Skull x-ray showing multiple deposits of myeloma causing the picture: ‘pepper pot’ skull
Multiple myeloma is a cancer of the plasma cells (derivative cells of the lymphoid system and normally a part of the bone marrow mix of cells – their normal function is to make antibodies against various specific foreign protein antigens). Specifically, each patient’s plasmacytoma/myeloma has arisen from one malignant clone, testified by the fact that the immunoglobulin/antibody secreted from that myeloma is identical from each cell; indeed, this is the best evidence in the subject of Oncology that cancer does have a single cell/clone origin. Where the clone of cells remains localised to one site we refer to the disease as plasamacytoma, whereas, when there are many lesions due to spread of the malignancy to multiple bones and marrow, we refer to the disease as multiple myeloma.
In 56% of cases of myeloma, the immunoglobulin is IgG, it is IgA in 27%, IgD in 1.5% and IgM in 0.2%. In 17% of cases, there is no whole immunoglobulin secreted but a Bence Jones protein (a part of the immunoglobulin molecule, specifically the light chain part) is detectable in the urine. The myeloma is then termed IgG myeloma, IgA myeloma etc.
Occasionally, there occurs in a normal bone containing normal active bone marrow, a malignant clone of plasma cells that grows as a single tumour and causes bone destruction such that the patient comes to clinical attention with bone pain; an x-ray at this time shows destruction within the bone; on further staging (see below), there is no sign of any other disease elsewhere in the body. Such a single bone lesion is known as a solitary plasmacytoma and is treated as such – viz. a solitary tumour (see below).
However, there is no doubt that such single clones of malignant cells/plasmacytomata often seed off cells, and this frequently occurs early in the natural history; these take hold and grow in the other bones of the body and permeate the marrow. Then the disease is called multiple myeloma. Multiple myeloma is more frequently encountered than single plasmacytoma in clinical practice.
Exposure to ionising radiation predisposes to myeloma and the Japanese nuclear weapon survivors have an increased incidence of this disease, as did the early generations of radiologists. Other predisposing causes are not well established.
Malignant plasma cells
Incidence and predisposing factors
Multiple myeloma is a disease caused by a malignant clone of plasma cells; the lineage of bone marrow cells that physiologically have the function of making antibodies (the immune serum proteins that attach to specific foreign proteins and allow their immune destruction). There are several types of antibody, all of them immunoglobulins (Ig A,D,E,G, and M) but only IgA,D,G, and M, need to be considered in this context.
Multiple myeloma accounts for 1% of cancer in the UK with 3000 cases per year, with a slightly higher incidence in the Afro-Caribbean population. There is a slight male preponderance of the disease. The mean age of clinical presentation is 70 years and the incidence seems to be slightly increasing in recent years.
The photo shows a cluster of malignant plasma cells from a bone marrow sample, taken from a patient with myeloma and viewed (after staining of a smear on a microscope slide) under the high power of a microscope.
Symptoms & diagnosis: Myeloma and plasmacytoma
The most common cause of presentation to the doctor is bone pain, usually pain in the spine where the disease has weakened the vertebra and caused painful and sometimes collapsed vertebrae, pinching or crushing the exiting nerve roots from the spinal canal. Sometimes, the collapsed vertebrae may compromise the integrity of the spinal canal itself causing pressure on the spinal cord and leading to weakness in the legs, which is a serious development that is always taken very seriously.
Alternatively, as most of the marrow containing bones are ‘softened’ by the myeloma process, the patient may present with a fracture of a long bone (e.g. the upper arm bone or leg bone), following minor trauma.
Other less common presentation symptoms relate to anaemia due to the disease ‘over-running’ the bone marrow (and an increased bleeding tendency may have the same origin) or kidney failure (a well recognised secondary phenomenon in this disease).
Metabolic complications account for the minority of cases and include a very high serum calcium (hypercalcaemia) or a hyperviscosity state due to an excess circulating IgM, both these events causing drowsiness and general ill health. The excess of IgM occurs in a variant disease called Waldenstrom’s macroglobulinaemia.
Lastly and very importantly, these patients are very immune deficient and are at high risk of infection. Indeed, they may present with a serious infection.
Lateral skull X-ray showing multiple lytic deposits.
The basic peripheral blood count usually demonstrates an anaemia and the erythrocyte sedimentation rate (ESR, a basic test of active disease ongoing in the body) is usually very elevated due to the coating of the erythrocytes (red cells) with immunoglobulin.
An immunoglobulin electrophoresis performed on the blood serum gives a characteristic picture in most cases. There is a very high spike on the electrophoretic strip indicating an over-expression in the serum of one protein type, (which is, of course, the immunoglobulin that the malignant clone of cells makes) and is often a suppression (immune paresis) of the other immunoglobulins.
The abnormal immunoglobulin is referred to as the abnormal paraprotein and the level of this paraprotein can and will be quantified by the doctor; serial measurements of this level assist the monitoring of the disease.
The immunoglobulin molecules are made up of two component heavy chains of peptides and two light chains; in myeloma, there is an overproduction and mismatch of light chain and heavy chain synthesis and an excess of the light chains, which are of sufficiently low molecular weight that they pass through the kidneys unimpeded and appear in the urine. They are detectable in the urine by a relatively simple test, and this test for such proteins is called the Bence-Jones protein test after the man who observed it first; a positive test is almost pathognomonic/diagnostic for myeloma. Nowadays, it is routine that the levels of free light chains in the serum can also be measured and the serial assessment of these levels of the abnormal paraprotein or free light chains help the doctor in the serial assessment of the disease process once the diagnosis has been made.
A skeletal survey refers to the x-raying of the entire skeleton to look for bony lesions and is performed in the work up of all myeloma cases; interestingly, isotope bone scans under-read the situation in myeloma and are considered inferior diagnostic tests to plain x-rays. In a typical case, there are multiple lytic (i.e. black on x-ray) lesions in multiple bones.
For example, the skull is very typically involved and where this is heavily diseased, it has multiple holes in it on lateral skull x-ray and the term ‘pepper pot skull’ is used in the medical profession, as the skull appears with the rounded holes, such as is seen in the top of a pepper pot – the photo shows a typical ‘pepper-pot’ skull – a side x-ray view of a myeloma patient’s skull showing the many ‘punched-out’ lytic skull lesions of myeloma). These are truly multiple plasmacytomata.
The last and most important test is the bone marrow examination, the discovery of abnormal/malignant plasma cells in the bone marrow proves for sure that the diagnosis is that of multiple myeloma (the photo in the ‘Incidence’ sub-section of this myeloma section shows a typical example of the marrow appearances of myeloma in the bone marrow).
It should be noted that routine scanning of internal organs such as abdominal contents is not routinely helpful in this disease, because myeloma rarely affects organs outside the bones although soft tissue plasmacytoma (particularly in the head and neck region) are well recognised.
To establish the diagnosis of plasmacytoma, the doctor has to prove that there is plasmacytoma on biopsy of a lesion.
To prove the diagnosis of myeloma, there has to be bone disease, the bone marrow biopsy must contain at least 30% of malignant plasma cells and there is the monoclonal spike of the paraprotein on protein electrophoresis of the serum (indicating the overproduction of clonally derived immunoglobulin) or free light chains (see above).
There is a group of patients who are suspected as having early or incipient myeloma with a low serum concentration of monoclonal immunoglobulin (the paraprotein), whose bone marrow contains less than 10% of plasma cells and whose skeletal survey shows no bone lesions; such patients do not qualify for the diagnosis of myeloma but are referred to as ‘monoclonal gammopathy of uncertain significance’ (or MGUS).
These patients and those with bone marrow infiltration of 10-30% of plasma cells (also called ‘smouldering myeloma’), as well as all the ‘solitary plasmacytoma’ patients must be kept under careful observation as multiple myeloma may well develop in the future in all these categories.
In patients who ‘qualify’ as suffering multiple myeloma, the prognosis depends on several other factors: patients who present with anaemia, kidney failure, a bone marrow with a very high infiltrate of plasma cells (or worse a plasma cell leukaemia on the peripheral blood film) and/or those with a very high serum paraprotein level, all have a worse outlook for survival than those who do not demonstrate these characteristics on presentation. The foregoing relates to the time honoured Salmon staging system, which concentrated on these clinical features to give a forecast/prognosis as to how any patient is likely to fare.
More recently, other factors that can be ascertained at the time of diagnosis have been demonstrated to impact on the prognosis. For example, a high serum level of beta-2-microglobulin is an independent marker of a poor prognosis. Anaemia (as mentioned above), high blood calcium and low serum level of albumin are also of poor prognostic influence. Atypical plasma cell appearances in the bone marrow (e.g. in terms of mitotic activity) are poorly prognostic.
Further, cytogenetic abnormalities (structural genetic abnormalities detectable in the genes of the malignant plasma cells) have been shown to be prognostic e.g. gene expression profiling is likely in the future to further refine the classification of myeloma in terms of prognostic impact.
Treatment and outcomes: Myeloma and plasmacytoma
X-rays of neck showing a myeloma deposit affecting a mid-cervical vertebra (left panel). After surgical stabilisation and radiotherapy (metal surgical stabilisation device and radiotherapy portal shown in right panel) a good result ensued.
Some patients with early or smouldering myeloma can be watched carefully without therapy and their long term survival will not be jeopardised if the careful watch policy is assiduously carried out such that disease progression is picked up early and treatment instituted at the appropriate time. The reason for this is that the usual types of chemotherapy for this disease are not curative and the life prolonging properties of chemotherapy are as useful at a time when the patient is symptomatic as early in the course of the disease (see below).
The choice of drug therapy in myeloma is based on the patient’s age, performance status and renal function – all of which influence the decision as to whether the patient is suitable for autologous stem cell therapy; a procedure that follows very high dose chemotherapy, itself used as a part of curative chemotherapy in appropriate patients. Where such high dose chemotherapy will never be utilised (e.g. due to old age and frailty) then simple chemotherapy with alkylating agents such as melphalan, coupled with steroids or thalidomide is often used first but in patients who will later be harvested of their blood/marrow stem cells for the high dose procedure, the doctor will try to avoid alkylating agent chemotherapy.
Induction therapy often involves immuno-modulatory drugs (IMID’s) such as thalidomide (or one of its derivative drugs e.g. lenalidomide).
Proteosome inhibitory drugs such as Bortezomib add to the systemic induction therapy in many protocols and often these induction agents are coupled with steroids , as steroids are cytotoxic against all lymphoma lineage cancers including myeloma
Daratumumab is a targeted monoclonal antibody that has high anti-myeloma activity in relapsed disease and trtails are in progress to see if it is active in earler disesase stages. It was approved after pivotal trial called SIRIUS, for myeloma t hat has become refractory to other therapies and trials are in progress to find its place in earlier therapy protocols. It is certainly a powerful addition to the therapy armamentarium.
Particular care is needed when the patient has presented in renal failure, first reversing the factors that are conspiring to worsen the renal condition (e.g. high uric acid, calcium, dehydration, infection etc).
Systemic therapy (often without chemotherapy) is usually continued until the patient has achieved a ‘plateau’ phase (this is when the immunoglobulin marker has achieved a partial remission and remained at this level for 3 months). Following this maximal response to therapy the patient either proceeds to high dose chemotherapy plus the autograft (nowadays with peripheral blood stem cells) or maintenance therapy with lenalidomide of other, or a careful watch policy. There are now data supportive of maintenance therapy.
The former (high dose-chemo followed by autograft) is the more aggressive approach and reserved for those who are fit enough to withstand the procedure (the potential advantage of which is the hope of eradication of the disease). In patients who have disappearance of their serum immunoglobulin marker following this procedure, there is a real hope of long disease-free life.
In this context, the use of bisphosphonate therapy should be discussed. The bisphosphonates are an interesting group of compounds, which attach to bone and make it less likely to be broken down by any disease process, particularly here the bony absorption by myeloma. It is now standard practice to give bisphosphonate therapy (either intravenous pamidronate ) in the maintenance period, so long as the renal function is good.
Lastly it should be stated that local radiotherapy has a very important role in the therapy of multiple myeloma in controlling bony pain. The patient, who comes with low back pain or limb pain because of destructive plasmacytoma in the particular bone, will be most quickly out of pain if he receives local radiotherapy to that bone. Radiotherapy has an important and potentially curative role in the therapy of isolated plasmacytoma.
In the photo, the left panel shows a side view of the neck of a patient with myeloma. The bones are so thin that it is hardly possible to make out the cervical vertebrae and one of them has crush fractured. In the right panel we see the same side view of the cervical spine after therapy. Firstly, the bones are now stronger (more radio-opaque and hence more visible on the x-ray), this is due to drug therapy and local radiotherapy to the neck/cervical spine and secondly a spinal stabilisation operation has been performed and we can see the metal stabiliser in situ. Kyphoplasty is an alternative therapy for the vertebra which is collapsing due to myeloma.
What to do if the disease recurs despite the foregoing?
In other patients, maintenance therapy (e.g. lenolidomide) is given, until the marker rises or some other event (e.g. bone fracture due to local progression) prompts further therapy. At this time, the patient is treated again, perhaps with the same therapy if first remission was lengthy, or alternative drugs (combinations of active cytotoxic drugs or immuno-modulatory drugs such as thalidomide or bortezomib) will be brought into the therapy. Steroids are also useful. New drugs that will be considered include the SMART drugs: Carfilzomib and pomalidomide – both bringing some new dimensions to the therapy of refractory myeloma.
Next generation sequencing of the refractory myeloma case may bring new light to this difficult situation as occasionally ‘druggable’ mutations may be found; the chance is low but worth the test.
For the better prognosis patients who have high dose chemotherapy and a peripheral stem cell transplant, there is a 50% survival of approximately 6 years, with some patients living much longer, disease free.
Dr P N Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced Genomics; tel +44-2076311632).
Overall, this is a rare disease and a population based screening programme is not indicated.
However, if a patient is found (usually incidentally) to have a slightly raised level of a (monoclonal) immunoglobulin in the blood on some routine blood test (see monoclonal gammopathy of unknown significance below) then this individual requires to be followed carefully with repeat testing of the blood immunoglobulin levels over time, and further tests such as bone x-rays and bone marrow sampling if the levels rise.