Multiple myeloma

Overview

Multiple myeloma (MM) is a haematological malignancy characterised by the clonal proliferation of malignant plasma cells within the bone marrow. Plasma cells are a type of white blood cell (B-lymphocyte derivative) responsible for producing antibodies (immunoglobulins) that help the body fight infection. In multiple myeloma, these cells become cancerous, accumulating in the bone marrow and crowding out healthy blood cells. Instead of producing useful antibodies, the malignant cells produce an abnormal protein—commonly referred to as M-protein (monoclonal protein), paraprotein, or M-spike—which serves no protective function and can cause damage to organs, particularly the kidneys.

The term “multiple” refers to the frequent presence of multiple bone lesions (lytic lesions) at the time of diagnosis, although some patients present with a solitary plasmacytoma (a single mass of myeloma cells). It is the second most common haematological malignancy after non-Hodgkin lymphoma, accounting for approximately 1–2% of all cancers and roughly 15–20% of haematological cancers.

While historically considered incurable, advances in proteasome inhibitors, immunomodulatory drugs (IMiDs), monoclonal antibodies, and autologous stem cell transplantation have transformed multiple myeloma into a highly manageable chronic condition for many patients, with significantly improved overall survival rates over the last two decades.

Epidemiology and Risk Factors

Incidence and Demographics

• Age: The median age at diagnosis is 69 years. It is exceedingly rare before age 40 (< 1% of cases).
• Sex: Slightly more common in men than women (male-to-female ratio ~1.5:1).
• Ethnicity: Incidence is twice as high in Black populations compared to White populations. Asian populations have the lowest incidence.
• Geography: Higher rates in industrialised nations (North America, Europe, Australia).

Established Risk Factors

Precursor Conditions

Understanding the spectrum of plasma cell disorders is crucial for context:

1. MGUS: Asymptomatic, M-protein < 30 g/L, bone marrow plasma cells < 10%, no end-organ damage (CRAB criteria negative). Prevalence ~3–5% in adults > 50.
2. Smouldering Multiple Myeloma (SMM): Asymptomatic, but higher tumour burden (M-protein ≥ 30 g/L or bone marrow plasma cells 10–60%). Higher risk of progression (~10% per year for first 5 years).
3. Active (Symptomatic) Multiple Myeloma: Meets diagnostic criteria including end-organ damage (CRAB features) or specific biomarkers of malignancy.

Pathophysiology: How Does It Develop?

The development of multiple myeloma is a multi-step process involving genetic instability and a permissive bone marrow microenvironment.

1. Initiation (MGUS): A single B-cell/plasma cell acquires a primary genetic hit. The two main pathways are:

• Hyperdiploidy (Trisomies): Gain of odd-numbered chromosomes (3, 5, 7, 9, 11, 15, 19, 21). ~50–55% of cases. Generally better prognosis.
• Non-Hyperdiploidy (IgH Translocations): Translocations involving the immunoglobulin heavy chain (IgH) locus on chromosome 14q32. Common partners: CCND1 (11q13, t(11;14)), MMSET/FGFR3 (4p16, t(4;14)), MAF (16q23, t(14;16)), MAFB (20q11, t(14;20)). ~40–45% of cases.

1. Progression (SMM to MM): Secondary genetic events drive progression. These include:

• RAS mutations (KRAS, NRAS).
• TP53 deletion/mutation (del 17p) – associated with high risk.
• MYC rearrangements.
• Epigenetic modifications (DNA methylation, histone modification).

1. Bone Marrow Microenvironment: Myeloma cells do not grow in isolation. They interact with stromal cells, osteoblasts, osteoclasts, endothelial cells, and immune cells (T-cells, NK cells).

• Osteolytic Disease: Myeloma cells secrete factors (RANKL, DKK1, sclerostin, MIP-1α) that stimulate osteoclasts (bone resorption) and inhibit osteoblasts (bone formation). This uncoupling causes lytic lesions, osteoporosis, and hypercalcaemia.
• Angiogenesis: VEGF and other factors promote new blood vessel formation, feeding the tumour.
• Immune Evasion: Myeloma cells downregulate MHC class I, upregulate PD-L1, and expand regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs), paralysing immune surveillance.

How Does It Look? (Clinical Presentation & Physical Findings)

Note: “How does it look” in a clinical context refers to the phenotypic presentation**—the constellation of physical signs, laboratory abnormalities, and imaging findings that a clinician observes or elicits during assessment. It does not refer to a visible external rash or tumour in most cases (unlike lymphoma), as the disease is primarily internal (bone marrow/bones).

1. The “Classic” Clinical Picture (CRAB Features)

The acronym CRAB defines the end-organ damage diagnostic of active myeloma. This is the “look” of symptomatic disease.

2. Other Physical & Clinical “Looks”

• Recurrent Infections: Patients look unwell, febrile. Encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae) due to hypogammaglobulinaemia (suppression of normal polyclonal immunoglobulins) and impaired neutrophil function.
• Neurological Signs:
• Spinal Cord Compression (Emergency): Back pain + limb weakness, sensory level, bowel/bladder incontinence, hyperreflexia/Babinski sign. Caused by extramedullary plasmacytoma or vertebral collapse.
• Peripheral Neuropathy: Numbness, tingling, “stocking-glove” distribution. Can be disease-related (amyloid) or treatment-related (bortezomib).
• Cranial Nerve Palsies: Rare, due to skull base infiltration.
• Hyperviscosity Syndrome (Emergency): Seen in IgA or IgG3 myeloma (rarely IgM/Waldenström’s). Looks like: Blurred vision, retinal haemorrhages/venous engorgement (fundoscopy), headache, confusion, stroke-like symptoms, mucosal bleeding.
• Amyloidosis (AL Amyloidosis): ~10–15% overlap. Looks like: Macroglossia (enlarged tongue with scalloped edges), periorbital purpura (“raccoon eyes”), carpal tunnel syndrome, hepatosplenomegaly, restrictive cardiomyopathy (heart failure signs with low voltage ECG), nephrotic syndrome (massive oedema).
• Extramedullary Plasmacytomas: Soft tissue masses (purplish/red nodules) in sinuses, nasopharynx, lung, liver, skin. Sign of aggressive disease/high-risk biology.
• Skin Manifestations: Rare specific lesions (plasmacytoma cutis), but commonly: Petechiae/ecchymoses (thrombocytopenia), acquired cutis laxa (amyloid), herpes zoster (reactivation due to immune suppression).

3. Laboratory “Look” (Diagnostic Hallmarks)

Symptoms: What the Patient Experiences

While “How Does It Look” describes the clinician’s objective findings, Symptoms describe the patient’s subjective experience. These often develop insidiously over months.

1. Bone Pain – The Hallmark Symptom

• Character: Deep, aching, constant, worse with movement/weight-bearing, improved with rest (unlike metastatic bone pain which may be night-worse).
• Distribution: Lower back (lumbar spine) is #1 site, followed by ribs, thoracic spine, pelvis, skull, femur, humerus.
• Mechanism: Periosteal stretching from lytic lesions, microfractures, nerve root compression.
• Red Flag: New severe focal pain → Pathological fracture or cord compression.

2. Fatigue – The Most Common Symptom

• Prevalence: > 70% at diagnosis.
• Nature: Disproportionate to activity, unrelieved by sleep, “heavy” limbs, cognitive fog (“chemo brain” pre-treatment).
• Drivers: Anaemia (primary), cytokine release (TNF-α, IL-6), renal dysfunction, psychological distress, sleep disruption from pain.

3. Neurological Symptoms

• Radiculopathy: Shooting pain, numbness, weakness in dermatomal distribution (nerve root compression by plasmacytoma or collapsed vertebra).
• Spinal Cord Compression (SCC): Medical Emergency. Back pain → Band-like tightness → Leg weakness/numbness → Urinary retention/incontinence. Requires immediate MRI and dexamethasone/radiotherapy/surgery.
• Peripheral Neuropathy: Symmetrical distal sensory loss, paraesthesia, burning pain. Often length-dependent.

4. Renal Symptoms (Often Silent Until Late)

• Polyuria/Nocturia/Thirst: Nephrogenic diabetes insipidus (renal tubular damage) + Hypercalcaemia.
• Oedema: Ankle swelling, periorbital puffiness (nephrotic syndrome from amyloid/LCDD or fluid overload from renal failure).
• Nausea/Vomiting/Anorexia: Uraemia.

5. Infection-Related Symptoms

• Recurrent sinusitis, bronchitis, pneumonia, UTIs, skin infections.
• Fever without obvious source (neutropenia risk during treatment, but also inherent immune dysfunction pre-treatment).
• Herpes Zoster (Shingles): High incidence (15–30% lifetime risk), often multi-dermatomal or disseminated.

6. Hypercalcaemia Symptoms (“Stones, Bones, Groans, Moans, Psychiatric Overtones”)

• Groans: Constipation, abdominal pain, nausea, vomiting, peptic ulcer exacerbation.
• Moans: Lethargy, confusion, depression, coma.
• Stones: Renal colic (nephrolithiasis).
• Psychiatric: Anxiety, agitation, hallucinations.

7. Hyperviscosity Symptoms (Specific to High M-Protein/IgA)

• Visual disturbances (blurring, diplopia, blind spots).
• Headache, dizziness, vertigo.
• Mucosal bleeding (epistaxis, gingival bleeding).
• Confusion, ataxia.

8. “B Symptoms” (Systemic Inflammatory Symptoms)

• Drenching night sweats (soaking sheets).
• Unexplained fever (> 38°C).
• Unintentional weight loss (> 10% body weight in 6 months).
• Note: B symptoms are less common in MM than lymphoma but indicate high tumour burden/aggressive biology.

Diagnostic Criteria (IMWG 2014 / 2022 Updates)

Diagnosis requires ALL THREE of the following:

1. Clonal Bone Marrow Plasma Cells ≥ 10% (or biopsy-proven bony/soft tissue plasmacytoma).
2. Presence of Monoclonal Protein (M-protein) in serum and/or urine (except in true non-secretory myeloma ~1–3%).
3. Evidence of End-Organ Damage (CRAB) attributable to the plasma cell disorder OR SLiM Criteria (Biomarkers of Malignancy – allows diagnosis before CRAB develops):

SLiM Criteria (Biomarkers of Imminent Organ Damage): S: Bone marrow clonal plasma cells ≥ 60%. Li: Serum Involved/Uninvolved Free Light Chain Ratio ≥ 100 (provided involved FLC ≥ 100 mg/L). M: > 1 Focal Lesion** on MRI ( ≥ 5mm ) or PET-CT (FDG-avid).

Staging Systems

Staging guides prognosis and clinical trial eligibility.

1. Revised International Staging System (R-ISS) – Current Standard

Combines ISS (tumour burden) with High-Risk Cytogenetics and LDH.

High-Risk Cytogenetics (CA): del(17p), t(4;14), t(14;16).

2. ISS (Original) – Simpler, Tumour Burden Only

• Stage I: β2M < 3.5, Alb ≥ 35.
• Stage II: Not I or III.
• Stage III: β2M > 5.5.

3. R2-ISS (Second Revision – Emerging)

Incorporates TP53 mutation status and circulating plasma cells for finer granularity.

Treatment Landscape: A Modern Algorithm

Treatment is not one-size-fits-all. It depends on: Transplant Eligibility (Fitness), Cytogenetic Risk, Patient Preference, Comorbidities, and Access to Drugs.

General Principle: “Treat to Best Response” → MRD Negativity (Minimal Residual Disease < 10⁻⁵ or 10⁻⁶ by NGS/Flow) is the new therapeutic goal, correlating with longest PFS/OS.

A. Transplant-Eligible Patients (Typically < 70–75 yo, Fit, Adequate Organ Function)

1. Induction Therapy (Goal: Deep Response Pre-Transplant)

Standard of Care (SOC): Triplet Regimens (3 drugs). Quadruplets (4 drugs) emerging for High Risk.

Cycle duration: Typically 21 or 28 days. 4–6 cycles standard before stem cell collection.

2. Stem Cell Mobilisation & Collection

• G-CSF (Filgrastim) ± Plerixafor (Mozobil). Target: ≥ 2–4 x 10⁶ CD34+ cells/kg (allows single or tandem transplant).
• Chemomobilisation (Cyclophosphamide + G-CSF) used if plerixafor fails/access issues.

3. High-Dose Chemotherapy (HDT) & Autologous Stem Cell Transplant (ASCT)

• Conditioning: Melphalan 200 mg/m² (Mel-200). Mel-140 for frail/renal impairment.
• Procedure: Infusion of autologous CD34+ cells → Engraftment (Neutrophils > 0.5 x 10⁹/L ~ Day 10–14, Platelets > 20 x 10⁹/L ~ Day 14–21).
• Tandem Transplant: Second Mel-200 within 6 months. Historical benefit; modern data (EMN02/HO95, STaMINA) shows single transplant + maintenance non-inferior to tandem for standard risk. Tandem considered for suboptimal response (< CR) or high risk.

4. Consolidation (Post-ASCT, Pre-Maintenance)

• Optional. 2–4 cycles of Induction regimen (e.g., VRd, KRd, D-VRd) to deepen response.
• Benefit clearest for patients not achieving CR/sCR or MRD-negativity post-ASCT.

5. Maintenance Therapy (Until Progression/Toxicity)

• Standard: Lenalidomide (10–15 mg/day, days 1–21/28). (CALGB 100104, IFM 2005-02, Myeloma XI).
• High Risk / Post-Dara Induction: Lenalidomide + Bortezomib or Lenalidomide + Daratumumab (CASSIOPEIA maintenance arm, DRAMMATIC trial).
• Duration: Indefinite (until progression or unacceptable toxicity). Stopping early increases relapse risk.

B. Transplant-Ineligible Patients (Frail, Elderly, Significant Comorbidities)

Goal: Disease control, quality of life, preserving function. Continuous therapy preferred over fixed duration.

Frailty Assessment is Mandatory: Use IMWG Frailty Score or Geriatric Assessment (GA) to guide dosing (e.g., Reduced dose Dex 20mg weekly, Reduced Len 15mg/25mg alt days, Weekly SubQ Bortezomib).

C. Relapsed/Refractory Multiple Myeloma (RRMM)

Treatment selection depends on: Prior lines, Prior drug classes exposed (PI, IMiD, anti-CD38), Refractoriness status, Time since last therapy, Cytogenetics, Comorbidities.

Sequencing Paradigm: Use a novel mechanism of action (MoA) at each relapse if possible.

• 1st Relapse (Len-refractory common): Daratumumab-based triplets (D-Vd, DKd, DPd, DRd) or Carfilzomib-based (KPd, Kd, KRd) or Pomalidomide-based (PVd, KPd, DPd).
• 2nd/3rd Relapse (Double/Triple-Class Refractory):
• BCMA-Targeted: Teclistamab (Bispecific), Talquetamab (GPRC5D Bispecific), Elranatamab (Bispecific), Idecabtagene vicleucel / Ciltacabtagene autoleucel (CAR-T).
• Novel MoAs: Selinexor (XPO1 inhibitor), Belantamab mafodotin (BCMA ADC – withdrawn US, avail elsewhere), Iberdomide/CC-92480 (Celn mod – investigational), Modakafusp alfa (IFNα-ADC – investigational).
• Extramedullary/High Risk: CAR-T or Bispecifics preferred over standard chemo.

Refractory to ≥1 PI, ≥1 IMiD, ≥1 anti-CD38 mAb. This population drives current clinical trial innovation (Bispecifics, CAR-T).

Supportive Care: Essential for Survival & Quality of Life

Multiple myeloma management is not just anti-myeloma therapy.

Prognosis and Survival Statistics

• Median Overall Survival (OS): Has improved from ~3 years (pre-2000) to > 8–10 years (current era) for standard-risk patients.
• High-Risk Cytogenetics (del17p, t(4;14), t(14;16), TP53 mut): Median OS historically ~2–3 years, but improving with quadruplets, CAR-T, Bispecifics.
• Cure Fraction: A small but growing subset (especially Standard Risk, MRD-negative post-ASCT + Maintenance) may achieve functional cure (normal life expectancy).
• Key Prognostic Factors:

1. Cytogenetics (FISH) – Most important.
2. Stage (R-ISS).
3. Depth of Response (sCR/MRD-negativity).
4. Age/Frailty/Comorbidities.
5. Renal Function at diagnosis (Reversible vs Irreversible).

Living with Multiple Myeloma: Practical Guidance

Monitoring Schedule (Post-Induction / On Maintenance)

• Monthly (First Year): CBC, CMP (Renal/Liver/Ca), SPEP/IFE, sFLC, Quantitative Ig.
• Every 3 Months: Imaging (PET-CT or MRI if prior focal lesions; otherwise clinical), Bone Marrow (if confirm MRD-neg or suspected progression).
• Annual: Cardiac Echo (if Carfilzomib/Anthracycline exposure), Dexa Scan, Ophthalmology (if on long-term steroids/cataract risk), Skin Cancer Screen (increased risk).

Diet and Lifestyle

• No specific “Myeloma Diet”. Balanced, high protein, high fibre.
• Food Safety: Critical during neutropenia/lymphopenia (No raw fish/meat/eggs, wash produce well, avoid unpasteurised dairy).
• Exercise: Weight-bearing/resistance training essential for bone density and fatigue management. Physiotherapy referral recommended.
• Smoking Cessation: Imperative.
• Alcohol: Minimise (hepatic metabolism of drugs, neuropathy risk).

Financial and Psychosocial Support

• Cost of Oral Therapy: Lenalidomide/Pomalidomide are expensive. Social work/Pharma Patient Assistance Programs (PAP) vital.
• Mental Health: Anxiety, depression, “scanxiety” common. Psycho-oncology referral, support groups (IMF, MMRF, Leukemia & Lymphoma Society).
• Caregiver Burden: High. Respite care, caregiver support groups.

Emerging Therapies & Future Directions (2024–2025+)

1. Bispecific Antibodies (Teclistamab, Talquetamab, Cevostamab, Linvoseltamab): “Off-the-shelf” T-cell redirectors. Moving earlier lines (1st–3rd relapse). Step-up dosing to mitigate Cytokine Release Syndrome (CRS). Infection risk (IVIG support needed).
2. CAR-T Cell Therapy (Cilta-cel, Ide-cel): Autologous, manufacturing time (3–6 wks). Bridging therapy needed. Cranial nerve toxicities (ICANS-like), prolonged cytopenias, infection risk. Moving to 2nd line (CARTITUDE-4, KARMMA-3).
3. GPRC5D Targeting (Talquetamab): Novel target for BCMA-relapsed disease. Side effects: Skin (nail changes, rash), Dysgeusia (taste loss), Weight loss.
4. Menin Inhibitors (e.g., Revumenib): For KMT2A-rearranged / NPM1 mutant (rare in MM, more AML) – investigational in MM subsets.
5. Cereblon E3 Ligase Modulators (CELMoDs): Iberdomide, Mezigdomide – Next-gen IMiDs active in Len/Pom refractory disease. Oral.
6. XPO1 Inhibitors (Selinexor): Oral, nuclear export inhibitor. Used in TCR MM. Side effects: Nausea, anorexia, thrombocytopenia, fatigue.
7. MRD-Guided Therapy: Trials testing treatment cessation vs continuation in sustained MRD-negative patients (e.g., DRAMMATIC, MASTER, IFM 2020).
8. Quadruplets Upfront (D-VRd, Isa-VRd, D-KRd): Becoming new standard for Transplant-Eligible, especially High Risk.

Frequently Asked Questions (FAQ)

Q: Is Multiple Myeloma hereditary?

A: It is not inherited in a simple Mendelian pattern. However, having a first-degree relative with MM or MGUS increases risk 2–4 fold. Genetic susceptibility loci (GWAS) have been identified, but no single “myeloma gene” exists for clinical testing.

Q: Can MGUS or Smouldering Myeloma be treated early to prevent cancer?

A: Generally, NO. Standard of care is Active Surveillance (Watch & Wait). Early treatment has not proven to improve OS in standard-risk SMM/MGUS and exposes patients to toxicity. Exceptions: High-Risk SMM (20/2/20 criteria or SLiM criteria) – Clinical trials (e.g., QuiRedex, GEM-CESAR) or off-label Len/Dex/Dara considered. Discuss with a myeloma specialist.

Q: What is the difference between Myeloma and Metastatic Bone Disease?

A: Myeloma is a primary bone marrow cancer. Metastatic bone disease (e.g., breast, prostate, lung) is secondary spread. Myeloma causes purely lytic (“punched out”) lesions with no sclerotic rim (no bone formation attempt). Metastases often show mixed lytic/sclerotic patterns. Myeloma does not typically elevate Alkaline Phosphatase (ALP) unless fracture healing; metastases often raise ALP.

Q: Why do I need a Bone Marrow Biopsy if blood tests show the M-spike?

A: Blood tests show the protein the cells make. The biopsy shows the cells themselves (percentage, morphology), allows FISH cytogenetics (critical for risk stratification), and assesses marrow architecture (fibrosis, cellularity). It is mandatory for diagnosis and risk stratification.

Q: Can I have dental work while on Bisphosphonates/Denosumab?

A: Ideally, complete invasive dental work (extractions, implants) BEFORE starting. If already on therapy: Routine cleaning/fillings are safe. Invasive procedures: Drug holiday (Zoledronic: 3 months prior/after if possible; Denosumab: shorter half-life, coordinate with oncologist). Maintain excellent oral hygiene.

Q: What is “MRD Negativity” and why does my doctor talk about it?

A: Minimal Residual Disease (MRD) testing (Next-Gen Flow or NGS sequencing) detects 1 myeloma cell in 100,000–1,000,000 normal cells. MRD-negative status (10⁻⁵ or 10⁻⁶) is the strongest predictor of long PFS/OS, superseding CR/sCR. It is increasingly used to guide therapy decisions (e.g., stop maintenance?).

Glossary of Key Terms

• Amyloidosis (AL): Misfolded light chain deposition in organs (heart, kidney, nerve, gut).
• ASCT: Autologous Stem Cell Transplant.
• BCMA: B-cell Maturation Antigen (Target on myeloma cells).
• Bence Jones Protein: Free monoclonal light chains in urine.
• Bispecific Antibody: Engages T-cells (CD3) and Myeloma target (BCMA/GPRC5D).
• CAR-T: Chimeric Antigen Receptor T-cell therapy.
• CRAB: Hypercalcaemia, Renal failure, Anaemia, Bone lesions.
• CR/sCR: Complete Response / Stringent Complete Response (IFE negative + normal FLC ratio).
• FISH: Fluorescence In Situ Hybridisation (Cytogenetics).
• FLC / sFLC: Free Light Chains / Serum Free Light Chain Assay.
• HDT: High-Dose Therapy (Melphalan).
• IMiD: Immunomodulatory Drug (Lenalidomide, Pomalidomide, Thalidomide).
• ISS / R-ISS: International Staging System / Revised ISS.
• IVIG: Intravenous Immunoglobulin.
• MGUS: Monoclonal Gammopathy of Undetermined Significance.
• M-Protein / Paraprotein / M-Spike: Monoclonal immunoglobulin.
• MRD: Minimal Residual Disease.
• ONJ: Osteonecrosis of the Jaw.
• PI: Proteasome Inhibitor (Bortezomib, Carfilzomib, Ixazomib).
• PFS / OS: Progression-Free Survival / Overall Survival.
• SMM: Smouldering Multiple Myeloma.
• SLiM: Biomarkers (60% PCs, FLC ratio ≥100, MRI lesions).
• TCR: Triple-Class Refractory.
• VGPR: Very Good Partial Response (M-protein ↓ 90%).

References

Guidelines & Major Consensus Reports

• International Myeloma Working Group (IMWG) (2022) ‘Diagnostic criteria for multiple myeloma: 2022 update’, Blood Cancer Journal, 12(1), p. 126. Available at: https://doi.org/10.1038/s41408-022-00715-7.
• Rajkumar, S.V. et al. (2022) ‘International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma’, The Lancet Oncology, 23(10), pp. e441–e452.
• National Comprehensive Cancer Network (NCCN) (2024) NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma, Version 3.2024. Plymouth Meeting, PA: NCCN. Available at: https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf.
• European Society for Medical Oncology (ESMO) / European Haematology Association (EHA) (2023) ‘Multiple Myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up’, Annals of Oncology, 34(10), pp. 882–905.
• British Society for Haematology (BSH) (2023) ‘Guidelines on the diagnosis and management of multiple myeloma 2023’, British Journal of Haematology, 201(4), pp. 462–488.

Landmark Clinical Trials (Induction/Transplant/Maintenance)

• Moreau, P. et al. (2019) ‘Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study’, The Lancet, 394(10192), pp. 29–38.
• Facon, T. et al. (2019) ‘Daratumumab plus lenalidomide and dexamethasone for untreated myeloma (MAIA)’, New England Journal of Medicine, 380(22), pp. 2104–2115.
• Voorhees, P.M. et al. (2020) ‘Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial’, Blood, 136(8), pp. 936–945.
• Perrot, A. et al. (2023) ‘Daratumumab, bortezomib, lenalidomide, and dexamethasone (D-VRd) versus VRd in transplant-eligible newly diagnosed multiple myeloma (PERSEUS): a randomised, open-label, phase 3 study’, The Lancet, 402(10416), pp. 1781–1792.
• Attal, M. et al. (2017) ‘Lenalidomide maintenance after stem-cell transplantation for multiple myeloma’, New England Journal of Medicine, 376(14), pp. 1311–1320.
• McCarthy, P.L. et al. (2017) ‘Lenalidomide maintenance after autologous stem-cell transplantation for multiple myeloma (CALGB 100104)’, Journal of Clinical Oncology, 35(29), pp. 3279–3285.

Relapsed/Refractory & Novel Agents

• Moreau, P. et al. (2021) ‘Teclistamab in relapsed or refractory multiple myeloma (MajesTEC-1)’, New England Journal of Medicine, 385(11), pp. 973–983.
• Berdeja, J.G. et al. (2021) ‘Ciltacabtagene autoleucel, a B-cell maturation antigen–directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study’, The Lancet, 398(10297), pp. 314–324.
• San-Miguel, J.F. et al. (2023) ‘Talquetamab in relapsed or refractory multiple myeloma (MonumenTAL-1)’, New England Journal of Medicine, 389(24), pp. 2231–2242.
• Usmani, S.Z. et al. (2023) ‘Elranatamab in relapsed or refractory multiple myeloma (MagnetisMM-3)’, Nature Medicine, 29(12), pp. 3105–3114.
• Chari, A. et al. (2022) ‘Selinexor, bortezomib, and dexamethasone in relapsed/refractory multiple myeloma (BOSTON)’, The Lancet Oncology, 23(9), pp. 1155–1166.

Pathophysiology & Prognostics

• Kumar, S.K. et al. (2020) ‘Multiple Myeloma’, Nature Reviews Disease Primers, 6(1), p. 84.
• Munshi, N.C. and Avet-Loiseau, H. (2011) ‘Genomic abnormalities in multiple myeloma’, Best Practice & Research Clinical Haematology, 24(4), pp. 547–557.
• Pawlyn, C. and Davies, F.E. (2019) ‘Risk stratification in multiple myeloma: current status and future directions’, British Journal of Haematology, 185(2), pp. 215–225.
• Cavo, M. et al. (2020) ‘Role of minimal residual disease detection in multiple myeloma: a consensus statement’, Blood Cancer Journal, 10(9), p. 98.

Supportive Care & Nursing

• Dimopoulos, M.A. et al. (2021) ‘Management of multiple myeloma-related bone disease: updated ESMO Clinical Practice Guidelines’, Annals of Oncology, 32(10), pp. 1229–1242.
• Palumbo, A. et al. (2018) ‘Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma’, Leukemia, 32(6), pp. 1339–1348.
• Ludwig, H. et al. (2019) ‘Myeloma and infection: a review’, Journal of Clinical Oncology, 37(6), pp. 500–510.

Patient Advocacy & Information Portals

• International Myeloma Foundation (IMF) – https://www.myeloma.org
• Multiple Myeloma Research Foundation (MMRF) – https://www.themmrf.org
• Leukemia & Lymphoma Society (LLS) – https://www.lls.org/myeloma
• Myeloma Patients Europe (MPE) – https://www.mpeurope.org
• Cancer.Net (ASCO) – https://www.cancer.net/cancer-types/multiple-myeloma