Multiple Myeloma

1. Clinical Overview

Summary

Multiple Myeloma is a malignant neoplasm of plasma cells (terminally differentiated B lymphocytes that produce antibodies/immunoglobulins). Clonal plasma cells proliferate in the bone marrow and produce a monoclonal immunoglobulin (M-protein/paraprotein) that can be detected in serum and/or urine. Myeloma is the second most common haematological malignancy after non-Hodgkin lymphoma, accounting for approximately 1% of all cancers and 10% of haematological malignancies. [1,2]

The disease primarily affects older adults with a median age at diagnosis of approximately 70 years (range 65-74 years). The classic clinical features are remembered by the mnemonic "CRAB": Calcium elevation (hypercalcaemia), Renal insufficiency, Anaemia, and Bone disease (lytic lesions, pathological fractures). Diagnosis requires ≥10% clonal plasma cells on bone marrow biopsy (or a plasmacytoma) plus evidence of end-organ damage (CRAB) or specific myeloma-defining events (SLiM criteria). [3]

Treatment has improved dramatically over the past two decades with novel agents including proteasome inhibitors (bortezomib, carfilzomib, ixazomib), immunomodulatory drugs or IMiDs (lenalidomide, pomalidomide, thalidomide), and monoclonal antibodies (daratumumab, isatuximab, elotuzumab), combined with autologous stem cell transplant (ASCT) in eligible patients. The addition of daratumumab to standard triplet regimens (VRd, VTd) has shown superior progression-free and overall survival in newly diagnosed multiple myeloma. [4,5]

Myeloma remains incurable but is now considered a chronic manageable disease with median survival extending from 3 years in the 1990s to 7-10+ years in the modern era with novel agent combinations and cellular therapies. Depth of response, particularly achievement of minimal residual disease (MRD) negativity, correlates strongly with improved survival outcomes. [6,7]

Clinical Pearls

"Old Man + Back Pain + Anaemia = Think Myeloma": Classic presentation in a patient over 60 years. Don't miss it. Check FBC, U&Es, calcium, serum protein electrophoresis, and serum free light chains.

"Rain Drop Skull": Classic X-ray appearance of multiple lytic lesions in the skull resembling raindrops. Myeloma causes LYTIC (not sclerotic) lesions due to osteoclast activation and osteoblast suppression.

"Normal Immunoglobulins Reduced (Immunoparesis)": The clonal M-protein dominates. Normal (polyclonal) IgG, IgA, IgM levels are suppressed → increased infection risk, particularly encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae).

"Rouleaux Formation": On blood film – stacked red cells resembling coins due to high protein (paraprotein). Non-specific but suggestive. Also causes elevated ESR (often > 100 mm/hr).

"Bence Jones Protein": Free immunoglobulin light chains (kappa or lambda) in urine. Detectable by urine protein electrophoresis (UPEP) and immunofixation, NOT by standard urine dipstick (which detects albumin). Present in approximately 75% of patients with multiple myeloma.

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2. Epidemiology

Demographics

Risk Factors

Precursor Conditions

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3. Pathophysiology

Plasma Cell Biology and Malignant Transformation

Plasma cells are terminally differentiated B cells that normally reside in the bone marrow and produce polyclonal immunoglobulins (antibodies: IgG, IgA, IgM, IgD, IgE). In multiple myeloma, a single plasma cell clone undergoes malignant transformation and proliferates, producing:

1. Monoclonal Immunoglobulin (Paraprotein/M-protein): A single type of immunoglobulin produced in excess
2. Bone Marrow Infiltration: Crowding out of normal haematopoiesis
3. Bone Marrow Microenvironment Alterations: Interaction with stromal cells, cytokine production, angiogenesis

Genetic and Molecular Pathogenesis

Multiple myeloma is a genetically heterogeneous disease arising through a multistep process:

Clonal Evolution: Myeloma exhibits significant spatial and temporal heterogeneity with multiple subclones competing and evolving under treatment pressure, contributing to relapse and treatment resistance. [10]

Paraprotein Types

Light Chain Types: Kappa (κ) vs Lambda (λ). Normal ratio: κ:λ = 2:1. In myeloma, one light chain type dominates. SFLC ratio less than 0.26 (lambda) or > 1.65 (kappa) is abnormal.

Mechanisms of End-Organ Damage (CRAB)

Additional Pathophysiological Mechanisms

Bone Marrow Microenvironment

The bone marrow microenvironment plays a critical role in myeloma pathogenesis and drug resistance:

• Stromal Cells: Bone marrow stromal cells (BMSCs) secrete growth factors (IL-6, IGF-1, VEGF) that promote myeloma cell survival and proliferation
• Cell Adhesion: VLA-4/VCAM-1, CD44/hyaluronan interactions → adhesion-mediated drug resistance (CAM-DR)
• Angiogenesis: Increased microvessel density mediated by VEGF, bFGF
• Immune Evasion: Suppression of T-cells, NK cells. Upregulation of immune checkpoint molecules (PD-L1)

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4. Clinical Presentation

CRAB Criteria (Myeloma-Defining End-Organ Damage)

SLiM Criteria (Myeloma-Defining Events – Biomarkers of Malignancy)

These criteria define active myeloma even in the absence of CRAB features:

Clinical Presentations by Frequency

Spectrum of Presentations

Red Flags and Emergencies

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5. Investigations

Diagnostic Pathway

The diagnosis of multiple myeloma requires systematic investigation to:

1. Confirm the presence of clonal plasma cells
2. Identify the paraprotein type and quantity
3. Assess end-organ damage (CRAB)
4. Risk-stratify for prognosis
5. Plan treatment

First-Line Investigations (Myeloma Screen)

Protein Studies (Essential for Diagnosis)

Note: Standard urine dipstick does NOT detect Bence Jones protein (detects albumin only). Always request UPEP if myeloma suspected.

Bone Marrow Examination (Diagnostic)

Imaging (Detect Bone Disease – CRAB "B")

Classic Imaging Findings:

• Skull: "Raindrop" or "punched-out" lytic lesions
• Spine: Vertebral compression fractures, lytic lesions, loss of height
• Pelvis: Multiple lytic lesions
• Ribs, Long bones: Lytic lesions, pathological fractures
• Diffuse osteoporosis (generalized bone loss without discrete lesions in 20%)

Diagnostic Criteria (IMWG 2014)

Multiple Myeloma Diagnosis Requires BOTH:

1. Clonal bone marrow plasma cells ≥10% OR biopsy-proven plasmacytoma

AND

2. At least ONE of the following:

   • CRAB criteria (Myeloma-defining end-organ damage):

     • Calcium: Corrected calcium > 2.75 mmol/L (> 11 mg/dL)
     • Renal insufficiency: Creatinine > 177 µmol/L (> 2 mg/dL) or eGFR less than 40 mL/min
     • Anaemia: Haemoglobin less than 100 g/L (less than 10 g/dL) or > 20 g/L below lower limit of normal
     • Bone lesions: ≥1 lytic lesion on skeletal survey, CT, or PET-CT

   • OR SLiM criteria (Biomarkers of malignancy):

     • Sixty percent: ≥60% clonal plasma cells in bone marrow
     • Light chain ratio: Involved/uninvolved SFLC ratio ≥100 (with involved FLC ≥100 mg/L)
     • MRI lesions: > 1 focal lesion (≥5 mm) on MRI

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6. Staging and Risk Stratification

Revised International Staging System (R-ISS)

The R-ISS combines tumour burden (β2-microglobulin, albumin), tumour biology (cytogenetics), and tumour aggressiveness (LDH) for prognostication. [11]

ISS Staging (Original):

• ISS I: β2M less than 3.5 mg/L AND Albumin ≥35 g/L
• ISS II: Neither I nor III
• ISS III: β2M ≥5.5 mg/L

Cytogenetic Risk Stratification

Note: del(13q) detected by FISH is prognostically neutral (common, ~50%). Only relevant if detected by conventional karyotype (implies poor proliferation).

Additional Prognostic Factors

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7. Management

Overview of Treatment Strategy

Multiple myeloma management is multi-modal, involving:

1. Emergency management of CRAB complications
2. Risk stratification (cytogenetics, R-ISS, performance status, age, comorbidities)
3. Transplant eligibility assessment
4. Induction therapy (novel agent combinations)
5. Autologous stem cell transplant (ASCT) in eligible patients
6. Consolidation/Maintenance therapy
7. Supportive care (bone-targeted therapy, infection prophylaxis, VTE prophylaxis)
8. Management of relapsed/refractory disease

Management Algorithm

       MULTIPLE MYELOMA DIAGNOSED
       (≥10% Clonal Plasma Cells + CRAB/SLiM)
                     ↓
       MANAGE EMERGENCIES FIRST
       - Spinal Cord Compression → Dexamethasone, MRI, RT/Surgery
       - Hypercalcaemia → IV Fluids (3-6L), Bisphosphonates
       - Renal Failure → Hydration, Avoid nephrotoxins, Dialysis if needed
       - Infection → Broad-spectrum antibiotics
       - Hyperviscosity → Plasmapheresis
                     ↓
       RISK STRATIFICATION
       - Cytogenetics (FISH): High-risk vs Standard-risk
       - R-ISS Staging (β2M, Albumin, LDH, FISH)
       - Comorbidities, Performance Status
                     ↓
       ASSESS TRANSPLANT ELIGIBILITY
       - Age (usually less than 70, consider less than 75)
       - Performance status (ECOG 0-2)
       - Cardiac, pulmonary, renal, hepatic function
       - Absence of severe comorbidities
    ┌────────────────┴────────────────┐
 TRANSPLANT ELIGIBLE            TRANSPLANT INELIGIBLE
    ↓                                 ↓
 INDUCTION THERAPY               INDUCTION THERAPY
 3-4 cycles                      Continuous or fixed duration
 - DaraVRd (preferred)           - DaraVRd or DaraRd (preferred)
 - VRd                           - VRd (if dara unavailable)
 - VTd, CyBorD                   - VMP, Rd
    ↓                                 ↓
 STEM CELL COLLECTION            CONTINUE TREATMENT
 G-CSF ± plerixafor              Until progression or intolerance
    ↓                            OR
 HIGH-DOSE MELPHALAN             MAINTENANCE THERAPY
 (140-200 mg/m²) +               (Lenalidomide or VRd lite)
 AUTOLOGOUS SCT (ASCT)                ↓
    ↓                            MONITOR RESPONSE
 POST-ASCT CONSOLIDATION         (M-protein, SFLC, Imaging, MRD)
 (2-4 cycles VRd) - Optional          ↓
    ↓                            RELAPSE / PROGRESSION
 MAINTENANCE THERAPY                   ↓
 Lenalidomide until progression  SALVAGE THERAPY
    ↓                            - Second-line: Daratumumab-based,
 MONITOR RESPONSE                  Carfilzomib, Pomalidomide
 (M-protein, SFLC, MRD)          - CAR-T (Ide-cel, Cilta-cel)
    ↓                            - Bispecific antibodies
 RELAPSE / PROGRESSION                 ↓
    ↓                            PALLIATIVE CARE
 SALVAGE THERAPY
 - Consider 2nd ASCT if late relapse (> 3 years)
 - Novel agents, CAR-T, clinical trials

Transplant Eligibility Criteria

Induction Therapy for Transplant-Eligible Patients

Goal: Achieve maximal tumour reduction (deep response: ≥VGPR or CR) prior to ASCT.

Duration: 3-4 cycles (approximately 3-4 months) before stem cell collection.

Bortezomib Dosing: 1.3 mg/m² SC (preferred over IV to reduce neuropathy) on days 1, 4, 8, 11 (traditional) or weekly dosing (days 1, 8, 15, 22) to reduce toxicity.

Lenalidomide Dosing: 25 mg PO days 1-21 of 28-day cycle. Reduce dose in renal impairment (CrCl less than 50 mL/min).

Dexamethasone: 40 mg PO/IV weekly OR 20 mg on day of and day after bortezomib. Lower doses reduce toxicity without compromising efficacy.

Daratumumab: 16 mg/kg IV weekly × 8 weeks, then every 2 weeks × 8 weeks, then every 4 weeks OR 1800 mg SC (faster administration).

Stem Cell Collection

Timing: After 3-4 cycles of induction, once good response achieved (≥PR).

Mobilization:

• G-CSF (filgrastim 10 µg/kg SC daily × 4-6 days) ± Plerixafor (CXCR4 antagonist) if poor mobilization
• Target: Collect ≥4 × 10⁶ CD34+ cells/kg (allows 2 transplants if needed)

Autologous Stem Cell Transplant (ASCT)

Conditioning: High-dose melphalan 140-200 mg/m² IV (single dose). Dose reduction to 140 mg/m² if age > 70 or renal impairment (CrCl less than 40 mL/min).

Stem Cell Infusion: Day 0 (typically 2 days after melphalan).

Engraftment: Neutrophil recovery (~day +10-14). Platelet recovery (~day +14-21).

Supportive Care: G-CSF (from day +5), antimicrobial prophylaxis (aciclovir, fluconazole, levofloxacin), transfusion support.

Outcomes:

• Complete Response (CR) rate: 40-60%
• Progression-Free Survival (PFS): ~50-60 months (median)
• Overall Survival (OS): ~8-10 years (median)
• Treatment-related mortality: less than 2-3% in experienced centers

Tandem ASCT (Two transplants 3-6 months apart): May benefit high-risk cytogenetics or suboptimal response to first ASCT. Controversial. Increased use in Europe.

Maintenance Therapy Post-ASCT

Goal: Prolong remission, improve PFS and possibly OS.

Duration: Continue until disease progression, intolerance, or patient preference. Median duration ~2-3 years but may continue > 5 years.

Induction Therapy for Transplant-Ineligible Patients

Goal: Disease control, symptom palliation, maintain quality of life.

Approach: Continuous therapy or fixed-duration therapy followed by maintenance.

Key Drug Classes

Supportive Care

Relapsed/Refractory Multiple Myeloma

Definition:

• Relapsed: Disease progression after achieving response (≥PR), with ≥60 days between response and progression.
• Refractory: less than 25% response to therapy OR progression within 60 days of last therapy.

Salvage Therapy Principles:

• Use agents from different classes (if not previously exposed or refractory)
• Re-use previously effective regimens if relapse > 12 months after stopping treatment
• Consider clinical trials, novel agents, CAR-T therapy

CAR-T Therapy: Chimeric Antigen Receptor T-cell therapy targeting BCMA (B-cell maturation antigen). Requires leukapheresis, T-cell modification, lymphodepleting chemotherapy, infusion. High efficacy but requires specialized centers. Toxicities: Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, infections.

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8. Complications

Disease-Related Complications

Treatment-Related Complications

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9. Prognosis and Outcomes

Overall Survival

5-Year Survival Rate: ~55-60% overall (all stages). Varies widely by age and stage (R-ISS I: ~80%, R-ISS III: ~40%).

Prognostic Factors

Response Criteria (IMWG)

MRD (Minimal Residual Disease): Assessed by next-generation flow cytometry (NGF) or next-generation sequencing (NGS). Sensitivity: 10⁻⁵ to 10⁻⁶. MRD negativity increasingly used as treatment endpoint in clinical trials.

Quality of Life

Myeloma significantly impacts quality of life due to:

• Pain (bone pain, neuropathy)
• Fatigue (anaemia, disease burden, treatment)
• Psychological distress (anxiety, depression, uncertainty)
• Financial toxicity (cost of novel agents, inability to work)
• Treatment burden (frequent hospital visits, infusions, monitoring)

Supportive Care and Palliative Care: Essential throughout disease course. Pain management (analgesia, radiotherapy), psychological support, rehabilitation, end-of-life planning.

Incurable but Manageable

Multiple myeloma remains incurable for the majority of patients. Relapse is expected. However, with modern therapies:

• Many patients achieve long periods of disease control (years)
• Sequential lines of therapy available (median: 3-5 lines during disease course)
• Quality of life can be maintained
• Survival has improved dramatically

Goals of Treatment:

1. Maximize depth and duration of response
2. Delay progression and prolong survival
3. Maintain quality of life
4. Minimize treatment-related toxicity

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10. Evidence and Guidelines

Key Guidelines

Landmark Trials

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11. Patient and Layperson Explanation

What is Multiple Myeloma?

Multiple myeloma is a type of blood cancer that affects special white blood cells called plasma cells. Plasma cells are normally found in the bone marrow (the soft, spongy tissue inside your bones) and their job is to make antibodies (proteins that fight infections).

In myeloma, one plasma cell becomes abnormal and starts multiplying out of control, creating many copies of itself (a "clone"). These abnormal plasma cells:

• Crowd out normal blood cells in the bone marrow → leading to low blood counts
• Produce too much of one type of antibody (called a "paraprotein" or "M-protein") → this can damage organs
• Interfere with normal antibody production → making you more prone to infections
• Damage your bones → causing pain, fractures, and releasing calcium into the blood

What Problems Does It Cause?

Doctors use the mnemonic "CRAB" to remember the main problems:

• C – Calcium (high): The cancer damages bones, releasing calcium into the blood → thirst, confusion, constipation, kidney problems
• R – Renal (kidney) problems: The abnormal proteins can clog up the kidneys → kidney failure
• A – Anaemia (low red blood cells): The cancer cells crowd out normal blood-making cells → tiredness, weakness, breathlessness
• B – Bone disease: The cancer weakens bones → pain (especially back pain), broken bones, fractures from minor injuries

Other problems:

• Infections: Because normal antibodies are reduced, you're more likely to get chest infections, urine infections, etc.
• Bleeding or clotting problems: Due to effects on blood
• Nerve damage: Causing numbness, tingling, or weakness (from treatment or the disease)

Can It Be Cured?

Currently, multiple myeloma cannot be cured. However, treatments have improved dramatically in the last 20 years. Myeloma is now considered a chronic (long-term) manageable disease, similar to diabetes or heart disease.

What this means:

• Many people live for many years (average 7-10+ years, some much longer)
• Treatment can control the disease, sometimes for years at a time
• When the disease comes back (relapses), there are often further treatments available
• Many people maintain a good quality of life during treatment

What Is the Treatment?

Treatment depends on:

• Your age and general health
• How aggressive the myeloma is
• Results of genetic tests on the myeloma cells

Main treatments:

1. Chemotherapy combinations (often tablets and injections):

   • Modern myeloma treatment uses combinations of drugs (e.g., "VRd" = bortezomib, lenalidomide, dexamethasone)
   • These target myeloma cells in multiple ways
   • Given as induction therapy (first treatment to reduce the disease)

2. Stem cell transplant (in younger, fitter patients):

   • Your own blood stem cells are collected and frozen
   • You receive high-dose chemotherapy to kill myeloma cells
   • Your stem cells are given back to you to help your bone marrow recover
   • Called an "autologous" stem cell transplant (using your own cells, not a donor)
   • Can achieve longer remissions

3. Maintenance therapy (long-term tablets):

   • After initial treatment, you may take tablets (e.g., lenalidomide) for months or years
   • Keeps the myeloma under control
   • Delays relapse

4. Newer treatments:

   • Monoclonal antibodies (e.g., daratumumab) – given by injection or drip, target myeloma cells
   • CAR-T cell therapy – your immune cells are genetically modified to fight myeloma (for advanced disease)
   • Bispecific antibodies – help your immune system attack myeloma

5. Bone-protecting drugs (bisphosphonates):

   • Strengthen bones
   • Reduce fractures and bone pain
   • Given as an injection every 3-4 weeks

6. Radiotherapy:

   • For painful bone areas or fractures
   • Emergency treatment if spine is affected

What About Side Effects?

All treatments have side effects, but doctors work to minimize them:

• Fatigue, nausea, diarrhoea
• Low blood counts (increasing infection risk)
• Nerve damage (tingling, numbness in hands/feet)
• Blood clots (prevented with aspirin or blood thinners)
• Infections (prevented with vaccines and antibiotics)

Your medical team will monitor you closely and adjust treatment if needed.

What Is the Outlook?

• Most people respond well to initial treatment (70-90% achieve significant disease reduction)
• Remissions (periods where the disease is controlled) can last months to years
• When the disease comes back, there are usually further treatment options
• Survival varies widely: Some people live 3-5 years, others 10-15+ years or longer
• Younger, fitter patients with less aggressive disease tend to do better
• Older or frail patients can still benefit from gentler treatments

Living With Myeloma

• Regular monitoring: Blood tests, urine tests, scans to check disease status
• Infection prevention: Vaccines (flu, pneumonia, COVID-19), avoiding sick contacts, good hygiene
• Bone health: Calcium and vitamin D supplements, weight-bearing exercise, fall prevention
• Pain management: Painkillers, radiotherapy if needed
• Psychological support: Counselling, support groups (e.g., Myeloma UK)
• Staying active: Exercise (within limits), maintaining social connections, hobbies

Where to Get Support

• Myeloma UK: National charity providing information, support groups, helpline (0800 980 3332, www.myeloma.org.uk)
• Macmillan Cancer Support: Practical and emotional support (0808 808 00 00)
• Your hospital team: Haematology nurses, specialist nurses, social workers

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12. References

Primary Sources

1. Cowan AJ, et al. Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018;4(9):1221-1227. PMID: 29800119.

2. Malard F, Neri P, Bahlis NJ. Multiple myeloma. Nature Reviews Disease Primers. 2024;10(1):45. PMID: 38937492.

3. Rajkumar SV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-548. PMID: 25439696.

4. Voorhees PM, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. PMID: 32530028.

5. Facon T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma (MAIA). N Engl J Med. 2019;380(22):2104-2115. PMID: 30843565.

6. Kumar SK, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28(5):1122-1128. PMID: 24157580.

7. Munshi NC, et al. A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma. Blood Adv. 2020;4(23):5988-5999. PMID: 33276374.

8. John G, et al. Multiple Myeloma in Young Adults-Insights From a Tertiary Care Cancer Centre in India. EJHaem. 2025;6(1):123-131. PMID: 41384226.

9. Kikuchi T. Smoldering multiple myeloma: advances in diagnosis and risk stratification, and evolving therapeutic strategies. Int J Hematol. 2025;121(2):145-158. PMID: 41175246.

10. Bolli N, et al. Genomic patterns of progression in smoldering multiple myeloma. Nat Commun. 2018;9(1):3363. PMID: 30135448.

11. Palumbo A, et al. Revised International Staging System for Multiple Myeloma: A Report From IMWG. J Clin Oncol. 2015;33(26):2863-2869. PMID: 26240224.

12. Moreau P, et al. 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. Lancet. 2019;394(10192):29-38. PMID: 31171419.

13. Durie BGM, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527. PMID: 28017406.

14. Attal M, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. PMID: 28379796.

15. Avet-Loiseau H, et al. Minimal Residual Disease Status as a Surrogate Endpoint for Progression-free Survival in Newly Diagnosed Multiple Myeloma Studies: A Meta-analysis. Clin Lymphoma Myeloma Leuk. 2020;20(1):e30-e37. PMID: 31757691.

16. National Institute for Health and Care Excellence. Myeloma: diagnosis and management (NG35). 2016, updated 2021. Available: https://www.nice.org.uk/guidance/ng35

17. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 3.2024. Available: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445

18. Munshi NC, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021;384(8):705-716. PMID: 33626253.

19. Berdeja JG, et al. 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. Lancet. 2021;398(10297):314-324. PMID: 34274728.

20. Moreau P, et al. Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2022;387(6):495-505. PMID: 35830649.

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13. Examination Focus

Common Exam Questions (MCQ/SBA)

1. CRAB Mnemonic: "What does CRAB stand for in multiple myeloma?"

   • Answer: Calcium (elevated), Renal insufficiency, Anaemia, Bone disease (lytic lesions)

2. Type of Bone Lesions: "What type of bone lesions are seen in multiple myeloma?"

   • Answer: LYTIC (punched-out, osteolytic) lesions. NOT sclerotic/blastic (sclerotic lesions suggest prostate metastases)

3. Most Common Presenting Symptom: "What is the most common presenting symptom of multiple myeloma?"

   • Answer: Bone pain (especially lower back pain), present in 60-70% at diagnosis

4. Investigation for Paraprotein: "What investigation detects the monoclonal protein (paraprotein)?"

   • Answer: Serum Protein Electrophoresis (SPEP) shows M-spike + Serum Free Light Chains (SFLC) (essential for light chain myeloma) + Immunofixation (identifies type)

5. Diagnostic Criteria: "What percentage of plasma cells in bone marrow is required for myeloma diagnosis?"

   • Answer: ≥10% clonal plasma cells (OR biopsy-proven plasmacytoma) PLUS CRAB or SLiM criteria

6. Bence Jones Protein: "What is Bence Jones protein?"

   • Answer: Free immunoglobulin light chains (kappa or lambda) in urine. Detected by urine protein electrophoresis (UPEP), NOT standard urine dipstick

7. First-Line Imaging: "What is the first-line imaging modality for detecting myeloma bone disease?"

   • Answer: Whole Body Low-Dose CT (WBLDCT). Superior to skeletal survey (X-ray). MRI most sensitive for bone marrow infiltration

8. First-Line Treatment (Transplant-Eligible): "What is the preferred first-line treatment for newly diagnosed myeloma in transplant-eligible patients?"

   • Answer: DaraVRd (Daratumumab + Bortezomib + Lenalidomide + Dexamethasone) followed by ASCT and lenalidomide maintenance

9. High-Risk Cytogenetics: "Which cytogenetic abnormalities confer high risk in multiple myeloma?"

   • Answer: del(17p), t(4;14), t(14;16), t(14;20), 1q gain/amplification

10. Bisphosphonates: "What is the role of bisphosphonates in multiple myeloma?"

    • Answer: Reduce skeletal-related events (fractures, bone pain, hypercalcaemia). Given to all patients with bone disease. Zoledronic acid 4 mg IV monthly

OSCE/Clinical Exam Scenarios

Scenario 1: History Taking

• Presentation: 72-year-old man with 6 months of worsening back pain, fatigue, recurrent chest infections
• Key Points to Elicit:
  • Bone pain (location, severity, worse with movement?)
  • Systemic symptoms (fatigue, weight loss, night sweats, fever)
  • Infection history (frequency, severity)
  • Neurological symptoms (leg weakness, bladder/bowel dysfunction – cord compression?)
  • Fractures (height loss, kyphosis)
  • Renal symptoms (reduced urine output, oedema)
  • Confusion, thirst, constipation (hypercalcaemia)
• Expected Diagnosis: Multiple myeloma (CRAB features)
• Next Steps: Bloods (FBC, U&Es, calcium, SPEP, SFLC), imaging (WBLDCT or skeletal survey), bone marrow biopsy

Scenario 2: Data Interpretation

• Given: Blood results showing Hb 85 g/L, Creatinine 220 µmol/L, Corrected Ca 3.1 mmol/L, Total Protein 95 g/L, Albumin 30 g/L
• Expected Answer: Suspect multiple myeloma (anaemia, renal impairment, hypercalcaemia, raised globulins). Next: SPEP, SFLC, UPEP, immunofixation, bone marrow biopsy, imaging
• Management: Treat hypercalcaemia (IV fluids, bisphosphonates), manage renal failure (hydration, avoid nephrotoxins), urgent haematology referral

Scenario 3: Emergency Management

• Presentation: Patient with known myeloma presents with acute back pain, bilateral leg weakness, urinary retention
• Diagnosis: Spinal cord compression (oncological emergency)
• Immediate Management:
  1. Dexamethasone 16 mg IV/PO immediately
  2. Urgent MRI whole spine (within 24 hours)
  3. Neurosurgical and oncology referral
  4. Radiotherapy ± surgical decompression
  5. Bladder catheterization for retention
• Prognosis: Window for neurological recovery less than 48 hours. Early treatment critical

Viva Voce Points

Examiner: "Tell me about the pathophysiology of myeloma bone disease"

• Answer:
  • Myeloma cells interact with bone marrow microenvironment
  • "Increased osteoclast activity: Myeloma cells secrete RANKL, MIP-1α, IL-6 → osteoclast activation → bone resorption"
  • "Decreased osteoblast activity: Secretion of DKK1, sFRP2/3 → WNT pathway inhibition → osteoblast suppression"
  • "Result: Uncoupled bone remodelling → PURE LYTIC lesions (no sclerotic component)"
  • "Consequences: Pathological fractures, bone pain, hypercalcaemia, osteoporosis"

Examiner: "Differentiate MGUS, smouldering myeloma, and multiple myeloma"

Examiner: "What is minimal residual disease (MRD) and why is it important?"

• Answer:
  • MRD = detection of very low levels of myeloma cells (1 in 10⁵-10⁶ cells) after treatment
  • "Detected by: Next-generation flow cytometry (NGF) or next-generation sequencing (NGS)"
  • "Importance: MRD negativity strongly correlates with longer PFS and OS"
  • Increasingly used as endpoint in clinical trials
  • "Goal of modern therapy: achieve sustained MRD negativity"
  • May guide treatment decisions (duration of maintenance, intensification)

Examiner: "Describe the R-ISS staging system"

• Answer: Revised International Staging System combines:
  1. Tumour burden: β2-microglobulin and albumin (original ISS)
  2. Tumour biology: Cytogenetics (high-risk vs standard-risk)
  3. Tumour aggressiveness: LDH
• R-ISS I: ISS I + Standard cytogenetics + Normal LDH → Best prognosis (~110 months median OS)
• R-ISS II: Not I or III → Intermediate (~83 months)
• R-ISS III: ISS III + (High-risk cytogenetics OR elevated LDH) → Poor prognosis (~43 months)

Examiner: "What are the complications of bisphosphonate therapy?"

• Answer:
  1. Osteonecrosis of the jaw (ONJ): 1-2% risk. Requires dental assessment before starting. Avoid invasive dental procedures during treatment
  2. Renal toxicity: Monitor renal function. Dose adjust if CrCl less than 60 mL/min
  3. Hypocalcaemia: Supplement with calcium and vitamin D
  4. Acute phase reaction: Flu-like symptoms after first infusion (common, self-limiting)
  5. Atypical femoral fractures: Rare with prolonged use

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