Myeloma:diagnosis complications and supportive care

Abstract

A key approach to current treatment is the rapid reduction of the myeloma clone to minimal disease levels. This approach has significantly improved outcomes but it remains critical to manage the side effects of the disease and of treatment emergent side effects. While these supportive care options are directed towards improving patient quality of life, they also have significant effect against the disease and can improve survival.

Keywords:

• Multiple myeloma
• Supportive care
• Bone disease
• Anaemia
• Thrombosis
• Zometa

Introduction

Myeloma is a malignant and clonal proliferation of plasma cells located primarily within the bone marrow. It belongs to a broader series of malignancies of plasma cells, including:

1. MGUS (monoclonal gammopathy of unknown significance), a benign condition that transforms to myeloma at a rate of approximately 1% per annum,

2. Smouldering or asymptomatic myeloma, a condition which has similar features to multiple myeloma but does not require treatment intervention,

3. Multiple myeloma,

4. Extramedullary,

5. Plasmacytomas,

6. Plasma cell leukaemia.

Diagnosis

It is interesting to consider the differences that distinguish smouldering myeloma, which is classically not treated, from multiple myeloma that requires treatment. The essential difference separating these two conditions is the presence of end organ damage, which is referred to as related organ or tissue impairment (ROTI).1^–4 This organ damage is composed of a number of different events which are described by the acronym CRAB, comprising of raised calcium, renal failure, anaemia and bone lesions. It is these organ impairments which require additional clinical consideration and management as well as the chemotherapeutic reduction in the bulk of the myeloma cell clone.5

Features of end organ damage

In the next paragraphs we will discuss each of these issues independently.

Bone disease

Mechanistically, the malignant plasma cells in the bone marrow uncouple the process of the normal bone formation from bone resorption. The net result of this is that there is an excess of bone resorption and failure of bone healing. This pathologic process results in clinical events, including pathological functions and osteoporosis. Notably, these changes also result in lytic bone lesions, which can cause bone pain and pathological bone fractures. Interestingly, the more indolent types of multiple myeloma, such as the t(11;14), seem to have more bone lesions than those with more aggressive disease such as that characterised by the t(4;14) translocation.

Renal failure

The increased bone resorption brought about by the malignant plasma cells can lead to hypercalcaemia. This in turn can cause a diuresis and precipitate renal failure as a result of concomitant dehydration and associated infection. It is, therefore, important to consider renal function in all presenting myeloma patients. Since early clinical trial results became available, the importance of hydration has been recognised; patients are now encouraged to drink >3 litres of fluid per day.6,7

Immunosuppression

Another of the key features of myeloma is immunosuppression. Here, the malignant plasma cells compete for the normal plasma cell niche in the bone marrow leading to a failure in production of normal polyclonal immunoglobulin. This puts patients at risk of bacterial infection, in particular, gram positive infections.8

Amyloidosis

One of the key potential features of myeloma is the deposition of light chains insoluble amyloid protein in the heart, kidney, gut and lung. The insoluble protein leads to abnormal function at the sites where it is laid down. In particular, this can lead to cardiac abnormalities and cardiac failure. Deposition in the kidney can contribute to renal failure. Importantly, when treating patients with autologous stem cell transplant, amyloid deposition in the gut can lead to gastrointestinal bleeding and bacterial overgrowth syndromes.

Anaemia

The marrow infiltration with plasma cells can lead to myelosuppression and low white cell counts and anaemia. In addition, the impact of the renal failure can result in low erythropoietin levels and further lower the haemoglobin levels. The main problem for patients, as a consequence of anaemia, is fatigue. This can be alleviated by therapeutic intervention with erythropoietin.

Neurological damage

There are a number of neurologic sequelae of multiple myeloma including peripheral neuropathy where the epitope of the paraprotein recognises proteins expressed in the peripheral nerves and can lead to both sensory and motor dysfunction. There seems to be a peculiar predisposition of myeloma patients to having an increased rate of B12. The cause for this is unknown.

Supportive Care

Treatment and prevention of bone disease

There is evidence of lytic bone disease in 70% of patients at presentation and this is a highly significant clinical symptom, which, if treated, is associated with improved quality of life and a reduction in the deterioration of their bones long-term. The standard treatment for lytic bone lesions is therapy with a bisphosphonate. The most clinically active of these drugs is the third generation aminobisphosphonate zoledronic acid, which, when given intravenously, can reduce rates of skeletal related events, as well as improving overall survival.9,10 This agent should be started as early as is feasible when the patient is still actively resorbing their bones. A number of guidelines suggest treatment for at least 2 years, however, more recently, a study used Zometa^® until disease progression showed that it was safe, well-tolerated and when used in this fashion was associated with markedly reduced bone disease as well as being associated with a survival benefit.

There are a number of new agents which have the potential to improve bone disease in myeloma by stimulating bone formation. These agents include the Dkk-1 inhibitor, BHQ880 and a novel bone anabolic agent, sotatercept, which is in the early stages of clinical evaluation.

There are other consequences of bone disease in myeloma, one of which being back pain occurring as a result of vertebral collapse. It is now possible to inject methacrylate resin into the site of spinal collapse and to rapidly relieve associated pain. There are two methods of doing this using either kyphoplasty or vertebroplasty, both of which seem to be clinically effective. There are a number of clinical questions about how best to use these procedures: It seems that if there are a limited number of sites of pain, these procedures can be helpful. However, the natural history of the bone pain is for it to resolve over time and chemotherapy treatment aimed at reducing the bulk of the disease should not be delayed by waiting for an appropriate time slot to carry out a procedure. As things stand currently, there is no good evidence that supports the contention that these approaches can improve either posture or restore height, lost as a result of the vertebral collapse. So these procedures should be used for people with severe pain at the sites of their vertebral collapse which can be used if appropriate.

In addition to spinal collapse, spinal cord compression is one of the most serious emergencies in multiple myeloma that can lead to spinal cord transection and paraparesis. It is, thus, important to investigate rapidly and appropriately any patient with back pain and neurological features in their lower limbs and/or loss of bladder or bowel function. These investigations should include MRI of the spine. Once the condition has been diagnosed, it is appropriate to start treatment immediately with either radiotherapy or high doses of steroids. Novel agents currently available for use in multiple myeloma lead to rapid tumour responses and the use of these agents can also be appropriate in certain settings.

Treatment of renal failure

Renal disease requires close attention to detail. It is very important to realise that, at presentation, many patients with multiple myeloma are dehydrated and require rehydration with intravenous fluids in order to prevent acute renal failure. At this point in time, as one of the common reasons for presentation is concurrent infections, blood cultures should be taken and prophylactic treatment for infection initiated. High free light chain levels also contribute significantly to the risk of developing renal failure and it is important that these are decreased as rapidly as possible.

Velcade^® is a highly appropriate treatment regime for patients with renal failure as it is associated with deep and rapid responses and is not nephrotoxic. It seems that the more rapid the reduction in the light chains the less likelihood there is of developing chronic renal failure. There are now renal dialysis membranes that can remove the light chains; clinical trials investigating the roles of these approaches are being carried out.

Management of treatment emergent side effects

There are a number of novel therapeutic options for multiple myeloma which include the immunomodulatory (ImiD) drugs, thalidomide and Revlimid^®, together with the proteasome inhibitor Velcade^®. Autologous stem cell transplant is still one of the commonly used treatments for multiple myeloma that is associated with very good responses.11

Since the introduction of novel agents for the treatment of myeloma, it has become very important to recognise and treat peripheral neuropathy. Thalidomide is associated with irreversible sensory and motor neuropathy, which relates to the total dose of thalidomide delivered. A genetic predisposition to the development of thalidomide related peripheral neuropathy has been shown, suggesting that some people are more sensitive than others. As the neuropathy is irreversible, it is important to recognise the presence of neuropathy early before it has become severe and to reduce or stop the dose of thalidomide.12 Patients should be counselled about neuropathy and told to stop or reduce the medication before they develop clinically significant symptoms, as the symptoms can deteriorate further following the cessation of the therapy.13 Once these precautions are instituted the rates of thalidomide related peripheral neuropathy fall to really quite low levels. The new more potent drug Revlimid® is not really associated with this side effect, although occasional patients can suffer this complication.

Velcade^®, a proteosome inhibitor, is also associated with peripheral neuropathy and in this case the clinical symptoms are different, as it tends to be idiosyncratic, come on rapidly, be painful and be ascending in nature. It is appropriate to reduce the dose of Velcade^® according to the manufacturer’s instructions before this occurs, but more recently, it has become recognised that there are a number of other strategies, which can reduce the neuropathy. These include weekly dosing and the use of subcutaneous rather than intravenous administration. This change has gratifyingly reduced the rates of neuropathy making the drug much more easy to use clinically. Carfilzomib is a drug that is becoming increasingly available. It is a next generation proteosome inhibitor which is not associated with the same degree of neuropathy that has been seen with Velcade®.

A further important treatment emergent side effect associated with treatment with thalidomide is venous thrombosis.14,15 Very high rates can be seen when thalidomide is used with steroids and chemotherapy and a genetic predilection is also well recognised now. This side effect needs careful management and a unifying guideline is available. In summary, this relies on identifying high risk individuals and treating them with anticoagulants and for standard risk patients to use aspirin.

High dose melphalan and autologous stem cell rescue are still clinically important. However, it should be recognised that high dose melphalan, an effective component of the treatment of multiple myeloma, is associated with clinically significant myelosuppression, mucositis and diarrhoea and it is important to manage these side effects adequately. Patients are also at risk of infection and appropriate antibiotics selection is appropriate. Following discharge from hospital, patients require prophylaxis against shingles and pneumocystis pneumonia and the use of granulocyte colony-stimulating factor given after the autologous transplant can improve in engraftment and reduce hospital stay.