• SMM accounts for approximately 10–15% of all newly diagnosed myeloma cases ^[3].
• Annual incidence: roughly 0.9 per 100,000 (estimated from myeloma epidemiology data, as SMM is often grouped with MM in registries).
• Median age at diagnosis: ~65–70 years (similar to MM, but SMM patients tend to be diagnosed slightly earlier because they are asymptomatic and found incidentally) ^[2].
• The risk of progression from SMM to active myeloma is approximately 10% per year in the first 5 years, then drops to ~3% per year for the next 5 years, and ~1–2% per year thereafter ^[1][2].
  • Contrast with MGUS: 1% per year risk of progression ^[1].
  • This declining hazard rate is important: patients who haven't progressed after 5 years have a biologically more indolent clone.

• Male > Female (slight male predominance, similar to MM, ~1.4:1)
• Racial variation: Higher incidence in persons of African descent (~2–3× more common than in Caucasians); relatively lower in East Asian populations, though data specific to Hong Kong Chinese is limited
• 5% of the population above 50 years of age have MGUS ^[1], from which a proportion progress through SMM to MM

• Multiple myeloma is the third most common haematological malignancy in Hong Kong (after NHL and leukaemia).
• The overall incidence of plasma cell neoplasms is lower in Chinese populations compared to Western populations, but it is rising with an ageing population.
• Many SMM cases in Hong Kong are detected incidentally during routine blood tests (e.g., incidental finding of raised globulin, elevated ESR, or abnormal protein on serum protein electrophoresis during health screening) ^[4].

To understand SMM, you need to understand what plasma cells are and where they live:

1. B-cell maturation pathway: Haematopoietic stem cell → Pro-B cell → Pre-B cell → Immature B cell → Mature naïve B cell → (antigen stimulation in germinal centres) → Plasma cell
2. Plasma cells are the terminally differentiated effector cells of B-lymphocytes. Their sole job is to produce immunoglobulins (antibodies) — they are essentially antibody factories.
3. Normal plasma cells reside primarily in the bone marrow (also in mucosal tissues like the gut — MALT).
4. Each plasma cell produces one type of immunoglobulin with one specific heavy chain (IgG, IgA, IgM, IgD, or IgE) and one specific light chain (kappa κ or lambda λ). This is the basis of clonality — if you see a population of cells all making the exact same immunoglobulin, that's a clone.

The bone marrow microenvironment is critical in myeloma biology:

• Stromal cells, osteoblasts, osteoclasts, endothelial cells, and immune cells form a niche that supports plasma cell survival
• Key cytokines: IL-6 (the major myeloma growth factor), VEGF, RANKL, TNF-α, IGF-1
• In SMM, the malignant clone has expanded but has not yet fully co-opted the microenvironment to cause bone destruction or significant immunosuppression — this is why there are no CRAB features yet

• Each antibody molecule consists of 2 heavy chains + 2 light chains linked by disulfide bonds
• In myeloma/SMM, the clone produces a monoclonal immunoglobulin (= M-protein = paraprotein = M-spike on electrophoresis)
• Some clones produce only free light chains (FLC) without intact immunoglobulin — these are small enough to be filtered by the glomerulus and appear in urine (historically called "Bence Jones protein")

Myeloma is a spectrum/timeline, and multiple myeloma is considered to be the "end-of-the-spectrum" manifestation of plasma cell dyscrasia. ^[1]

Stage 1: MGUS → Stage 2: Smoldering myeloma → Stage 3: Myeloma (multiple myeloma) ^[1]

Even in SMM, the malignant clone suppresses normal plasma cell function:

• Uninvolved immunoglobulins are reduced (e.g., if the clone produces IgG, then IgA and IgM levels fall)
• This immunoparesis is a marker of disease burden and a risk factor for progression
• It also explains the mild increase in infection susceptibility even before frank MM develops

The International Myeloma Working Group (IMWG) defines SMM as: ^[2][5]

Smoldering MM (SMM): M protein ≥ 3g/dL and/or 10-60% BM plasma cell but no CRAB ^[2]

If ANY of these are present, it is no longer SMM — it is active MM:

CRAB (end-organ damage):

• Calcium: Serum calcium > 0.25 mmol/L above upper limit of normal OR > 2.75 mmol/L
• Renal: Creatinine > 177 μmol/L (> 2 mg/dL) OR CrCl < 40 mL/min
• Anaemia: Hb < 10 g/dL OR > 2 g/dL below lower limit of normal
• Bone: ≥ 1 osteolytic lesion on skeletal survey, CT, or PET-CT

SLiM (biomarkers of malignancy — added in 2014):

• Sixty: Bone marrow clonal plasma cells ≥ 60%
• Light chains: Involved:uninvolved serum free light chain ratio ≥ 100 (with involved FLC ≥ 100 mg/L)
• MRI: > 1 focal lesion (≥ 5mm) on MRI

The SLiM criteria were added because studies showed these patients had ≥ 80% probability of progression to active MM within 2 years — so waiting for organ damage was considered unethical.

Not all SMM is equal. The Mayo Clinic 2018 ("20/2/20") risk stratification model is the most widely used:

Additional high-risk features:

• Cytogenetics: t(4;14), del(17p), amp(1q21), MYC rearrangements
• Evolving M-protein (progressive rise over time = "evolving" type)
• Immunoparesis (reduction of ≥ 1 uninvolved immunoglobulin)
• Circulating plasma cells in peripheral blood
• Abnormal MRI pattern (diffuse marrow involvement)
• PET-CT avid lesions (FDG-uptake in marrow without lytic destruction)

^[1][2]

By definition, SMM is asymptomatic — that is the whole point of the diagnosis. The patient does NOT have CRAB features. However, some subtle features may be present, and these are what you must look for (and also what you must ensure are NOT progressing to active MM):

Physical examination in SMM is typically normal. However, subtle findings may include:

Since the clinical features are essentially "absence of disease manifestations," the clinical approach to SMM is centred on surveillance for progression. At each visit:

1. Symptoms screen: New bone pain? Fatigue? Infections? Weight loss? Symptoms of hypercalcaemia?
2. Blood tests: FBC (Hb, WCC, platelets), renal function (creatinine, eGFR), calcium, serum protein electrophoresis + immunofixation, serum free light chains, quantitative immunoglobulins
3. Urine: 24-hour urine protein electrophoresis (if applicable)
4. Imaging: As clinically indicated (e.g., new bone pain → MRI/PET-CT)

Only multiple myeloma patients will be symptomatic with organ involvement → requires treatment. Other forms do not require treatment → require monitoring. ^[1]

Risk of progression of MGUS to myeloma is 1% per year, whereas for smouldering it is 10% per year in the first 5 years, beyond 5 years it is lower. ^[1]

Risk factors for progression include: ^[1][2]

• AL Amyloidosis: The most important differential diagnosis of MGUS (and by extension SMM) is AL amyloidosis ^[1]. A patient with a paraprotein and suggestive symptoms (nephrotic syndrome, cardiomyopathy, neuropathy, macroglossia) should be investigated for AL amyloidosis regardless of whether they meet criteria for MGUS or SMM.
• Light chain cast nephropathy (myeloma kidney): Occurs in 30%–50% of patients with multiple myeloma ^[6]. If renal impairment develops in a patient with SMM, this must be urgently investigated as it may represent progression.
• Other renal diseases associated with monoclonal light chains ^[6]:
  • Amyloidosis (AL type)
  • Light chain deposition disease
  • Light chain proximal tubulopathy
  • Type I cryoglobulinaemic glomerulonephritis

• In active MM, hypercalcaemia results from local osteolysis (myeloma cells secrete RANKL, IL-6, TNF-β → osteoclast activation → bone destruction → calcium release) ^[7][8]
• In SMM, calcium should be normal (if elevated → re-classify as active MM)
• Malignancy is one of the two most common causes of hypercalcaemia (along with primary hyperparathyroidism), accounting for ~90% of cases ^[7]

• Why this distinction matters: MGUS is very common — 5% of the population above 50 years of age ^[1]. Most patients with an incidental paraprotein will have MGUS, not SMM. The monitoring frequency and intensity differ: MGUS patients can be followed annually; SMM patients need more frequent surveillance.
• How to distinguish: The distinction is purely quantitative — you need bone marrow biopsy to count plasma cells and accurate M-protein quantification via SPE.
• The formal definition of having MGUS is: presence of paraprotein of less than 30 g/L, and bone marrow plasma cells of < 10%, without evidence of B cell lymphoproliferative disorder, and absence of organ damage. ^[1]
• Some patients can convert from MGUS back to normal ^[1] — this does NOT happen with SMM (once you have that degree of clonal expansion, spontaneous regression is exceedingly rare).

Risk factors increasing a patient's risk of progression from MGUS to myeloma include: size of paraprotein (small, lower chance) and type of paraprotein. ^[1]

This is the most critical differential — because misclassifying active MM as SMM means delaying essential treatment.

IMWG 2014 diagnostic criteria for active MM: Clonal bone marrow plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma, PLUS one or more myeloma-defining events. ^[3]

Myeloma-defining events (SLiM-CRAB) ^[3]:

• HyperCalcaemia: Serum calcium level > 0.25 mmol/L higher than the upper limit of normal or > 2.75 mmol/L
• Renal insufficiency: creatinine > 177 μmol/L or creatinine clearance < 40 mL/min
• Anaemia: haemoglobin < 10 g/dL or haemoglobin > 2 g/dL below the lower limit of normal
• Bone lesions: One or more osteolytic bone lesions on skeletal radiography, CT, or FDG PET-CT
• Clonal bone marrow plasma cells ≥ 60%
• Involved:uninvolved serum free light chain ratio > 100 with involved free light chain > 100 mg/L
• One or more (≥ 5 mm) focal lesions on MRI scans

Key pitfalls in distinguishing SMM from active MM:

• Definition: A single mass of clonal plasma cells, either in bone (solitary bone plasmacytoma) or soft tissue (extramedullary plasmacytoma), without systemic marrow involvement (< 10% BM PC) and without CRAB
• Why it's in the differential: A patient may present with a single lytic lesion and a small M-protein. If BM biopsy shows < 10% plasma cells, this is a plasmacytoma, not SMM
• Key distinction from SMM: Plasmacytoma is a localised disease; SMM is a systemic marrow process. Plasmacytomas can be treated with local radiation therapy. However, ~50–70% of solitary bone plasmacytomas eventually progress to MM over 10 years.

• Definition: ≥ 2 × 10⁹/L circulating plasma cells OR > 20% plasma cells in peripheral blood differential
• Why it's in the differential: Rarely, what appears to be SMM on marrow biopsy may have an unrecognised circulating plasma cell component → check PBS carefully
• Key distinction: PCL is an aggressive disease with very poor prognosis; it is the extreme end of the spectrum. Finding significant circulating plasma cells immediately reclassifies the patient out of SMM.

The most important differential diagnosis of MGUS is AL amyloidosis — especially if the patient has suggestive symptoms. ^[1]

This principle extends to SMM. AL amyloidosis can occur with any level of paraprotein — even a small M-protein or just an abnormal FLC ratio. The critical point is:

• In AL amyloidosis, misfolded monoclonal light chains deposit as amyloid fibrils in tissues (heart, kidney, liver, nerves, GI tract)
• The clone may be small (often < 10% BM PC, technically MGUS-level), yet the patient has devastating organ damage from amyloid deposition — not from direct tumour effects
• Symptoms that should trigger suspicion: nephrotic-range proteinuria (with normal SPE!), unexplained heart failure with preserved EF (restrictive cardiomyopathy), peripheral/autonomic neuropathy, macroglossia, periorbital purpura, hepatomegaly without explanation

Why this matters for SMM: A patient classified as SMM who develops nephrotic syndrome or heart failure might not have "progressed to active MM" — they may have developed AL amyloidosis as a parallel complication of the same clone. The treatment is different (amyloid-directed therapy, not standard MM therapy).

Other renal diseases associated with monoclonal light chains ^[6]:

• Amyloidosis (AL type)
• Light chain deposition disease
• Light chain proximal tubulopathy
• Type I cryoglobulinaemic glomerulonephritis

• Definition: A B-cell lymphoma characterised by BM infiltration with lymphoplasmacytic cells and an IgM monoclonal paraprotein
• Why it's in the differential: Both WM and SMM have a paraprotein and BM infiltration. However:
  • WM produces IgM (a large pentameric molecule) → causes hyperviscosity more commonly
  • WM cells are lymphoplasmacytic (mix of lymphocytes and plasma cells), not pure plasma cells
  • WM typically has the MYD88 L265P mutation (~90%), which is absent in myeloma
• How to distinguish: Immunofixation showing IgM paraprotein + BM morphology showing lymphoplasmacytic infiltrate + MYD88 testing → WM, not SMM

Several lymphomas/leukaemias can produce a small paraprotein:

The formal definition of MGUS requires absence of evidence of B-cell lymphoproliferative disorder ^[1] — this is precisely to exclude these conditions.

• Definition: Increased marrow plasma cells (usually 5–10%, rarely up to 20%) due to a reactive/inflammatory process, NOT clonal
• Causes: Autoimmune diseases (SLE, RA, Sjögren syndrome), chronic infections (HIV, HBV, HCV), chronic liver disease, metastatic carcinoma in BM
• How to distinguish from SMM:
  • Reactive plasma cells are polyclonal (produce a mixture of κ and λ light chains in normal ratio)
  • SMM plasma cells are monoclonal (restricted to either κ or λ)
  • Normal κ:λ ratio in bone marrow = 2:1. Ratio > 4:1 or < 1:2 is considered κ or λ monoclonality. Ratio = 2:1 is considered normal or reactive plasmacytosis. ^[10]
  • Significance: Differentiate monoclonal gammopathies from reactive plasmacytosis due to autoimmune disease, metastatic carcinoma, chronic liver disease and AIDS ^[10]
• SPE in reactive conditions may show polyclonal hypergammaglobulinaemia (broad-based elevation in gamma region) rather than a sharp M-spike

• Rare lymphoproliferative disorders characterised by production of truncated heavy chains without light chains
• Types: α-heavy chain disease (Mediterranean lymphoma), γ-heavy chain disease (Franklin disease), μ-heavy chain disease
• How to distinguish: Immunofixation shows heavy chain without associated light chain; clinical picture differs (α-HCD → GI involvement; γ-HCD → lymphadenopathy)

• Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes
• Rare paraneoplastic syndrome associated with an underlying plasma cell neoplasm (usually osteosclerotic myeloma or Castleman disease)
• Key distinction from SMM: POEMS has osteosclerotic (not osteolytic) lesions, prominent neuropathy, and organomegaly — all absent in SMM. The M-protein is usually small and almost always λ light chain restricted
• POEMS requires treatment even with a small clone, because the symptoms are from cytokine-mediated damage (VEGF is markedly elevated)

• A relatively new concept (coined 2012): a small clone (MGUS-level or SMM-level) that causes renal disease through its paraprotein, WITHOUT meeting CRAB criteria for active MM
• Examples: Light chain deposition disease, proliferative GN with monoclonal deposits, C3 glomerulopathy with monoclonal gammopathy, immunotactoid GN
• Why it's important: These patients have organ damage from the paraprotein but do NOT meet criteria for active MM. They require clone-directed therapy despite having MGUS/SMM-level disease. This is an exception to the "don't treat SMM" rule.

Differential:

• Multiple myeloma / SMM / MGUS (monoclonal ↑globulin) ^[7]
• Chronic infection (HIV, HBV, HCV → polyclonal)
• Autoimmune disease (SLE, RA, Sjögren → polyclonal)
• Chronic liver disease / cirrhosis (polyclonal)
• AL amyloidosis (with or without significant M-protein)

• Paraproteinaemia (rouleaux formation → ↑ESR)
• Chronic infection, autoimmune disease, malignancy (all ↑acute phase response)
• Anaemia per se (↑ESR is partly artefactual with low Hb)

Differential of back pain with possible myeloma ^[12][13]:

• Degenerative disease (spondylosis, OA spine, disc disease)
• Osteoporotic compression fracture
• Multiple myeloma with lytic vertebral lesions ^[12]
• Metastatic disease (lung, breast, prostate, kidney, thyroid)
• Infection (TB spine, epidural abscess)
• Inflammatory (ankylosing spondylitis, psoriatic arthritis)

Both osteoporosis and myeloma cause reduced bone mass, but in osteoporosis the ratio of bone mineral to bone matrix is normal, whereas in osteomalacia the ratio is low. ALP is normal in osteoporosis ^[12] — and importantly, ALP is usually normal in myeloma (because myeloma causes purely lytic lesions with suppressed osteoblast activity, and ALP is an osteoblast marker).

Myeloma (CRAB), Monoclonal gammopathy is listed among the differential causes of CKD ^[14].

Light chain cast nephropathy — also known as myeloma kidney — occurs in 30%–50% of patients with multiple myeloma. 90% of cases greater than age of 50 years old — median age 70 years old. Presentations: acute renal failure and proteinuria. ^[6]

If a patient has AKI/CKD and a paraprotein is found, the differential for the renal lesion includes ^[6][9]:

• Light and heavy chain deposition disease — complication of monoclonal gammopathy
• Amyloidosis
• NSAID-induced AKI
• Hypercalcaemic nephropathy / nephrocalcinosis
• Cast nephropathy

ALL of the following must be met ^{[1][3][10][15]}:

SMM: All criteria must be met: Serum monoclonal protein (i.e. IgA, IgG, IgM) ≥ 3 g/dL AND/OR Clonal bone marrow plasma cells ≥ 10% (10–60%); Absence of myeloma-defining events and amyloidosis. ^[10]

IMWG 2014 diagnostic criteria: Clonal bone marrow plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma, PLUS one or more myeloma-defining events. ^[3]

CRAB (end-organ damage) ^[1][3][15]:

• HyperCalcaemia: Serum calcium level > 0.25 mmol/L higher than the upper limit of normal or > 2.75 mmol/L (> 11 mg/dL)
• Renal insufficiency: creatinine > 2 mg/dL (> 177 μmol/L) or creatinine clearance < 40 mL/min
• Anaemia: haemoglobin < 10 g/dL or haemoglobin > 2 g/dL below the lower limit of normal
• Bone lesions: One or more osteolytic bone lesions on skeletal radiography, CT, or FDG PET-CT

SLiM (biomarkers of malignancy) ^[1][3][10]:

• Sixty: Clonal bone marrow plasma cells ≥ 60%
• Light chain ratio: Involved:uninvolved serum free light chain ratio > 100 with involved free light chain > 100 mg/L
• MRI: One or more (≥ 5 mm) focal lesions on MRI scans

Asymptomatic patients with one or more myeloma-defining events listed above are considered to have MM rather than SMM since they have a risk of progression with complications of ≥ 80% within 2 years. ^[10]

^{[1][3][10][15]}

Multiple myeloma presents with characteristic laboratory findings including anaemia, hypercalcaemia, renal impairment, and a monoclonal protein spike on serum protein electrophoresis. The diagnostic workup requires serum free light chains, bone marrow biopsy, and skeletal survey to assess disease burden and staging. ^[17]

Bone Marrow Aspirate and Trephine Biopsy

Both aspirate AND trephine are required ^[18]:

Morphology of myeloma/SMM plasma cells ^[10]:

• Normal mature plasma cells: oval with abundant basophilic cytoplasm; nucleus is round and eccentrically located with cytoplasmic clearing ("perinuclear hof"); nucleus has "clock-face" chromatin without nucleoli
• Myeloma cells may show: multiple pale bluish-white grape-like accumulations, cherry-red refractive round bodies, vermilion-staining glycogen-rich IgA, overstuffed fibrils, crystalline rods

Immunophenotyping ^[10]:

• Detection of either κ and λ light chains in cytoplasm of myeloma
• Normal κ:λ ratio in bone marrow = 2:1
• Ratio > 4:1 or < 1:2 is considered to be κ or λ monoclonality
• Ratio = 2:1 is considered normal or reactive plasmacytosis
• Significance: Differentiate monoclonal gammopathies from reactive plasmacytosis due to autoimmune disease, metastatic carcinoma, chronic liver disease and AIDS

Flow cytometry immunophenotype of myeloma/SMM plasma cells:

• CD38+, CD138+ (plasma cell markers)
• Aberrant: CD56+ (abnormal — not on normal plasma cells), CD19−, CD45−/dim
• Helps distinguish clonal from reactive plasmacytosis

Cytogenetics by FISH — essential for risk stratification:

^[2]

Bloods: CBC (↓Hb), ESR↑, LRFT (reversed A:G ratio, ↑Cr), CaPO4 (↑Ca), urate, glucose, PBS (rouleaux). Pre-Tx: HBsAg, anti-HBc ± HBV DNA, G6PD. ^[15]

Peripheral blood smear findings:

• Rouleaux formation: Red cells stacking like coins — indicates elevated protein levels (especially paraprotein), causing RBCs to aggregate. This is why ESR is typically very high in myeloma spectrum disorders.
• No blast cells (unlike leukaemia)
• Circulating plasma cells: If ≥ 2 × 10⁹/L or > 20% differential → plasma cell leukaemia (NOT SMM)

Why β2-microglobulin is prognostically important: β2-microglobulin is a component of MHC class I molecules, shed from the surface of nucleated cells. Its level reflects two things: (1) tumour burden (more myeloma cells → more β2M shed), and (2) renal function (β2M is filtered by the kidney, so renal impairment raises it independently). The ISS staging system uses β2M and albumin ^[2]:

The Revised ISS (R-ISS) adds LDH and FISH cytogenetics to the original ISS for more refined prognostication ^[15].

This is one of the most critical steps — you must exclude bone lesions before confirming SMM. Even a single lytic lesion reclassifies the patient as active MM.

CT/MRI should be performed routinely before making the diagnosis of solitary plasmacytoma or smoldering myeloma. ^[10]

Imaging Modalities Compared

Skeletal survey: conventional 1st line imaging to detect lesions. Includes: PA chest, AP/lateral C/T/L-spine, AP/lateral femur/humerus, AP/lateral skull, AP pelvis. Findings: punched out lytic lesions (60%), diffuse osteopenia, pathological fractures (20%). WB cross-sectional imaging: now preferred due to ↑sensitivity. Options: WB low-dose CT, WB MRI (or spine/pelvis), WB PET/CT (usually preferred in QMH). ^[2]

For SMM specifically: Imaging must show NO lytic lesions on CT/X-ray and ≤ 1 focal lesion < 5 mm on MRI (since > 1 focal lesion ≥ 5 mm on MRI is a SLiM criterion → active MM).

This is a question students often ask, and it deserves a first-principles answer:

1. Not all SMM progresses at the same rate: The overall 10%/year rate is an average. Low-risk SMM patients may have only 5% progression at 2 years — many will never progress in their lifetime.
2. Treatment has toxicity: Anti-myeloma drugs cause peripheral neuropathy (bortezomib), teratogenicity (lenalidomide/thalidomide), myelosuppression, infections, and second primary malignancies (lenalidomide). Exposing patients who may never progress to these risks is harmful.
3. No proven overall survival benefit for standard-risk SMM: Until recently, no randomised controlled trial demonstrated that early treatment of standard-risk SMM improved overall survival compared to watchful waiting.

Frequency of monitoring (risk-adapted):

• Low risk: Every 6–12 months (after initial 2–3 monthly visits in the first year)
• Intermediate risk: Every 3–6 months
• High risk: Every 2–3 months

Key triggers for urgent reassessment:

• Rising M-protein ≥ 25% from baseline (= "evolving" type)
• Falling Hb approaching 10 g/dL
• Rising creatinine
• New bone pain or fracture
• Rising sFLC ratio towards 100

The question of whether to treat high-risk SMM has been addressed by several key trials:

Current approach (2025–2026):

• For standard-risk and intermediate-risk SMM: Observation remains standard of care
• For high-risk SMM: Early intervention with lenalidomide ± dexamethasone OR daratumumab is increasingly supported, especially if the patient is enrolled in a clinical trial
• The paradigm is shifting but not yet universally adopted — many centres still prefer observation even for high-risk SMM, with very close monitoring

Mechanism:

• Lenalidomide ("len-a-LID-oh-mide") is an immunomodulatory drug (IMiD)
  • Binds cereblon (CRBN), a component of an E3 ubiquitin ligase → leads to selective degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) → essential for myeloma cell survival
  • Also enhances T-cell and NK-cell anti-tumour immunity
  • Anti-angiogenic properties
• Dexamethasone is a glucocorticoid → direct lymphocytotoxic effect on myeloma cells; also reduces cytokine production by the microenvironment

Dosing: Lenalidomide 25 mg daily D1–21 of 28-day cycle + dexamethasone 40 mg weekly

Side effects: Myelosuppression (neutropenia), venous thromboembolism (VTE — requires thromboprophylaxis with aspirin or LMWH), teratogenicity (absolute contraindication in pregnancy — strict pregnancy prevention programme), diarrhoea, fatigue, rash, second primary malignancies

Contraindications:

• Pregnancy or women of childbearing potential without reliable contraception
• Severe renal impairment (dose adjustment needed for CrCl < 30 mL/min)
• Active VTE without anticoagulation
• Known hypersensitivity

• Mechanism: Targets CD38 on the surface of plasma cells → ADCC, CDC, ADCP, and direct apoptosis
• Approved for high-risk SMM based on the AQUILA trial (2024) — subcutaneous daratumumab significantly delayed progression vs observation
• Side effects: Infusion reactions (subcutaneous formulation has lower rates), infections (due to immunosuppression), neutropenia
• Interference with blood bank testing: CD38 is present on RBCs → daratumumab can cause a positive indirect Coombs test (pan-reactive antibody screen) → blood bank must be informed pre-treatment

Bisphosphonate details ^[20]:

• Side effects: flu-like symptoms, renal impairment, osteonecrosis of the jaw (prolonged use), atypical fractures (prolonged use)
• IV bisphosphonates cannot be used in patients with eGFR less than 35 mL/min → use denosumab instead
• Denosumab is not excreted through kidneys, can be given to these CKD patients ^[20]

Induction: triple therapy ^[15]

Side effect of proteasome inhibitors: peripheral neuropathy ^[15] — bortezomib causes a dose-limiting sensory neuropathy (demyelinating), which is why subcutaneous administration and weekly dosing are preferred over IV biweekly.

Constant evolution and drug development, from bortezomib → carfilzomib → ixazomib (oral form of bortezomib). ^[1]

Determine transplant candidate: depend on patient's risk (age < 60, co-morbidities) ^[15]

Why autologous HSCT?:

• High-dose melphalan (200 mg/m²) is highly effective at killing myeloma cells but is also profoundly myeloablative
• The patient's own stem cells (collected beforehand by leukapheresis) are reinfused to "rescue" the bone marrow
• Autologous HSCT is not curative but provides prolonged control of disease ^[10]
• Allogeneic HSCT is curative for multiple myeloma but the procedure-related mortality is high and is reserved only for young patients with HLA-compatible donors ^[10]

Consolidation and maintenance therapy (lenalidomide monotherapy): ≥ 2 years ^[15]

• After induction ± HSCT, lenalidomide maintenance prolongs progression-free survival and overall survival
• Continued until progression or intolerance

Relapse / refractory: Anti-CD38 (daratumumab, isatuximab), SLAMF7 (elotuzumab) ^[15]

Novel agents: Monoclonal antibodies (saved for refractory cases): daratumumab, elotuzumab, belantamab mafodotin (immunoconjugate); Nuclear cytoplasmic transport receptor inhibitor: selinexor; BCL-2 inhibitors: venetoclax; CAR-T cell therapy ^[1]

Immunotherapy against BCMA: Antibody-drug conjugate (ADC), Bi-specific T-cell engager (BiTE), CAR-T ^[15]

BCMA (B-Cell Maturation Antigen) is a surface protein highly expressed on myeloma cells — it has become the key target for next-generation therapies:

• Belantamab mafodotin: Anti-BCMA antibody-drug conjugate (ADC) — delivers cytotoxic payload directly to myeloma cells
• Teclistamab: Anti-BCMA × CD3 bispecific T-cell engager (BiTE) — bridges T-cells to myeloma cells
• Ide-cel / Cilta-cel: Anti-BCMA CAR-T cells — patient's T-cells are engineered to express a chimeric antigen receptor targeting BCMA

Bone lesions (osteolytic): pain, vertebral collapse, pathological fracture, cord compression ^[15]

Pathophysiology: Myeloma cells secrete factors that activate osteoclasts (via ↑RANKL, IL-6, MIP-1α, TNF-β) and simultaneously inhibit osteoblasts (via DKK-1, sclerostin). This creates an uncoupled bone remodelling — all destruction, no formation — resulting in purely lytic lesions.

Local osteolysis due to mechanical compression or local active factors, e.g. multiple myeloma (IL-6, TNF-β) ^[7][21]

Clinical manifestations:

Punched-out lytic lesions (60%), diffuse osteopenia, pathological fractures (20%) ^[2]

Renal failure: important to know the cause (SAQ!) ^[15]

This is one of the most commonly examined complications. The causes of renal failure in myeloma are numerous:

Other renal diseases associated with monoclonal light chains: Amyloidosis (AL type), Light chain deposition disease, Light chain proximal tubulopathy, Type I cryoglobulinaemic glomerulonephritis ^[6]

The most common cause of kidney failure in multiple myeloma is due to proteins secreted by the malignant cells. ^[9]

HyperCalcaemia: confusion, constipation, polyuria/polydipsia ^[15]

Pathophysiology: Myeloma cells activate osteoclasts via lymphokine production by haematological malignancies that activate osteoclasts (e.g. multiple myeloma) ^[21]. The key cytokines are RANKL, IL-6, and TNF-β. This causes massive osteolysis → calcium released from bone into blood → hypercalcaemia.

Unlike solid tumour hypercalcaemia (which is often PTHrP-mediated), myeloma hypercalcaemia is locally osteolytic. Therefore:

• PTH is low → adequate suppression response by the axis ^[21]
• PTHrP is usually not elevated (unlike lung SCC)
• The mechanism is direct osteoclast activation by tumour-derived cytokines

Clinical effects of hypercalcaemia (mnemonic: "Bones, Stones, Abdominal Groans, Psychiatric Overtones"):

• Bones: bone pain, fractures
• Stones: nephrolithiasis, nephrocalcinosis
• Abdominal groans: anorexia, nausea, vomiting, constipation
• Psychiatric overtones: confusion, drowsiness, psychosis, coma

Hypercalcemia in 20% cancer patients ^[7]

Anaemia (NcNc) / bleeding tendency: BM infiltration + acquired vWD ^[15]

Pathophysiology:

• Direct marrow infiltration: Clonal plasma cells physically displace normal haematopoietic precursors → reduced erythropoiesis, granulopoiesis, and megakaryopoiesis
• Cytokine-mediated suppression: IL-6 and hepcidin upregulation → functional iron deficiency (iron is trapped in macrophages, unavailable for erythropoiesis) → normocytic normochromic anaemia of chronic disease pattern
• Dilutional: High paraprotein levels increase plasma volume → relative anaemia
• Renal failure: Reduced erythropoietin production

Bleeding tendency: Acquired von Willebrand disease (paraprotein binds to vWF, impairing platelet adhesion) + thrombocytopenia from marrow infiltration

Bone marrow failure is listed as a complication ^[10] — when the marrow is severely infiltrated, pancytopenia develops.

Recurrent infections: immunoparesis (↓↓other Ig) ^[15]

Pathophysiology: This is critically important and operates on multiple levels:

Common infections:

• Encapsulated organisms (S. pneumoniae, H. influenzae) — due to impaired antibody-mediated opsonisation
• Gram-negative bacteria (E. coli, Klebsiella) — especially with neutropenia
• Herpes zoster reactivation — especially with bortezomib (requires aciclovir prophylaxis)
• Opportunistic infections with prolonged immunosuppression (PJP, CMV, fungal)

Infections are the leading cause of morbidity and mortality in myeloma patients.

Hyperviscosity syndrome: rare c.f. WM ^[15]

Pathophysiology: Very high paraprotein levels (especially IgA, which polymerises, or IgG3 subclass) increase serum viscosity → sluggish blood flow → sludging in microvasculature.

Clinical features (triad):

• Mucosal bleeding: epistaxis, gingival bleeding
• Visual disturbances: blurred vision, "sausage-link" retinal veins (dilated, segmented retinal veins on fundoscopy), retinal haemorrhages
• Neurological symptoms: headache, confusion, dizziness, seizures, coma

Management: Plasmapheresis — physically removes the excess immunoglobulin from the circulation. This is a bridge while definitive chemotherapy takes effect.

Serum viscosity if M protein > 5g/dL or S/S of hyperviscosity ^[2]

Note: Hyperviscosity is much more common in Waldenström macroglobulinaemia (IgM is a pentamer → very large → viscosity rises steeply with concentration) than in IgG/IgA myeloma.

AL amyloidosis possibly arising as a complication of myeloma in 10% of cases ^[4]

Pathophysiology: Monoclonal light chains (especially λ) misfold into β-pleated sheets → aggregate as insoluble amyloid fibrils → deposit in tissues → organ dysfunction.

Target organs and manifestations:

Amyloidosis affects the whole body. Autonomic neuropathy, postural hypotension caused by amyloidosis. ^[4]

Congo red stain, salmon pink colour → indicative of amyloid deposition. Electron microscopy to show non-branching fibrils in the extracellular compartment. ^[4]

Cardiac failure: secondary to amyloidosis / anaemia / hyperviscosity ^[15]

Three mechanisms:

1. AL amyloidosis → restrictive cardiomyopathy (most serious)
2. Chronic anaemia → high-output cardiac failure
3. Hyperviscosity → increased afterload → decompensation

Sensory ± motor neuropathy: usually secondary to amyloidosis ^[15]

• AL amyloid neuropathy: length-dependent sensorimotor polyneuropathy ± autonomic neuropathy
• Spinal cord compression: from vertebral collapse or direct plasmacytoma (discussed above)
• Treatment-related neuropathy: bortezomib causes dose-limiting peripheral neuropathy (sensory > motor, painful)
• Radiculopathy: from vertebral fracture fragment compressing nerve roots

• Long-term use of lenalidomide (especially in combination with melphalan) is associated with a small but real increased risk of secondary haematological malignancies (MDS, AML)
• This is important when counselling patients about maintenance therapy