Endgames Case Review

A man with a short history of lower back pain

BMJ 2016; 353 doi: https://doi.org/10.1136/bmj.i1722 (Published 07 April 2016) Cite this as: BMJ 2016;353:i1722
  1. Alison Edwards, foundation year 2 doctor1,
  2. Preethi Nalla, specialist registrar in diabetes and endocrinology1,
  3. L D Premawardhana, consultant in diabetes and endocrinology1
  1. 1Section of Endocrinology, Ysbyty Ystrad Fawr, Ystrad Fawr Way, Ystrad Mynach, Caerphilly CF82 7EP, UK
  1. Correspondence to: A Edwards Alison.Edwards6{at}wales.nhs.uk

A previously fit and well 69 year old man presented to his general practitioner with a four week history of lower back pain. He had no history of trauma, took no regular drugs, was an ex-smoker, and did not drink alcohol. Physiotherapy, sought privately, had provided no benefit. His GP prescribed painkillers and reviewed him two weeks later, at which point, with no improvement in symptoms, spinal radiography was organised. Radiography showed multiple compression fractures of vertebrae T11-L2 (fig 1; arrows).

Figure1

Fig 1 Plain radiograph showing multiple compression fractures of vertebrae T11-L2 (arrows)

The GP arranged blood tests and referred the patient to hospital for assessment. On further questioning, he had recently lost weight and had loss of appetite. Pallor was noted on examination. There were no neurological findings (in particular, no signs of spinal cord compression) and other systems examinations were normal. Rectal examination showed a smooth, enlarged prostate, with normal anal tone and sensation.

Blood tests showed normocytic anaemia (haemoglobin 99 g/L (reference range 130-180), mean cell volume 95 fL (80-100)), and normal white cell and platelet counts. A renal profile was normal, bone profile showed protein 86 g/L (60-80), albumin 35 g/L (35-50), globulin 51 g/L (22-43), alkaline phosphatase 163 U/L (30-130), adjusted calcium 2.74 mmol/L (2.20-2.60), and phosphate 1.64 mmol/L (0.80-1.50). Imaging studies comprised whole spine magnetic resonance imaging (MRI); computed tomography of the thorax, abdomen, and pelvis; and a skeletal survey (fig 2).

Figure2

Fig 2 Skull radiograph (with contrast) done as part of skeletal survey

Questions

  1. What is the diagnosis?

  2. What additional investigations would aid diagnosis?

  3. What complications may arise?

  4. How should this patient be managed?

Answers

1. What is the diagnosis?

Short answer

Multiple myeloma.

Discussion

The spinal radiograph shows pathological fractures of T11-L2 (fig 1), suggestive of metastatic disease (for example, from primary kidney, thyroid, or gastrointestinal cancer) or multiple myeloma. The combination of these findings with the blood test results (normocytic anaemia, hyperglobulinaemia, hypercalcaemia) makes multiple myeloma the most likely diagnosis. The radiograph of the skull (fig 3) shows multiple lytic lesions that are also characteristic of multiple myeloma. It is important to consider red flag symptoms in the investigation of lower back pain, specifically those relating to cauda equina syndrome (such as saddle anaesthesia, bladder, bowel, or sexual dysfunction), spinal fracture (such as history of trauma or osteoporosis), and cancer or infection (such as pain that remains when lying down or disturbs sleep, constitutional symptoms such as weight loss, evidence of immune suppression).1

Figure3

Fig 3 Skull radiograph (with contrast) showing lytic lesions characteristic of multiple myeloma (arrows)

Multiple myeloma is characterised by malignant proliferation of plasma cells, which accumulate in the bone marrow and secrete a monoclonal paraprotein (or M protein). The term multiple myeloma refers to the multiple locations affected by the malignant plasma cells.2 The paraprotein is a single immunoglobulin or immunoglobulin component—for example, part of a heavy chain attached to a light chain, or a light chain (κ or λ). Plasma cells are non-secretory in less than 1% of cases. Patients present as a result of myeloma related organ or tissue involvement: anaemia secondary to bone marrow failure; bony pain, pathological fractures, and hypercalcaemia secondary to disordered bone turnover; renal failure secondary to excess serum free light chains; and plasma hyperviscosity secondary to paraproteinaemia. Patients also have an increased risk of infection secondary to lack of normal immunoglobulins (immune paresis).3

2. What additional investigations would aid diagnosis?

Short answer

Serum protein and globulin levels, immunoglobulins, serum protein electrophoresis, and urine for Bence-Jones proteins (light chains).

Discussion

A full blood count will show normocytic anaemia caused by bone marrow involvement. Renal and liver function tests will show organ damage secondary to light chain deposition or hypercalcaemia. Serum calcium and phosphate levels may be deranged owing to increased osteoclastic activity. Immunoglobulins are measured to identify paraproteins—IgG in 70% of cases and IgA in 20%; IgM is uncommon; IgD and IgE are rare.3 Serum electrophoresis will show paraprotein bands and increased concentrations of immunoglobulin light chains (Bence-Jones proteins). Urine may also show immunoglobulin light chains, but this is variable because light chains are reabsorbed to some extent in the proximal renal tubule.4 A bone marrow aspirate should be obtained to confirm the diagnosis through phenotyping of the malignant plasma cell. The diagnostic criteria of symptomatic multiple myeloma recommended by the International Myeloma Working Group (IMWG) are all three of:

  • More than 10% monoclonal plasma cells in the bone marrow or biopsy confirmed plasmacytoma (or both)

  • Monoclonal protein present in the serum or urine (or both)

  • Any symptoms of myeloma related organ dysfunction.5

It is important to remember that plasma cells are non-secretory or oligosecretory in more than 3% of patients with myeloma,6 so negative protein electrophoresis or a lack of raised immunoglobulins does not rule out the diagnosis. Malignant plasma cells may secrete only the light chain of the immunoglobulin molecule, leading to so called light chain myeloma, which makes up about 15% of all myelomas.7 A newer form of assay designed to look specifically for light chains in blood and urine has enabled some myelomas that would previously have been thought to be non-secretory to be reclassified as light chain myeloma.8

Spinal radiography is not indicated in the initial diagnosis of non-specific lower back pain and, if serious spinal disease is suspected, imaging should be tailored to that disease.1 In myeloma, a skeletal survey of the skull, spine, pelvis, and long bones is useful to identify sites of disordered bone turnover, but 10-20% of lytic lesions may be missed. The IMWG therefore recommends low dose computed tomography or MRI to confirm bone lesions at diagnosis.9 MRI can also add further detail to the skeletal survey and identify any soft tissue masses. Plain film radiography can detect lytic lesions only when >30% trabecular bone is lost.10 MRI of the spine should be carried out urgently if cord compression is suspected. Bone mineral density scans are not indicated owing to practicalities of the technique and the fact that bisphosphonates are given to patients with myeloma and bone pain.11

3. What complications may arise?

Short answer

Hypercalcaemia, spinal cord compression, plasma hyperviscosity, infection, and renal failure.

Discussion

Hypercalcaemia in myeloma is caused by a combination of increased osteoclastic activity without an increase in osteoblastic activity. Myeloma cells directly stimulate osteoclast formation and indirectly suppress osteoblasts. These changes result in myeloma bone disease.12 Spinal cord compression occurs secondary to pathological vertebral fracture or extension of a plasmacytoma into the spinal canal. Presentation can be insidious—for example, altered gait, sensory deficits, continence problems, and loss of sexual function. Plasma hyperviscosity is secondary to the plasma cell dyscrasia itself but can be compounded by other factors such as infection and chemotherapy.13 Infection occurs secondary to immune paresis and neutropenia. Renal failure can be a complication of all the above and also a result of light chain deposition disease, amyloid light chain amyloidosis, or, most commonly, cast nephropathy.14 Amyloid light chain amyloidosis, in which amyloid deposits are formed by aggregated light chains, can affect multiple organs, such as the heart and peripheral nervous system; however, the kidneys are most commonly affected.

4. How should this patient be managed?

Short answer

Intravenous fluids and electrolyte supplements may be needed to correct dehydration, hypercalcaemia, and electrolyte abnormalities. Bisphosphonates may be needed to treat hypercalcaemia and bone pain. Ensure adequate analgesia. Refer to a haematologist as soon as the diagnosis is suspected.

Discussion

Any haematological malignancy suspected in primary care should be referred to specialist care urgently (within two weeks) or immediately (the same day, through a medical assessment unit) depending on the presentation. Refer the patient immediately if baseline electrolytes show hypercalcaemia or renal failure that requires urgent treatment. If initial blood test results do not indicate that urgent treatment is required but are consistent with myeloma, protein electrophoresis and Bence-Jones protein tests should be performed within 48 hours and referral made through the two week wait route if the results are positive.15 A high proportion of patients with myeloma are diagnosed at emergency presentation (37%), with 27% diagnosed after GP referral (not including referral through the two week wait route). The difference is important. For patients aged 65-84 years, 12 month survival rates are 48% for those presenting as an emergency and 78% for those referred by their GP.16

After confirmation of the diagnosis, patients are referred to a multidisciplinary team and assessed for their eligibility for treatment with high dose therapy and autologous stem cell transplantation.17 Age is an important part of this assessment, with both of these treatments being recommended for patients under 65 years, but not usually for those over 75 years. The guidance is less clear for those in between, and factors such as renal function, cytogenetics, disease stage, and baseline health status are taken into consideration.17 The international staging system defines risk categories on the basis of patients’ serum albumin and β2 microglobulin concentrations, but its use in determining an appropriate treatment choice is not clear.11

The introduction of three agents—thalidomide, lenalidomide, and bortezomib (often combined with dexamethasone)—has improved survival rates.11 More research is needed to maximise the outcomes of these chemotherapy agents, and it is recommended that patients are entered into clinical trials whenever possible.11 For people in whom high dose therapy or autologous stem cell transplantation (or both) is planned, or may be an option in the future, induction therapy with one of the three novel agents is used to achieve high remission rates as quickly as possible.11 The thalidomide regimen CTD (cyclophosphamide, thalidomide, and dexamethasone) is currently the most widely used induction regimen in the UK.11 This was trialled in the Myeloma IX study (1970 patients), which used minimal residual disease as a surrogate endpoint to compare CTD with CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) as induction therapy before autologous stem cell transplantation. The proportion of patients achieving less than 0.01% minimal residual disease was higher in the CTD arms of the study both after induction (25% v 13%), and after autologous stem cell transplantation (71% v 54%).18

Induction regimens based on the proteasome inhibitor bortezomib have also been successful before stem cell transplantation.11 The combination of two or more novel agents as induction therapy has shown good initial remission rates, although research is still needed into longer term outcomes after stem cell transplantation.11 The combined induction therapy regimen VTD (bortezomib, thalidomide, dexamethasone) is now included in National Institute for Health and Care Excellence guidelines after trials showed better outcomes before and after autologous stem cell transplantation than for thalidomide and dexamethasone alone.19 20 21 The VRD (bortezomib, lenalidomide, and dexamethasone) induction regimen has had good initial response rates; all 66 patients achieved a partial response, and 18 month progression-free survival rates and overall survival rates with or without transplantation were 75% and 97%, respectively (estimated from median follow-up 21 months).22 The VRD regimen is not currently used in the UK; however, with the recent approval of the VTD regimen, proteasome inhibitor based combination regimens may become more common. The side effect profiles of the various chemotherapy induction regimens may be an important factor in selecting the most appropriate regimen for a specific patient. After chemotherapy induction, patients can proceed to high dose therapy, usually with high dose melphalan, as conditioning for autologous stem cell transplantation.

For those patients in whom high dose therapy is not an option—those with lower base fitness because of age or comorbidities—treatment aims to achieve a balance between response and toxicity from chemotherapy. Traditionally, the drug regimens used in this patient population have been MP (melphalan and prednisolone) or MRC (melphalan and cyclophosphamide),11 but the use of the novel agents has also been trialled. In patients ineligible for autologous stem cell transplantation, the overall response rate increased from 32.6% to 63.8% (n=426) when CTD (cyclophosphamide, thalidomide, and dexamethasone) was used instead of MP.23 However, one study (n=289) that compared MP with TD (thalidomide and dexamethasone) found that although response rates were higher in the TD group, overall survival was lower, which was thought to be caused by toxicity of thalidomide and dexamethasone in the specific age group (60% of patients were aged 70-79 years).24 Trials generally find that high doses of thalidomide are not well tolerated in people over 70 years.11 The VISTA trial (n=682) compared MP with VMP (bortezomib, melphalan, prednisolone) in those ineligible for transplantation and found the VMP regimen was well tolerated and reduced the risk of death by 31% at a median follow-up of 60.1 months.25 In terms of using lenalidomide in older patients, one trial (n=459) comparing MP with MPR (melphalan, prednisolone, lenalidomide) followed by either lenalidomide or a placebo, found that the MPR plus lenalidomide regimen significantly improved progression-free survival rates, specifically in patients ≥65 years. The trial recommends consideration of this treatment option in older people newly diagnosed with myeloma.26 The current guidelines recommend either MPT (melphalan, prednisolone, thalidomide), CTD (with attenuated doses), or VMP, for patients who are not eligible for high dose therapy.11

The prognosis of multiple myeloma depends on eligibility for, and response to, high dose therapy and autologous stem cell transplantation. Younger patients with a high performance status who are eligible for high dose therapy have a very different prognosis from those whose frailty and comorbidities preclude high dose novel agents or transplantation. The UK survival rate for those diagnosed between 2010 and 2011 is 76.6% at one year, with predicted survival rates at five and 10 years of 47% and 32.5%, respectively.27 These figures are improving—predicted survival rates at one year for those diagnosed in 2013 are 81.6% for men and 80.3% for women, with predicted five year survival rates of 53.4% for men and 51.5% for women. Of all common UK cancers, the largest increase in one year survival from those diagnosed between 2008 and 2012 and those diagnosed in 2013 was in men with multiple myeloma.28 As survival rates increase and more patients are living with the complications of multiple myeloma, follow-up and support beyond haematological therapies is increasingly important. It is often the role of GPs to manage longer term symptoms, including ongoing pain, constipation, depression, and fatigue, and to diagnose complications such as peripheral neuropathy secondary to paraprotein levels and osteonecrosis of the jaw secondary to bisphosphonate use. Support should be provided with a multidisciplinary approach, including palliative and chronic pain services when necessary.29

Patient outcome

Our patient’s serum IgA was raised at 20.47 g/L (reference range 0.80-2.80) with characteristic suppression of IgG and IgM. Serum electrophoresis showed raised IgA κ light chains. Urine electrophoresis detected free κ light chains. A bone marrow aspirate confirmed the diagnosis of myeloma, with 24% plasma cells and κ plasma cells detected on flow cytometry. He was given high dose dexamethasone therapy (40 mg once daily) for four days. Management of pain was the main problem so he remained in hospital for control of this. After developing moderate hypercalcaemia, he was treated with pamidronate and was then discharged home. Participation in a clinical trial was offered—although he was over 65 years, he had a good base level of fitness and was eligible for high dose therapy and autologous stem cell transplantation. He began induction chemotherapy with lenalidomide and dexamethasone before transplantation. His pain is managed in the community by his GP, who also provides support by ensuring regular contact with him and his family.

Footnotes

  • Competing interests: We have read and understood BMJ policy on declaration of interests and have no competing interests to declare.

  • Patient consent obtained.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

References

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