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Teaching pack: Multiple myeloma

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  1. Teaching pack · Cancer · haematologic

    Multiple myeloma

    Multiple myeloma is a plasma-cell cancer with more new drug classes than any other: proteasome inhibitors, IMiDs, CD38 antibodies, BCMA CAR-T, bispecifics, and an ADC.

    Teaching pack: Multiple myeloma · OnCo, CC BY 4.0 · not medical advice1 / 10
  2. What it is

    In two paragraphs

    Multiple myeloma is a cancer of antibody-producing plasma cells in the bone marrow, causing anaemia, bone destruction, kidney failure and infections. It is preceded by MGUS and smouldering myeloma, which are common (MGUS in ~3% of people over 50) and mostly harmless; whether to treat high-risk smouldering disease (AQUILA, daratumumab) is a live debate, and Iceland is screening its whole adult population (iStopMM). Staging (R-ISS/R2-ISS) and cytogenetics (del17p, t(4;14), 1q gain) drive prognosis; MRD negativity at one in a million marrow cells has become both the best prognostic marker and, since 2024, an accepted regulatory endpoint.

    No cancer has gained more drug classes: proteasome inhibitors (bortezomib 2003, carfilzomib), immunomodulatory cereblon modulators (thalidomide, lenalidomide, pomalidomide; next-generation CELMoDs iberdomide and mezigdomide), CD38 antibodies (daratumumab, isatuximab), BCMA-directed CAR-T (ide-cel, cilta-cel; anito-cel decision December 2026), BCMA and GPRC5D bispecific T-cell engagers (teclistamab, elranatamab, linvoseltamab, talquetamab), a BCMA ADC (belantamab, withdrawn 2022 and re-approved 2025), plus XPO1 and BCL-2 inhibitors for subsets. Newly diagnosed patients receive a quadruplet (Dara-VRd or Isa-VRd) whether or not they proceed to autologous transplant (PERSEUS, CEPHEUS, IMROZ), then lenalidomide maintenance; median survival in fit patients now exceeds ten years. At relapse, cilta-cel (CARTITUDE-4, OS HR 0.55) and teclistamab plus daratumumab (MajesTEC-3, approved March 2026) are second-line options, with sequencing by prior antigen exposure.

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  3. Standard of care

    What is given today, by setting

    SettingApproachGuideline
    Newly diagnosedDara-VRd ± ASCT → lenalidomide maintenance.not mapped
    RelapsedCAR-T or bispecific; belantamab combinations; sequencing by prior exposure.not mapped
    MGUS / low-risk smoulderingObservation with periodic labs; no treatment outside trials.NCCN Observation
    High-risk smouldering myelomaConsider daratumumab monotherapy (AQUILA) or lenalidomide (E3A06), or trial enrolment; shared decision given indolent course in many.NCCN Category 2A (daratumumab or lenalidomide for high-risk SMM)
    Newly diagnosed, transplant-eligibleDara-VRd (or Isa-VRd) induction × 4-6 → stem-cell collection → high-dose melphalan + autologous transplant → Dara-VRd consolidation → lenalidomide (± daratumumab) maintenance; MRD-guided de-escalation emerging (PERSEUS design). Tandem transplant or extended therapy for high risk.NCCN Category 1 (Dara-VRd), ESMO-MCBS A
    Newly diagnosed, transplant-ineligibleDara-VRd (CEPHEUS) or Isa-VRd (IMROZ) with bortezomib de-escalation after induction; Dara-Rd (MAIA) for frailer patients; continuous therapy with dose adjustment for frailty.NCCN Category 1
    MaintenanceLenalidomide until progression (CALGB 100104, Myeloma XI); daratumumab added for high-risk or per PERSEUS; MRD-guided discontinuation in trials (DRAMMATIC, MASTER); iberdomide maintenance (EXCALIBER) pending.not mapped
    First relapse (1-3 prior lines)Cilta-cel if lenalidomide-refractory (CARTITUDE-4); teclistamab + daratumumab (MajesTEC-3, 2026); ide-cel after ≥2 lines; belantamab-Vd or -Pd (DREAMM-7/8); CD38-based triplets (Dara-Kd, Isa-Kd, Dara-Pd) by prior exposure; carfilzomib or pomalidomide combinations.NCCN Category 1 (cilta-cel ≥1 line; tec-dara ≥1 line)
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  4. State of the art

    Where the field stands

    • CAR-T in second line.
    • Bispecifics after one prior line (2026).
    • Functional cure discussions.
    • Quadruplet induction (CD38 antibody + PI + IMiD + dexamethasone) for all newly diagnosed patients, with MRD negativity in 60-75%.
    • CAR-T with a survival benefit as early as second line (CARTITUDE-4, OS HR 0.55) and a third of late-line patients progression-free at five years without maintenance (CARTITUDE-1).
    • Two antigens for T-cell redirection (BCMA, GPRC5D) with four approved bispecifics; teclistamab plus daratumumab approved at first relapse (March 2026).
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  5. History

    How we got here

    1. 1844First described case (Solly); Bence Jones protein 1847
    2. 1958Melphalan introduced; melphalan-prednisone standard for 40 years
    3. 1983High-dose melphalan with autologous marrow rescue (McElwain)
    4. 1996IFM 90: transplant improves survival over chemotherapy
    5. 1999Thalidomide shown active in refractory myeloma (Singhal, NEJM)
    6. 2003Bortezomib approved
    7. 2003Bortezomib: first proteasome inhibitor approved
    8. 2006Lenalidomide approved
    9. 2012Carfilzomib approved; International Staging refined
    10. 2015Daratumumab approved
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  6. Pipeline

    What is coming

    • Teclistamab (product)
    • Ciltacabtagene autoleucel (product)
    • Anitocabtagene autoleucel (product)
    • iMMagine-1 (trial)
    • CARTITUDE-5 (trial)
    • Iberdomide (product)
    • Mezigdomide (product)
    • Talquetamab (product)
    • Linvoseltamab (product)
    • Elranatamab (product)
    • iStopMM (trial)
    • MRD-guided treatment-free intervals in myeloma (idea)
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  7. Evidence

    The trials that set the standard

    • PERSEUS (phase 3, n=709): Progression-free survival at 48 months: 84.3% vs 67.7%, HR 0.42
    • CARTITUDE-4 (phase 3, n=419): Progression-free survival: pending
    • DREAMM-7 (phase 3, n=494): Progression-free survival (median): 36.6 months vs 13.4 months, HR 0.41
    • MajesTEC-3 (phase 3, n=587): Progression-free survival at 36 months: 83.4% vs 29.7%, HR 0.17
    • IMROZ (phase 3, n=446): Progression-free survival at 60 months: 63.2% vs 45.2%, HR 0.6
    • KarMMa-3 (phase 3, n=386): Progression-free survival (median): 13.3 months vs 4.4 months, HR 0.49
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  8. Open problems

    What nobody has solved

    • High-risk cytogenetics.
    • Infections with T-cell redirecting therapy.
    • Cost and access.
    • High-risk cytogenetics and extramedullary disease respond briefly to every class; no regimen closes the gap.
    • Infections are a leading cause of death on bispecifics; hypogammaglobulinaemia and T-cell exhaustion need better mitigation than IVIG and dose de-intensification.
    • Delayed neurotoxicity (parkinsonism, cranial neuropathies) after BCMA CAR-T and second primary malignancies after cereblon modulators and CAR-T.
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  9. Quiz

    Check understanding

    1. What is accelerated approval and what are its risks for patients?
      Answer
      FDA approval based on early evidence such as tumour shrinkage or pCR, conditional on a confirmatory trial; if confirmation fails the drug is withdrawn (atezolizumab in TNBC, belantamab in 2022, sacituzumab in bladder cancer), so benefit is not yet proven when prescribed.
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  10. Sources

    Read the primary sources

    • Wikipedia: https://en.wikipedia.org/wiki/Multiple_myeloma
    • Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445
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