Abstracts of Annual Education Meeting on 25-Nov-2002
Complications Of Myeloma
Dr Diana Samson, Senior Lecturer in Haematology, Imperial College, London
Bone disease
Bone pain is the most common presenting symptom in myeloma, affecting 60 per cent of patients. The back and ribs are the most frequent sites of pain. X-rays may show lytic lesions and generalized osteoporosis is also common. Some patients have osteoporosis without lytic lesions. Vertebral collapse is frequent in myeloma patients, leading to back pain, kyphosis and loss of height, and occasionally resulting in cord compression. Pathological fracture of a long bone may also occur.
Localized painful bone lesions are best treated by radiotherapy, which usually improves the pain within a few days. Analgesia is obviously important. Non-steroidal anti-inflammatory drugs are helpful, but caution is needed because of the risk of renal toxicity. Patients with progressive bone disease often require opiate analgesia.
Long-term bisphosphonate therapy has been shown in randomised trials to reduce complications of myeloma bone disease such as fractures and loss of height, and to reduce bone pain. Oral clodronate, intravenous pamidronate and intravenous zoledronate have all been shown to be effective. The UKMF guidelines recommend long-term bisphosphonate therapy for all patients with myeloma who require treatment for the myeloma.
Orthopaedic intervention may be required to treat pathological fractures . There are also new procedures for treating collapsed vertebrae, called vertebroplasty and kyphoplasty. Vertebroplasty involves injection of cement into vertebrae to strengthen them, while in kyphoplasty the vertebrae are also re-inflated.
It has recently been established that myeloma bone disease results from the deregulation of the balance between RANK-ligand, the major physiological activator of osteoclast activity, and OPG (osteoprotegerin) which normally inhibits the activity of RANK-L. Both RANK-L and OPG are produced by bone marrow stromal cells (BMSC), but in myeloma the production of RANK-L by BMSC is up regulated, leading to increased osteoclast activation. This pathway offers a new target for treating myeloma bone disease. Data from mouse models of myeloma show that treatment with OPG prevents bone loss by inhibiting RANK-L activity. Analogues of OPG and other inhibitors of RANK-L are currently undergoing clinical trials in patients.
Hypercalcaemia
Increased bone destruction may result in hypercalcaemia, which causes symptoms such as polyuria, polydipsia, constipation, nausea, malaise, and neuromuscular weakness. Severe hypercalcaemia can lead to acute renal failure, cardiac arrhythmia, and somnolence followed by coma. Hypercalcaemia is a medical emergency. Hypercalcaemia leads to dehydration and so intravenous rehydration is the first line of treatment. An intravenous bisphosphonate is the most effective treatment for hypercalcaemia, which is not rapidly corrected by rehydration. As all patients with symptomatic myeloma are now treated with long-term bisphosphonates, recurrent hypercalcaemia is not common unless there is disease progression.
Renal failure
Renal failure is also a common problem in myeloma patients. Twenty-five to 30% of patients have some degree of renal impairment and 5-10% will present with severe renal failure. Renal failure is most commonly due to Bence Jones protein (BJP), which damages the tubules as it passes through the kidney. Patients with BJP-only myeloma are at particular risk of renal failure. The classic histological features are of fractured distal tubular casts with a surrounding chronic inflammatory infiltrate including giant cells ('myeloma kidney').
Other factors, which can contribute to renal failure, include hypercalcaemia, infection, dehydration, hyperuricaemia, amyloid deposition and non-steroidal anti-inflammatory drugs. Renal failure that results acutely from hypercalcaemia or dehydration is often reversible with appropriate management, but that due to BJP is less likely to recover.
Renal failure is an adverse prognostic feature. Patients with severe renal failure have a higher risk of early death, and treatment options are limited, for example high dose therapy is not generally recommended.
Maintaining a high fluid intake, correcting dehydration and treating hypercalcaemia can often prevent renal failure. Patients with established renal failure may need dialysis. In some patients renal function recovers as the disease responds to treatment, but in other patients long-term dialysis may be needed. Early plasmapheresis may improve the chance of recovery of renal function, but the evidence is not clear-cut. The UKMF and the Renal Association have therefore designed a trial to answer this question (the MERIT trial), which is due to commence early in 2003.
Anaemia
Anaemia is another common presenting feature, with a haemoglobin below 12 g/dl in 60 per cent of patients. Severe anaemia, neutropenia and thrombocytopenia are, however, rare at presentation and the anaemia appears to be mediated by cytokines, such as IL-1, rather than being directly due to marrow replacement. In some patients, renal failure may also contribute to the anaemia. Anaemia usually improves when the disease responds to treatment. Blood transfusions may be needed to improve the haemoglobin level if there is severe anaemia. Erythropoietin injections can also improve the anaemia, even in the absence of renal failure, and the UKMF guidelines recommend a trial of Epo in patients with symptomatic anaemia.
Infections
There is impairment of both humoral and cell-mediated immunity, leading to an increased susceptibility to infection, both bacterial and viral. Chest infections are particularly common. Any infection must be treated promptly and vigorously. Patients should be advised what to do in the event of symptoms of infection, and in some cases provision of standby antibiotics may be appropriate. Patients with recurrent infections may benefit from immunoglobulin replacement. All patients should receive influenza vaccine annually.
Other Complications
About 10 per cent of patients with myeloma develop primary amyloidosis. The kidney is usually affected, with deposition of amyloid in the glomeruli leading to generalized proteinuria and the nephrotic syndrome. Peripheral neuropathy (particularly carpal tunnel syndrome), congestive cardiac failure and involvement of skin, muscle and joints may also occur.
Peripheral neuropathy may also occur in myeloma patients without amyloidosis.
A very high paraprotein level, particularly of IgA, may result in hyperviscosity syndrome, with headaches, visual disturbance and loss of concentration. This is treated by plasma exchange and chemotherapy must also be started promptly.
Rare complications include skin manifestations, coagulation defects, fever of unknown origin, and involvement of the central nervous system.
Finally psychological and social problems are important factors for many myeloma patients.
References
UK Myeloma Forum. Guideline: Diagnosis and management of multiple myeloma. British Journal of Haematology, 2001; 115: 522-540.
Levine SA, Perin LA, Hayes D, Hayes WS. (2000); An evidence-based evaluation of percutaneous vertebroplasty. Manag Care 9:56-60, 63. Hardouin P, Fayada P, Leclet H, Chopin D. (2002); Kyphoplasty. Joint Bone Spine 69:256-261.
Blade J, Fernandez-Llama P, Bosch F et al. Renal failure in myeloma. Presenting features and predictors of outcome in 94 patients from a single institution. Archives of Internal Medicine 1998; 158: 1889-93
Clark AD, Shetty A and Soutar R Renal failure and multiple myeloma: pathogenesis and treatment of renal failure and management of underlying myeloma. Blood Reviews, 199; 13, 79-90
Knudsen LM, Hjorth M, Hippe E. Renal failure in myeloma: reversibility and impact on prognosis. European Journal of Haematology 2000; 65: 175-181
Dammacco F, Castoldi G, Rodjer S. Efficacy of epoetin alfa in the treatment of anaemia of multiple myeloma. Br J Haematol 2001; 113: 172-9.
Jacobson DR, Zolla-Pazner S. Immunosuppression and infection in multiple myeloma. Semin Oncol 1986; 13: 282-90
Poulos AR, Gertz MA, Pankratz VS, Post-White J. Pain, mood disturbance, and quality of life in patients with multiple myeloma. Oncol Nurs Forum 2001; 28: 1163-71.