower doses frequently used in older/frail patients | Hyperglycemia, insomnia, infection, delirium, myopathy | These are reference doses, not a chemotherapy order. Exact schedule, cycle length, renal adjustment, steroid attenuation, prophylaxis, and holding parameters must follow the chosen protocol and current prescribing information. ### Transplant-ineligible or frail patients Use **frailty-adapted** rather than age-only treatment. Anti-CD38–containing triplets/quadruplets are major options, but dose attenuation may be more important than adding every active drug in a vulnerable patient. In January 2026, FDA approved daratumumab-hyaluronidase with bortezomib/lenalidomide/dexamethasone for newly diagnosed adults ineligible for ASCT. In the pivotal trial, MRD negativity was **52.3% versus 34.8%** with bortezomib/lenalidomide/dexamethasone alone; PFS HR was **0.60**.[8] ## Autologous stem-cell transplantation ASCT uses high-dose melphalan followed by autologous hematopoietic rescue as consolidation. It remains an important strategy in appropriate patients despite highly active quadruplets. Important toxicities include mucositis, prolonged cytopenias, infection, transfusion requirement, organ toxicity, thromboembolism, infertility, and later second malignancy. Discuss fertility preservation when relevant before gonadotoxic therapy. ## Maintenance and response monitoring Lenalidomide remains a common maintenance backbone after ASCT. High-risk disease may justify proteasome-inhibitor– or anti-CD38–containing strategies depending on induction, cytogenetics, tolerance, and jurisdiction. Follow the measurable disease present at baseline: - M-protein; - serum FLCs; - CBC, calcium, renal function; - symptoms and functional status; - imaging when clinically indicated. MRD by validated next-generation flow or sequencing is strongly prognostic. Do not automatically stop, intensify, or switch therapy solely because of one MRD result outside a validated protocol; marrow sampling error and extramedullary disease can make a single result incomplete. ## Myeloma-related renal impairment IMWG recommends creatinine/eGFR and serum FLC measurement together with **24-hour urine total protein, electrophoresis, and immunofixation** in MM with renal impairment.[2] Consider kidney biopsy when: - proteinuria is predominantly albumin, or - involved serum FLC is **<500 mg/L** and the renal cause remains uncertain.[2] ### Suspected cast nephropathy pathway 1. Stop NSAIDs and avoid unnecessary iodinated contrast and other nephrotoxins. 2. Correct dehydration and hypercalcemia while avoiding fluid overload. 3. Obtain serum FLCs urgently and characterize urine protein. 4. Involve hematology and nephrology early. 5. Start a rapidly active, **bortezomib-based** antimyeloma regimen when cast nephropathy is sufficiently likely.[2] 6. Do not delay systemic treatment for mechanical light-chain removal; IMWG concludes mechanical approaches have not improved overall survival.[2] ## Bone disease IMWG recommends bone-targeted therapy in active MM, with zoledronic acid a preferred option in many patients and denosumab useful when renal impairment makes bisphosphonate exposure problematic.[3] | Intervention | Role | Main cautions | |---|---|---| | Zoledronic acid | Reduce skeletal events | Renal toxicity, hypocalcemia, osteonecrosis of jaw | | Denosumab | Reduce skeletal events; no renal clearance | Hypocalcemia, osteonecrosis; rebound bone loss if stopped without a plan | | Vertebral augmentation | Selected painful vertebral compression fractures | Procedure/anatomic risk | | Radiation | Focal pain, selected lesions, cord-compression pathway | Marrow exposure | | Orthopedic/spine surgery | Long-bone fracture, instability, structural cord compromise | Perioperative infection/thrombosis risk | Assess calcium/vitamin D and dental health before antiresorptive therapy when feasible. IMWG permits less frequent zoledronic acid or discontinuation after at least 12 months in selected patients with very good partial response or better.[3] ## Infection prevention Disease-related immunoparesis combines with steroid exposure, cytopenias, cellular therapy, bispecific antibodies, and hypogammaglobulinemia to create substantial infection risk.[4] Practical prevention includes: - influenza, COVID-19, pneumococcal, and recombinant zoster vaccination according to current immunocompromised schedules; - herpesvirus prophylaxis with proteasome inhibitors and many cellular/bispecific protocols; - Pneumocystis prophylaxis when cumulative immunosuppression warrants it; - early evaluation of fever or respiratory symptoms; - selected antibacterial prophylaxis in high-risk periods according to protocol; - immunoglobulin replacement for selected patients with recurrent serious infection and significant hypogammaglobulinemia.[4] BCMA-directed therapy can cause profound, prolonged hypogammaglobulinemia; infection prevention and immunoglobulin replacement thresholds should be protocolized. ## Thrombosis prevention Lenalidomide, pomalidomide, and iberdomide increase thrombotic risk, particularly with dexamethasone and additional patient factors. Use a validated institutional risk assessment to select aspirin or anticoagulant prophylaxis. Account for renal function, platelet count, bleeding risk, drug interactions, and concurrent antithrombotic indications. ## Neuropathy Bortezomib and some older immunomodulatory drugs can worsen peripheral neuropathy. Document baseline symptoms, use subcutaneous/less-frequent bortezomib schedules when appropriate, and reduce or hold neurotoxic therapy when symptoms progress. Consider amyloidosis, diabetes, vitamin deficiency, radiculopathy, or the paraprotein itself when neuropathy does not fit treatment timing. ## Relapsed or refractory disease Before choosing therapy, record: - prior regimens, response, and duration; - refractory drug classes; - current renal function and marrow reserve; - neuropathy, infection history, and frailty; - cytogenetic risk and extramedullary disease; - prior ASCT; - prior BCMA and GPRC5D exposure; - tempo and symptoms of relapse. ### Major therapeutic classes | Class | Representative agents | Major bedside issues | |---|---|---| | Anti-CD38 antibodies | Daratumumab, isatuximab | Infection, cytopenia, transfusion-test interference | | Proteasome inhibitors | Bortezomib, carfilzomib, ixazomib | Neuropathy; cardiac/vascular toxicity with carfilzomib | | Immunomodulatory/cereblon-directed drugs | Lenalidomide, pomalidomide, iberdomide | Cytopenias, thrombosis, embryo-fetal toxicity | | BCMA CAR-T | Ciltacabtagene autoleucel, idecabtagene vicleucel | Cytokine-release syndrome, neurotoxicity, prolonged cytopenia, infection | | BCMA bispecific antibodies | Teclistamab, elranatamab, linvoseltamab | Cytokine-release syndrome, neurotoxicity, infection, hypogammaglobulinemia | | GPRC5D bispecific antibody | Talquetamab | Cytokine-release syndrome, neurologic toxicity, taste change, weight loss, skin/nail toxicity | | BCMA antibody-drug conjugate | Belantamab mafodotin | Corneal toxicity; protocolized ophthalmic monitoring | ### Teclistamab plus daratumumab: 2026 U.S. change In March 2026, FDA approved teclistamab plus daratumumab-hyaluronidase for adults with relapsed/refractory MM after at least one prior line containing a proteasome inhibitor and immunomodulatory agent. The pivotal randomized study reported a PFS HR of **0.17** compared with control therapy.[9] This combination requires structured monitoring for cytokine-release syndrome, immune-effector-cell neurologic toxicity, cytopenias, hypogammaglobulinemia, and serious infection. ### Iberdomide combination: August 2026 U.S. change On August 13, 2026, FDA granted **accelerated approval** to iberdomide with daratumumab-hyaluronidase and dexamethasone for adults who had received at least one prior line including a proteasome inhibitor and immunomodulatory agent.[10] The approved iberdomide dose is **1 mg orally once daily on days 1-21 of a 28-day cycle** with the companion agents. The pivotal trial’s major efficacy endpoint was MRD-negative complete response: **41% versus 21%** in the comparator arm.[10] The label carries major warnings for embryo-fetal toxicity and venous/arterial thromboembolism, with additional concerns including neutropenia and infection. Because approval is accelerated, confirmatory evidence remains important when placing the regimen in sequence. ### Belantamab mafodotin combination In October 2025, FDA approved belantamab mafodotin with bortezomib/dexamethasone after at least two prior lines including a proteasome inhibitor and immunomodulatory agent.[11] In the U.S. efficacy population, median PFS was **31.3 months versus 10.4 months** with the comparator triplet (HR 0.31). Corneal toxicity can be severe and requires current label-directed ophthalmic monitoring. ## Special populations ### Frailty Use a formal frailty approach when possible. Early steroid reduction, less neurotoxic scheduling, and simplified regimens may improve treatment persistence. The objective is durable disease control without sacrificing function to avoidable toxicity. ### AL amyloidosis suspicion Consider coexisting AL amyloidosis with nephrotic albuminuria, restrictive cardiomyopathy, unexplained autonomic/peripheral neuropathy, hepatomegaly, macroglossia, periorbital purpura, or disproportionate cardiac biomarkers. Tissue confirmation and amyloid typing are essential because treatment intensity and prognosis differ. ### Reproductive potential Lenalidomide, pomalidomide, thalidomide, and iberdomide have major embryo-fetal toxicity. Follow required pregnancy-prevention programs and current prescribing information. Discuss fertility preservation before high-dose melphalan/ASCT when relevant. ## Monitoring and follow-up At each cycle or clinically relevant interval, assess: - measurable disease marker trend; - CBC and renal function; - calcium and symptoms of bone disease; - infection and vaccination/prophylaxis status; - neuropathy and functional change; - thrombotic and bleeding events; - regimen-specific organ toxicity; - adherence and access to oral drugs/supportive medicines. Re-image for new focal pain, neurologic deficits, biochemical progression with unclear distribution, suspected extramedullary disease, or when required by the treatment protocol. ## Related library topics - [Hypercalcemia in Adults](../endocrinology/hypercalcemia-in-adults.md) - [Acute Kidney Injury](../nephrology/acute-kidney-injury.md) - [Chronic Kidney Disease](../nephrology/chronic-kidney-disease.md) - [Nephrotic Syndrome in Adults](../nephrology/nephrotic-syndrome-in-adults.md) - [Pneumocystis jirovecii Pneumonia in Adults](../infectious-disease/pneumocystis-jirovecii-pneumonia-in-adults.md) - [Aplastic Anemia in Adults](../hematology/aplastic-anemia-in-adults.md) ## References 1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. *Lancet Oncol.* 2014;15(12):e538-e548. DOI: 10.1016/S1470-2045(14)70442-5. PMID: 25439696. https://pubmed.ncbi.nlm.nih.gov/25439696/ 2. Dimopoulos MA, Sonneveld P, Leung N, et al. Management of multiple myeloma-related renal impairment: recommendations from the International Myeloma Working Group. *Lancet Oncol.* 2023;24:e293-e311. DOI: 10.1016/S1470-2045(23)00223-1. PMID: 37414019. https://pubmed.ncbi.nlm.nih.gov/37414019/ 3. Terpos E, Zamagni E, Lentzsch S, et al. Treatment of multiple myeloma-related bone disease: recommendations from the Bone Working Group of the International Myeloma Working Group. *Lancet Oncol.* 2021;22(3):e119-e130. DOI: 10.1016/S1470-2045(20)30559-3. PMID: 33545067. https://pubmed.ncbi.nlm.nih.gov/33545067/ 4. Raje NS, Anaissie E, Kumar SK, et al. Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group. *Lancet Haematol.* 2022;9(2):e143-e161. DOI: 10.1016/S2352-3026(21)00283-0. PMID: 35114152. https://pubmed.ncbi.nlm.nih.gov/35114152/ 5. D'Agostino M, Cairns DA, Lahuerta JJ, et al. Second Revision of the International Staging System (R2-ISS) for Overall Survival in Multiple Myeloma. *J Clin Oncol.* 2022;40(29):3406-3418. DOI: 10.1200/JCO.21.02614. PMID: 35605179. https://pubmed.ncbi.nlm.nih.gov/35605179/ 6. Hillengass J, Usmani S, Rajkumar SV, et al. International Myeloma Working Group consensus recommendations on imaging in monoclonal plasma cell disorders. *Lancet Oncol.* 2019;20(6):e302-e312. DOI: 10.1016/S1470-2045(19)30309-2. https://doi.org/10.1016/S1470-2045(19)30309-2 7. U.S. Food and Drug Administration. *FDA approves daratumumab and hyaluronidase-fihj for high-risk smoldering multiple myeloma.* November 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-high-risk-smoldering-multiple-myeloma 8. U.S. Food and Drug Administration. *FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma.* January 27, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-bortezomib-lenalidomide-and-dexamethasone-newly 9. U.S. Food and Drug Administration. *FDA approves teclistamab in combination with daratumumab-hyaluronidase-fihj for relapsed or refractory multiple myeloma.* March 5, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-combination-daratumumab-hyaluronidase-fihj-relapsed-or-refractory-multiple 10. U.S. Food and Drug Administration. *FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma.* August 13, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-iberdomide-daratumumab-and-hyaluronidase-fihj-and-dexamethasone 11. U.S. Food and Drug Administration. *FDA approves belantamab mafodotin for relapsed or refractory multiple myeloma.* October 23, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancerhematologic-malignancies-approval-notifications19:T67ed,## Summary Multiple myeloma (MM) is a clonal plasma-cell malignancy diagnosed when there are **≥10% clonal bone-marrow plasma cells or a biopsy-proven plasmacytoma plus at least one myeloma-defining event**. Defining events include attributable CRAB organ injury—hypercalcemia, renal impairment, anemia, or osteolytic bone disease—or one of three biomarker criteria: **≥60% clonal marrow plasma cells; involved:uninvolved serum free-light-chain (FLC) ratio ≥100 with involved FLC ≥100 mg/L; or >1 focal MRI lesion, each ≥5 mm**.[1] An M-protein alone is not sufficient for diagnosis. Initial workup should define the plasma-cell disorder, quantify measurable disease, identify emergencies, establish cytogenetic risk, and determine treatment fitness. Core studies include CBC, creatinine/eGFR, calcium, albumin, total protein, LDH, beta-2 microglobulin, SPEP with immunofixation, serum FLCs, quantitative immunoglobulins, urine protein studies when indicated, bone-marrow aspirate/biopsy with flow cytometry and FISH, and modern whole-body imaging.[1,2] **Renal injury, severe hypercalcemia, spinal cord compression, hyperviscosity, sepsis, unstable fracture, and major cytopenia are time-critical.** Suspected cast nephropathy requires rapid light-chain reduction, avoidance of nephrotoxins, correction of dehydration/hypercalcemia, and urgent hematology-nephrology coordination. Bortezomib-based therapy remains a cornerstone when myeloma causes renal impairment; mechanical light-chain removal has not shown an overall-survival benefit and must not delay effective systemic treatment.[2] Frontline therapy is selected by physiologic fitness, frailty, renal function, neuropathy, cytogenetic risk, and autologous stem-cell transplant (ASCT) candidacy. Anti-CD38–based quadruplets have become central in many U.S. frontline pathways. In January 2026, the U.S. FDA expanded daratumumab plus bortezomib, lenalidomide, and dexamethasone to adults with newly diagnosed MM who are ineligible for ASCT, after a randomized trial showed higher minimal-residual-disease (MRD) negativity and improved progression-free survival.[8] Relapse treatment is sequence-dependent. Prior exposure and refractoriness to lenalidomide, anti-CD38 therapy, proteasome inhibitors, BCMA-directed therapy, and GPRC5D-directed therapy are more useful than counting lines alone. Major 2025-2026 U.S. changes include daratumumab for selected **high-risk smoldering MM**, belantamab mafodotin with bortezomib/dexamethasone after at least two prior lines, teclistamab with daratumumab after at least one prior line containing a proteasome inhibitor and immunomodulatory agent, and accelerated approval of **iberdomide plus daratumumab and dexamethasone** after at least one such prior line.[7-10] Supportive care is part of antimyeloma treatment: prevent kidney injury, use bone-modifying therapy when indicated, assess venous-thromboembolism risk with immunomodulatory agents, vaccinate, plan infection prophylaxis, monitor neuropathy, and coordinate transfusion testing before anti-CD38 therapy because these antibodies can interfere with indirect antiglobulin testing.[3,4] ## Disease spectrum ### Monoclonal gammopathy of undetermined significance Typical non-IgM MGUS has a serum monoclonal protein <3 g/dL, clonal marrow plasma cells <10%, and no myeloma-defining event attributable to the clone.[1] It is monitored rather than treated. ### Smoldering multiple myeloma Smoldering MM generally has clonal marrow plasma cells **10-59%** and/or higher monoclonal-protein burden without a myeloma-defining event.[1] Risk is heterogeneous. A commonly used “20/2/20” framework identifies higher risk with: - marrow plasma cells >20%; - M-protein >2 g/dL; - FLC ratio >20. Cytogenetics and evolving biomarkers can further refine risk. ### U.S. 2025 change: high-risk smoldering MM In November 2025, the U.S. FDA approved subcutaneous daratumumab-hyaluronidase for **adults with high-risk smoldering MM** based on a randomized trial in which treatment reduced progression to active MM or death compared with active monitoring (HR 0.49, 95% CI 0.36-0.67).[7] This is a jurisdiction-specific option, not a reason to treat every patient with smoldering disease. Confirm the risk definition used by the applicable label/guideline and discuss long treatment duration, toxicity, competing risks, and patient preference. ## Diagnostic criteria: SLiM-CRAB Diagnosis requires clonal marrow plasma cells ≥10% or biopsy-proven plasmacytoma plus at least one defining event.[1] | Domain | Defining event | Interpretation | |---|---|---| | **C — Calcium** | Serum calcium >1 mg/dL above upper limit of normal or >11 mg/dL | Must be attributable to the plasma-cell disorder | | **R — Renal** | Creatinine clearance <40 mL/min or serum creatinine >2 mg/dL | Cast nephropathy is classic; other renal causes remain possible | | **A — Anemia** | Hemoglobin >2 g/dL below lower limit of normal or <10 g/dL | Exclude bleeding, nutrient deficiency, hemolysis, CKD, other marrow disease | | **B — Bone** | ≥1 osteolytic lesion on CT, PET/CT, or radiography | Osteoporosis alone is not a defining lytic lesion | | **S — Sixty** | Clonal marrow plasma cells ≥60% | Biomarker defining active MM | | **Li — Light chain** | Involved:uninvolved FLC ratio ≥100 **and involved FLC ≥100 mg/L** | Confirm context and renal function | | **M — MRI** | >1 focal lesion, each ≥5 mm | One focal lesion does not meet this biomarker criterion | CRAB injury must be attributable to the clone. Do not classify anemia from iron deficiency or renal failure from sepsis as myeloma-defining solely because an M-protein is present. ## Pathophysiology and clinical consequences Clonal plasma cells alter marrow, bone, kidney, and immune physiology. Common consequences include: | Mechanism | Clinical effect | |---|---| | Marrow infiltration and inflammatory signaling | Anemia; later thrombocytopenia/neutropenia | | Immunoparesis | Recurrent bacterial and viral infection | | Free-light-chain filtration and tubular injury | Cast nephropathy and [acute kidney injury](/library/acute-kidney-injury) | | Monoclonal deposition/amyloid | Proteinuria, cardiomyopathy, neuropathy, systemic organ injury | | Osteoclast activation + osteoblast suppression | Lytic lesions, fractures, hypercalcemia | | High circulating paraprotein | Hyperviscosity in selected cases | | Clonal evolution under therapy | Drug resistance and relapse | ## Presentation Common presentations include persistent back or rib pain, pathologic fracture, fatigue, anemia, recurrent infection, renal dysfunction, hypercalcemia, or an incidentally detected monoclonal protein. Some patients present through elevated total protein, proteinuria, neuropathy, or unexplained high ESR. ### Emergencies | Problem | Recognition | Immediate action | |---|---|---| | **Suspected cast nephropathy** | AKI/oliguria, high involved FLC, compatible urine pattern | Stop nephrotoxins, correct reversible factors, urgent FLC characterization and rapid antimyeloma treatment with hematology/nephrology | | **Spinal cord/cauda equina compression** | New weakness, sensory level, sphincter dysfunction, severe focal spine pain | Emergency spinal MRI; glucocorticoid and radiation/surgical pathway according to local protocol | | **Severe hypercalcemia** | Confusion, dehydration, AKI, arrhythmia | Isotonic fluid when appropriate, calcitonin for rapid effect, antiresorptive therapy, treat MM | | **Neutropenic sepsis** | Fever or instability with neutropenia | Cultures and immediate empiric antipseudomonal antibiotics | | **Hyperviscosity** | Headache, visual change, mucosal bleeding, confusion, dyspnea | Urgent hematology; plasma exchange when clinically indicated plus disease therapy | | **Unstable fracture** | Severe focal pain, deformity, mechanical instability | Protect limb/spine; urgent orthopedic/spine input | ## Diagnostic workup ### Laboratory studies Obtain: - CBC with differential and blood film; - creatinine/eGFR, electrolytes, corrected or ionized calcium, albumin, liver tests; - LDH and beta-2 microglobulin; - SPEP and serum immunofixation; - serum FLCs; - quantitative immunoglobulins; - urine total protein, electrophoresis, and immunofixation when light-chain disease or renal injury is suspected; - baseline type and screen before anti-CD38 therapy when possible. SPEP quantifies many intact immunoglobulin M-proteins; immunofixation identifies isotype; FLC testing increases sensitivity for light-chain and oligosecretory disease. Renal impairment raises polyclonal FLC levels and alters interpretation. ### Bone marrow Bone-marrow aspirate/biopsy establishes plasma-cell percentage and clonality and provides material for flow cytometry and FISH. Contemporary risk panels commonly include: - del(17p); - t(4;14); - t(14;16); - 1q gain/amplification; - additional abnormalities according to laboratory and current specialist guideline. ### Imaging Whole-body low-dose CT, FDG PET/CT, and MRI have complementary roles. CT is sensitive for lytic cortical disease; PET/CT adds metabolic and extramedullary assessment; MRI is especially useful for marrow infiltration and spinal/neurologic questions. A normal conventional skeletal survey does not exclude clinically important myeloma bone disease when suspicion remains high. ## Differential diagnosis | Disorder | Distinguishing feature | |---|---| | MGUS | Low clonal burden and no myeloma-defining event | | Smoldering MM | Higher clonal burden but no myeloma-defining event | | Solitary plasmacytoma | One biopsy-proven lesion without systemic MM criteria | | Waldenström macroglobulinemia | IgM paraprotein with lymphoplasmacytic lymphoma biology; lytic lesions uncommon | | AL amyloidosis | Amyloid-mediated organ injury; can coexist with MM | | Monoclonal gammopathy of renal significance | Kidney injury from a small clone that may not meet MM criteria | | Metastatic solid tumor | Bone lesions without a plasma-cell clone explaining disease | | Primary hyperparathyroidism | Hypercalcemia with elevated/inappropriately normal PTH | ## Staging and risk ### International Staging System | Stage | Criteria | |---|---| | I | beta-2 microglobulin <3.5 mg/L **and** albumin ≥3.5 g/dL | | II | Neither stage I nor III | | III | beta-2 microglobulin ≥5.5 mg/L | ### R2-ISS The Second Revision of the International Staging System improves risk discrimination by integrating ISS stage, LDH, del(17p), t(4;14), and 1q gain/amplification.[5] | Feature | Points | |---|---:| | ISS II | 1 | | ISS III | 1.5 | | del(17p) | 1 | | t(4;14) | 1 | | Elevated LDH | 1 | | 1q gain/amplification | 0.5 | Score groups: **I = 0; II = 0.5-1; III = 1.5-2.5; IV = 3-5**.[5] Extramedullary disease, circulating plasma cells, TP53 abnormalities, early relapse, and multiple high-risk lesions can confer additional risk beyond a staging score. ## Initial treatment ### Decide whether therapy is indicated Treat **active MM**. MGUS is observed. Smoldering MM is monitored with risk-adapted intervals except where a jurisdiction-specific high-risk treatment pathway is selected.[1,7] ### Transplant-intended patients For fit adults, contemporary pathways commonly use an anti-CD38 antibody plus **bortezomib, lenalidomide, and dexamethasone**, followed by stem-cell collection and ASCT when appropriate, then risk-adapted maintenance. ASCT candidacy depends on physiologic fitness, organ function, frailty, goals, and center criteria—not chronological age alone. A common component-dose framework in protocolized quadruplet therapy is: | Drug | Reference dose used in common regimens | Key monitoring | |---|---|---| | Daratumumab-hyaluronidase | **1,800 mg/30,000 units SC** on regimen-specific schedule | Administration reaction, infection, cytopenias, transfusion-test interference | | Bortezomib | Commonly **1.3 mg/m² SC** on protocol-defined days | Peripheral neuropathy, thrombocytopenia, zoster reactivation | | Lenalidomide | Commonly **25 mg PO daily** on protocol-defined treatment days when renal function permits | Cytopenias, thrombosis, rash, embryo-fetal toxicity; renal dose adjustment | | Dexamethasone | Commonly **40 mg weekly** in fit adults; lower doses frequently used in older/frail patients | Hyperglycemia, insomnia, infection, delirium, myopathy | These are reference doses, not a chemotherapy order. Exact schedule, cycle length, renal adjustment, steroid attenuation, prophylaxis, and holding parameters must follow the chosen protocol and current prescribing information. ### Transplant-ineligible or frail patients Use **frailty-adapted** rather than age-only treatment. Anti-CD38–containing triplets/quadruplets are major options, but dose attenuation may be more important than adding every active drug in a vulnerable patient. In January 2026, FDA approved daratumumab-hyaluronidase with bortezomib/lenalidomide/dexamethasone for newly diagnosed adults ineligible for ASCT. In the pivotal trial, MRD negativity was **52.3% versus 34.8%** with bortezomib/lenalidomide/dexamethasone alone; PFS HR was **0.60**.[8] ## Autologous stem-cell transplantation ASCT uses high-dose melphalan followed by autologous hematopoietic rescue as consolidation. It remains an important strategy in appropriate patients despite highly active quadruplets. Important toxicities include mucositis, prolonged cytopenias, infection, transfusion requirement, organ toxicity, thromboembolism, infertility, and later second malignancy. Discuss fertility preservation when relevant before gonadotoxic therapy. ## Maintenance and response monitoring Lenalidomide remains a common maintenance backbone after ASCT. High-risk disease may justify proteasome-inhibitor– or anti-CD38–containing strategies depending on induction, cytogenetics, tolerance, and jurisdiction. Follow the measurable disease present at baseline: - M-protein; - serum FLCs; - CBC, calcium, renal function; - symptoms and functional status; - imaging when clinically indicated. MRD by validated next-generation flow or sequencing is strongly prognostic. Do not automatically stop, intensify, or switch therapy solely because of one MRD result outside a validated protocol; marrow sampling error and extramedullary disease can make a single result incomplete. ## Myeloma-related renal impairment IMWG recommends creatinine/eGFR and serum FLC measurement together with **24-hour urine total protein, electrophoresis, and immunofixation** in MM with renal impairment.[2] Consider kidney biopsy when: - proteinuria is predominantly albumin, or - involved serum FLC is **<500 mg/L** and the renal cause remains uncertain.[2] ### Suspected cast nephropathy pathway 1. Stop NSAIDs and avoid unnecessary iodinated contrast and other nephrotoxins. 2. Correct dehydration and hypercalcemia while avoiding fluid overload. 3. Obtain serum FLCs urgently and characterize urine protein. 4. Involve hematology and nephrology early. 5. Start a rapidly active, **bortezomib-based** antimyeloma regimen when cast nephropathy is sufficiently likely.[2] 6. Do not delay systemic treatment for mechanical light-chain removal; IMWG concludes mechanical approaches have not improved overall survival.[2] ## Bone disease IMWG recommends bone-targeted therapy in active MM, with zoledronic acid a preferred option in many patients and denosumab useful when renal impairment makes bisphosphonate exposure problematic.[3] | Intervention | Role | Main cautions | |---|---|---| | Zoledronic acid | Reduce skeletal events | Renal toxicity, hypocalcemia, osteonecrosis of jaw | | Denosumab | Reduce skeletal events; no renal clearance | Hypocalcemia, osteonecrosis; rebound bone loss if stopped without a plan | | Vertebral augmentation | Selected painful vertebral compression fractures | Procedure/anatomic risk | | Radiation | Focal pain, selected lesions, cord-compression pathway | Marrow exposure | | Orthopedic/spine surgery | Long-bone fracture, instability, structural cord compromise | Perioperative infection/thrombosis risk | Assess calcium/vitamin D and dental health before antiresorptive therapy when feasible. IMWG permits less frequent zoledronic acid or discontinuation after at least 12 months in selected patients with very good partial response or better.[3] ## Infection prevention Disease-related immunoparesis combines with steroid exposure, cytopenias, cellular therapy, bispecific antibodies, and hypogammaglobulinemia to create substantial infection risk.[4] Practical prevention includes: - influenza, COVID-19, pneumococcal, and recombinant zoster vaccination according to current immunocompromised schedules; - herpesvirus prophylaxis with proteasome inhibitors and many cellular/bispecific protocols; - Pneumocystis prophylaxis when cumulative immunosuppression warrants it; - early evaluation of fever or respiratory symptoms; - selected antibacterial prophylaxis in high-risk periods according to protocol; - immunoglobulin replacement for selected patients with recurrent serious infection and significant hypogammaglobulinemia.[4] BCMA-directed therapy can cause profound, prolonged hypogammaglobulinemia; infection prevention and immunoglobulin replacement thresholds should be protocolized. ## Thrombosis prevention Lenalidomide, pomalidomide, and iberdomide increase thrombotic risk, particularly with dexamethasone and additional patient factors. Use a validated institutional risk assessment to select aspirin or anticoagulant prophylaxis. Account for renal function, platelet count, bleeding risk, drug interactions, and concurrent antithrombotic indications. ## Neuropathy Bortezomib and some older immunomodulatory drugs can worsen peripheral neuropathy. Document baseline symptoms, use subcutaneous/less-frequent bortezomib schedules when appropriate, and reduce or hold neurotoxic therapy when symptoms progress. Consider amyloidosis, diabetes, vitamin deficiency, radiculopathy, or the paraprotein itself when neuropathy does not fit treatment timing. ## Relapsed or refractory disease Before choosing therapy, record: - prior regimens, response, and duration; - refractory drug classes; - current renal function and marrow reserve; - neuropathy, infection history, and frailty; - cytogenetic risk and extramedullary disease; - prior ASCT; - prior BCMA and GPRC5D exposure; - tempo and symptoms of relapse. ### Major therapeutic classes | Class | Representative agents | Major bedside issues | |---|---|---| | Anti-CD38 antibodies | Daratumumab, isatuximab | Infection, cytopenia, transfusion-test interference | | Proteasome inhibitors | Bortezomib, carfilzomib, ixazomib | Neuropathy; cardiac/vascular toxicity with carfilzomib | | Immunomodulatory/cereblon-directed drugs | Lenalidomide, pomalidomide, iberdomide | Cytopenias, thrombosis, embryo-fetal toxicity | | BCMA CAR-T | Ciltacabtagene autoleucel, idecabtagene vicleucel | Cytokine-release syndrome, neurotoxicity, prolonged cytopenia, infection | | BCMA bispecific antibodies | Teclistamab, elranatamab, linvoseltamab | Cytokine-release syndrome, neurotoxicity, infection, hypogammaglobulinemia | | GPRC5D bispecific antibody | Talquetamab | Cytokine-release syndrome, neurologic toxicity, taste change, weight loss, skin/nail toxicity | | BCMA antibody-drug conjugate | Belantamab mafodotin | Corneal toxicity; protocolized ophthalmic monitoring | ### Teclistamab plus daratumumab: 2026 U.S. change In March 2026, FDA approved teclistamab plus daratumumab-hyaluronidase for adults with relapsed/refractory MM after at least one prior line containing a proteasome inhibitor and immunomodulatory agent. The pivotal randomized study reported a PFS HR of **0.17** compared with control therapy.[9] This combination requires structured monitoring for cytokine-release syndrome, immune-effector-cell neurologic toxicity, cytopenias, hypogammaglobulinemia, and serious infection. ### Iberdomide combination: August 2026 U.S. change On August 13, 2026, FDA granted **accelerated approval** to iberdomide with daratumumab-hyaluronidase and dexamethasone for adults who had received at least one prior line including a proteasome inhibitor and immunomodulatory agent.[10] The approved iberdomide dose is **1 mg orally once daily on days 1-21 of a 28-day cycle** with the companion agents. The pivotal trial’s major efficacy endpoint was MRD-negative complete response: **41% versus 21%** in the comparator arm.[10] The label carries major warnings for embryo-fetal toxicity and venous/arterial thromboembolism, with additional concerns including neutropenia and infection. Because approval is accelerated, confirmatory evidence remains important when placing the regimen in sequence. ### Belantamab mafodotin combination In October 2025, FDA approved belantamab mafodotin with bortezomib/dexamethasone after at least two prior lines including a proteasome inhibitor and immunomodulatory agent.[11] In the U.S. efficacy population, median PFS was **31.3 months versus 10.4 months** with the comparator triplet (HR 0.31). Corneal toxicity can be severe and requires current label-directed ophthalmic monitoring. ## Special populations ### Frailty Use a formal frailty approach when possible. Early steroid reduction, less neurotoxic scheduling, and simplified regimens may improve treatment persistence. The objective is durable disease control without sacrificing function to avoidable toxicity. ### AL amyloidosis suspicion Consider coexisting AL amyloidosis with nephrotic albuminuria, restrictive cardiomyopathy, unexplained autonomic/peripheral neuropathy, hepatomegaly, macroglossia, periorbital purpura, or disproportionate cardiac biomarkers. Tissue confirmation and amyloid typing are essential because treatment intensity and prognosis differ. ### Reproductive potential Lenalidomide, pomalidomide, thalidomide, and iberdomide have major embryo-fetal toxicity. Follow required pregnancy-prevention programs and current prescribing information. Discuss fertility preservation before high-dose melphalan/ASCT when relevant. ## Monitoring and follow-up At each cycle or clinically relevant interval, assess: - measurable disease marker trend; - CBC and renal function; - calcium and symptoms of bone disease; - infection and vaccination/prophylaxis status; - neuropathy and functional change; - thrombotic and bleeding events; - regimen-specific organ toxicity; - adherence and access to oral drugs/supportive medicines. Re-image for new focal pain, neurologic deficits, biochemical progression with unclear distribution, suspected extramedullary disease, or when required by the treatment protocol. ## Related library topics - [Hypercalcemia in Adults](../endocrinology/hypercalcemia-in-adults.md) - [Acute Kidney Injury](../nephrology/acute-kidney-injury.md) - [Chronic Kidney Disease](../nephrology/chronic-kidney-disease.md) - [Nephrotic Syndrome in Adults](../nephrology/nephrotic-syndrome-in-adults.md) - [Pneumocystis jirovecii Pneumonia in Adults](../infectious-disease/pneumocystis-jirovecii-pneumonia-in-adults.md) - [Aplastic Anemia in Adults](../hematology/aplastic-anemia-in-adults.md) ## References 1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. *Lancet Oncol.* 2014;15(12):e538-e548. DOI: 10.1016/S1470-2045(14)70442-5. PMID: 25439696. https://pubmed.ncbi.nlm.nih.gov/25439696/ 2. Dimopoulos MA, Sonneveld P, Leung N, et al. Management of multiple myeloma-related renal impairment: recommendations from the International Myeloma Working Group. *Lancet Oncol.* 2023;24:e293-e311. DOI: 10.1016/S1470-2045(23)00223-1. PMID: 37414019. https://pubmed.ncbi.nlm.nih.gov/37414019/ 3. Terpos E, Zamagni E, Lentzsch S, et al. Treatment of multiple myeloma-related bone disease: recommendations from the Bone Working Group of the International Myeloma Working Group. *Lancet Oncol.* 2021;22(3):e119-e130. DOI: 10.1016/S1470-2045(20)30559-3. PMID: 33545067. https://pubmed.ncbi.nlm.nih.gov/33545067/ 4. Raje NS, Anaissie E, Kumar SK, et al. Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group. *Lancet Haematol.* 2022;9(2):e143-e161. DOI: 10.1016/S2352-3026(21)00283-0. PMID: 35114152. https://pubmed.ncbi.nlm.nih.gov/35114152/ 5. D'Agostino M, Cairns DA, Lahuerta JJ, et al. Second Revision of the International Staging System (R2-ISS) for Overall Survival in Multiple Myeloma. *J Clin Oncol.* 2022;40(29):3406-3418. DOI: 10.1200/JCO.21.02614. PMID: 35605179. https://pubmed.ncbi.nlm.nih.gov/35605179/ 6. Hillengass J, Usmani S, Rajkumar SV, et al. International Myeloma Working Group consensus recommendations on imaging in monoclonal plasma cell disorders. *Lancet Oncol.* 2019;20(6):e302-e312. DOI: 10.1016/S1470-2045(19)30309-2. https://doi.org/10.1016/S1470-2045(19)30309-2 7. U.S. Food and Drug Administration. *FDA approves daratumumab and hyaluronidase-fihj for high-risk smoldering multiple myeloma.* November 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-high-risk-smoldering-multiple-myeloma 8. U.S. Food and Drug Administration. *FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma.* January 27, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-bortezomib-lenalidomide-and-dexamethasone-newly 9. U.S. Food and Drug Administration. *FDA approves teclistamab in combination with daratumumab-hyaluronidase-fihj for relapsed or refractory multiple myeloma.* March 5, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-combination-daratumumab-hyaluronidase-fihj-relapsed-or-refractory-multiple 10. U.S. Food and Drug Administration. *FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma.* August 13, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-iberdomide-daratumumab-and-hyaluronidase-fihj-and-dexamethasone 11. U.S. Food and Drug Administration. *FDA approves belantamab mafodotin for relapsed or refractory multiple myeloma.* October 23, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancerhematologic-malignancies-approval-notifications7:["$","$L17",null,{"article":{"id":"medical-multiple-myeloma","title":"Multiple Myeloma","slug":"multiple-myeloma","description":"Multiple myeloma (MM) is a clonal plasma-cell malignancy diagnosed when there are ≥10% clonal bone-marrow plasma cells or a biopsy-proven plasmacytoma plus at least one myeloma-defining event. 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