Multiple Myeloma of the Spine

Multiple myeloma is a plasma cell neoplasm: clonal proliferation of malignant plasma cells in the bone marrow, a monoclonal protein in the blood or urine, and end-organ damage that includes bone disease. It is the second most common haematological malignancy, after non-Hodgkin lymphoma, and accounts for approximately 10% of haematological cancers.

Who. The median age at diagnosis is 65-70 years. The male to female ratio is 1.4:1, and the incidence is two to three times higher in African Americans.

Where the bone disease is. Eighty per cent of patients have bone disease at diagnosis, and the spine is the most common site. The distribution, and what each site produces:

How myeloma destroys bone. Myeloma cells activate osteoclasts and suppress osteoblasts, through:

• RANKL upregulation
• DKK1 (Dickkopf-1), which inhibits Wnt signalling
• MIP-1alpha (macrophage inflammatory protein)
• IL-6, IL-1beta and TNF-alpha secretion

Why the lesions are purely lytic. Because DKK1 suppresses osteoblast activity, there is no bone-forming response: the lesions are the classic, pathognomonic "punched out" lucencies without a sclerotic rim, and a bone scan, which depends on osteoblastic uptake of the radioisotope, is often negative. This is why MRI and CT are preferred over bone scan for myeloma. Metastatic carcinoma, by contrast, may be lytic, blastic or mixed, and its bone scan is usually positive. Myeloma itself never produces a blastic or sclerotic response; when a plasma-cell bone lesion is sclerotic, the diagnosis to consider is POEMS syndrome, dealt with below.

Disease Spectrum

Plasma-cell disorders run from a precursor state that needs no treatment to active myeloma that does. The distinctions rest on the M-protein level, the proportion of clonal plasma cells in the marrow, and whether there is end-organ damage or a myeloma-defining event.

Bone Marrow Infiltration

The MRI pattern carries prognosis. How the marrow is infiltrated on MRI correlates with outcome. A diffuse pattern indicates high tumour burden and correlates with a higher ISS stage and worse survival; these patients often have more severe cytopenias and higher beta-2 microglobulin levels. A focal pattern indicates a better treatment response.

IMWG Diagnostic Criteria (2014)

The required criterion. Diagnosis requires clonal bone marrow plasma cells of 10% or more, or a biopsy-proven plasmacytoma. That alone is not enough: it must be joined by evidence that the disease is damaging an organ, or by a biomarker that predicts it will.

CRAB: end-organ damage. Any one of these, with the clonal plasma cells, defines symptomatic myeloma and the need for treatment:

• Calcium elevated: serum calcium over 11 mg/dL, or 0.25 mmol/L above the upper limit of normal
• Renal insufficiency: creatinine over 2 mg/dL, or creatinine clearance under 40 mL/min
• Anaemia: haemoglobin under 10 g/dL, or more than 2 g/dL below normal
• Bone lesions: one or more osteolytic lesions on imaging

SLiM: the biomarkers added in 2014. Any one of these makes the diagnosis without CRAB, so that treatment can start before end-organ damage:

• Sixty: clonal bone marrow plasma cells of 60% or more
• Light chains: involved to uninvolved serum free light chain ratio of 100 or more
• MRI: two or more focal lesions, each 5 mm or larger

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Staging

International Staging System (ISS). Two readily available serum markers: beta-2 microglobulin reflects tumour burden, and albumin reflects performance status.

Revised ISS (R-ISS). Incorporates cytogenetics and LDH, and provides better prognostication than ISS alone. High-risk cytogenetics are del(17p), t(4;14) and t(14;16).

A sclerotic, rather than lytic, plasma-cell bone lesion should prompt thought of POEMS syndrome. POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes), also called osteosclerotic myeloma or Crow-Fukase syndrome, is a rare paraneoplastic syndrome driven by an underlying plasma-cell disorder, and it is the classic exception to the "myeloma is always lytic" rule. The neuropathy, not the bone disease, usually dominates the clinical picture.

Bone pain. The most common symptom, present in 70% at presentation, and often back pain from vertebral involvement. It is worse with movement and may improve at rest. Pathological fractures are common.

Systemic symptoms. Fatigue from anaemia, weight loss, recurrent infections from immunoparesis and, rarely, symptoms of hyperviscosity.

Vertebral compression fractures. Present in 55-70% at diagnosis and may be the presenting feature. Multiple levels are common, and the thoracolumbar junction is the most common site.

Spinal cord compression. An emergency presentation, in 5-10% of myeloma patients, usually from vertebral collapse and less commonly from extraosseous extension. It requires urgent assessment and treatment; because the tumour is radiosensitive the prognosis is good if it is treated promptly (see Management).

Radiculopathy. From neural foraminal narrowing or extraosseous tumour extension, and it may present before the diagnosis has been made.

Red flags. The features that should raise myeloma:

• Age over 50 with new back pain
• Pathological fracture (minimal trauma)
• Anaemia, renal insufficiency
• Hypercalcaemia
• Elevated ESR/plasma viscosity
• Recurrent infections

Differential Diagnosis of a Lytic/Destructive Vertebral Lesion

The discriminators. Myeloma and metastasis characteristically spare the intervertebral disc, whereas infection crosses the disc space and destroys the adjacent endplates. Marrow replacement on T1 MRI distinguishes a malignant collapse from a benign osteoporotic fracture.

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Laboratory Studies

The screening panel. The routine bloods:

• FBC (anaemia, rouleaux formation)
• Renal function, electrolytes
• Calcium (hypercalcaemia)
• Total protein, albumin (AG ratio)
• LDH, beta-2 microglobulin

The myeloma-specific tests. The tests that find and type the M-protein:

• Serum protein electrophoresis (SPEP) - M-spike
• Urine protein electrophoresis (UPEP) - Bence-Jones protein
• Serum free light chains (kappa/lambda ratio)
• Immunofixation (identifies M-protein type)

Bone marrow. Aspirate and trephine biopsy give the plasma cell percentage that the diagnosis rests on, and cytogenetics/FISH for the prognostic markers that feed the R-ISS.

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Imaging

Whole-body low-dose CT (WBLDCT). The first-line imaging for initial staging per the IMWG 2019 consensus, having replaced the skeletal survey: it has higher sensitivity than the conventional skeletal survey for osteolytic disease, detects rib and pelvic lesions better, and can assess fracture risk. One lytic lesion of 5 mm or larger on CT is itself a diagnostic criterion. The findings are punched-out lytic lesions with no sclerotic rim (unlike metastases), pathological fractures and osteopenia.

Whole-body MRI (WBMRI). The most sensitive test for bone marrow infiltration: it detects marrow involvement before any lysis has occurred, and two or more focal lesions is a myeloma-defining event. It is superior for assessing cord compression, and it is mandatory when the WBLDCT is negative but myeloma is still suspected. The infiltration patterns (focal, diffuse, mixed, variegated, normal) are described under Pathophysiology.

• T1-weighted: low signal (marrow replacement)
• T2-weighted/STIR: high signal (cellular infiltration)
• DWI: high signal (diffusion restriction)

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FDG-PET/CT. Complements MRI for comprehensive staging and is useful for specific indications:

• Assessment of extramedullary disease
• Treatment response monitoring
• Detection of minimal residual disease
• Oligo-secretory or non-secretory myeloma

Its advantages are the assessment of metabolic activity, whole-body coverage and prognostic value (the number of focal lesions). Its limitations are false negatives in low-grade disease and the radiation exposure.

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Skeletal survey. The traditional study, now replaced by WBLDCT and no longer recommended as first-line imaging: its sensitivity is lower than cross-sectional imaging because a lesion needs 30-50% bone loss before it shows. It is still useful if CT and MRI are unavailable. The classic findings are punched-out lesions with no sclerotic rim, the "pepper pot skull", pathological fractures and generalised osteopenia.

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Algorithm

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Systemic Treatment

First-line therapy belongs to haematology, but the surgeon should understand it. Induction is a triplet, VRd (bortezomib, lenalidomide, dexamethasone), or a quadruplet that adds daratumumab for fit patients, followed by autologous stem cell transplant for eligible patients under 70.

Bone-targeted therapy is monthly zoledronic acid, with denosumab as the alternative if there is renal impairment. It reduces skeletal events by 40%.

Orthopaedic Management

Most patients are managed non-operatively. Analgesia by the WHO ladder, bracing for vertebral fractures, activity modification and physiotherapy.

Vertebral augmentation. Kyphoplasty or vertebroplasty is first-line for painful compression fractures and highly effective, with 80-90% pain relief. It can be done under local anaesthesia, multiple levels can be treated in a single session, and it is a good option for pathological compression fractures.

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Radiotherapy. Myeloma is highly radiosensitive, and radiation is first-line for local control: local control in 80-90%, pain relief in 70-80%, at lower doses than are effective for carcinoma. The indications are:

• Painful bone lesions
• Impending pathological fracture
• Spinal cord compression
• Solitary plasmacytoma (curative intent)

The typical doses are conventional practice rather than guideline. The IMWG Bone Working Group recommends radiotherapy for uncontrolled pain, impending or symptomatic cord compression and pathological fracture, but does not specify a dose:

• Palliation: 20-30 Gy in 5-10 fractions
• Plasmacytoma: 40-50 Gy for cure

Surgery. Reserved for specific scenarios:

1. Mechanical instability (SINS 13+)
2. Spinal cord compression with instability
3. Failed radiation (rare in myeloma)
4. Tissue diagnosis if needed
5. Impending long bone fracture (Mirels 9+)

The IMWG Bone Working Group states the spinal indication narrowly: vertebral column instability, or cord compression caused by bone fragments in the canal rather than by soft tumour, which in a radiosensitive disease will often answer to radiotherapy alone. SINS grades the stability question: 0-6 stable, 7-12 potentially unstable and warranting surgical consultation, 13-18 unstable.

The principles are posterior decompression and stabilisation, cement augmentation of the screws, minimal blood loss in a marrow disease, and coordination with haematology. Radiation is usually given post-operatively and gives excellent local control; surgery plus radiation provides definitive local control.

Spinal Cord Compression

An oncological emergency with a better outlook than carcinoma. Unlike metastatic carcinoma, myeloma cord compression has an excellent prognosis if treated promptly, because the tumour is highly radiosensitive. Surgery is not automatically required, as it is in radioresistant tumours: if the spine is mechanically stable, radiation alone is often sufficient.

1. Dexamethasone 10mg IV bolus then 4mg q6h
2. MRI of the whole spine (skip lesions are common)
3. Assess for surgery: mechanically unstable (SINS 13+) means surgery plus radiation; stable (SINS under 7) means radiation alone is effective
4. Radiation, which is highly effective

Outcomes. Over 90% of ambulatory patients maintain ambulation, and 50-70% of non-ambulatory patients recover it, which is better than carcinoma.

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Skeletal. Vertebral compression fractures are the dominant skeletal complication (their frequency is given under Clinical Presentation); long bone fractures are less common, and rib fractures occur. Hypercalcaemia, from osteoclast activation, is present in 25-30% at diagnosis and is a medical emergency if severe.

Bisphosphonate therapy. The complications of bone-targeted treatment:

• Osteonecrosis of the jaw (ONJ) - 1-10%
• Renal toxicity (especially zoledronic acid)
• Atypical femoral fractures (rare)

Surgery. The surgical complications and their causes:

• Wound healing issues (immunosuppression)
• Hardware failure (poor bone quality)
• Infection risk (hypogammaglobulinaemia)

Extramedullary disease. Occurs in 10-20% during the disease course, has more aggressive biology, and requires a modified treatment approach.

Amyloidosis is listed among the events that define active disease and trigger treatment, but it is worth developing because the orthopaedic surgeon may be the first to encounter it. AL (primary, light-chain) amyloidosis is a plasma-cell dyscrasia in which misfolded monoclonal immunoglobulin light chains form amyloid fibrils that deposit in tissues; it can occur alone or alongside multiple myeloma. Treatment targets the underlying clone (bortezomib- or daratumumab-based) to switch off light-chain production, plus organ-supportive care.

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Global Epidemiology

Multiple myeloma accounts for roughly 1% of all cancers and about 10% of haematological malignancies, with an age-standardised incidence of approximately 2 per 100,000 worldwide and a marked rise in absolute case numbers driven by ageing populations. Incidence is two- to threefold higher in people of African ancestry than in white populations and lower in East Asian populations, a disparity that persists after adjustment for access to care. The spine is the most common site of skeletal involvement, so the orthopaedic and spinal surgeon is frequently the first clinician to encounter undiagnosed disease through a pathological vertebral fracture.

Major Guidelines, Side by Side

A key cross-guideline point of agreement, and a frequent exam discriminator, is that myeloma is radiosensitive: unlike most solid-tumour metastatic spinal cord compression (where decompressive surgery before radiotherapy improves ambulation, per Patchell), a mechanically stable myeloma cord compression can often be treated with radiotherapy alone.

Registry and Real-World Evidence

Myeloma bone disease is tracked less by arthroplasty-style implant registries than by national cancer and trials networks. Examples include the SEER programme (US), the Haematological Malignancy Research Network (UK), and the Myeloma and Related Diseases Registry (MRDR), which includes Australian and New Zealand cohorts. These provide population-level survival and practice-pattern data, consistently showing improving median survival (now exceeding 5-6 years in transplant-eligible patients) following the introduction of proteasome inhibitors, immunomodulatory drugs and anti-CD38 antibodies, while also documenting persistent under-use of bone-protective therapy and variation in time-to-diagnosis.

Practice Variation

In high-resource settings whole-body MRI or PET/CT and quadruplet induction with autologous transplant are standard. In limited-resource settings skeletal survey and plain radiography remain in use, and access to novel agents, denosumab and timely radiotherapy is restricted, so vertebral augmentation and conventional fractionated radiotherapy carry proportionally greater importance. The orthopaedic priorities, structural stabilisation, pain control and preservation of neurological function, are universal even where systemic options differ.

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