MYELOMA — THE INTEGRAL ROLE PLAYED BY THE PROFESSIONAL NURSE

INTRODUCTION Many of the clinical features and biochemical abnormalities of myeloma were described more than 100 years ago, and in the late stages of the disease there should be little difficulty in making the diagnosis. Patients typically have severe bone pain associated with lytic lesions in ^ t h e skeleton, while anaemia in the presence ^ A ) f a high erythrocyte sedimentation rate, progressive renal dysfunction and serious infections combine to produce a distinctive constellation of symptoms and signs. Despite this, a number of cases are still missed because many individual practitioners have limited experience, having seen few examples during their careers or through not maintaining a sufficiently high index of clinical suspicion to recognise the telltale findings. Understandably, this deficiency is transmitted to nursing and paramedical professionals since less attention is paid in their training to the diagnosis of this disease and consequently the role of these colleagues in management is significantly under-utilised. There are sound reasons for doctors and nurses alike to remain alert to this diagnostic possibility because, once established, many of the initial ^abnorm alitie s can be relatively easily ^ k v e r s e d , thereby improving the quality of Tife. Furtherm ore, using the appropriate combinations of chemotherapy and radiotherapy, survival can be extended from 7 to approximately 30 months. While these achievements are notable, they leave much to be desired when the outlook, especially in younger patients, is compared to other haematologic malignancies, such as Hodgkin’s disease, where cure has become the aim of treatment. Not surprisingly, therefore, much research and development is in progress to define the role of newer treatment options that include fractionated half-body irradiation, biologic immune response modulation with interferon and, particularly, high doses of cytotoxic drugs in combination with whole body radiotherapy as a prelude to bone marrow transplantation. To bring perspective to current management and to emphasize the role of the professional nurse, the more important clinical and laboratory features are briefly reviewed.

IN TR O D U CTIO N Many of the clinical features and biochemical abnormalities of myeloma were described more than 100 years ago, and in the late stages of the disease there should be little difficulty in making the diagnosis.Patients typically have severe bone pain associated with lytic lesions in ^the skeleton, while anaem ia in the presence ^A ) f a high erythrocyte sedimentation rate, progressive renal dysfunction and serious infections com bine to produce a distinctive constellation of symptoms and signs.Despite this, a num ber of cases are still missed because many individual practitioners have limited experience, having seen few examples during their careers or through not m aintaining a sufficiently high index of clinical suspicion to recognise the telltale findings.
Understandably, this deficiency is transm itted to nursing and paramedical professionals since less attention is paid in their training to the diagnosis of this disease and consequently the role of these colleagues in management is significantly under-utilised.
There are sound reasons for doctors and nurses alike to remain alert to this diagnostic possibility because, once established, many of the initial ^a b n o rm a litie s can be relatively easily ^k v e r s e d , thereby improving the quality of Tife.Furtherm ore, using the appropriate com binations of chem otherapy and radiotherapy, survival can be extended from 7 to approxim ately 30 months.While these achievements are notable, they leave much to be desired when the outlook, especially in younger patients, is com pared to other haematologic malignancies, such as H odgkin's disease, where cure has become the aim of treatm ent.Not surprisingly, therefore, much research and development is in progress to define the role of newer treatm ent options that include fractionated half-body irradiation, biologic immune response m odulation with interferon and, particularly, high doses of cytotoxic drugs in com bination with whole body radiotherapy as a prelude to bone marrow transplantation.
To bring perspective to current management and to emphasize the role of the professional nurse, the more im portant clinical and laboratory features are briefly reviewed.

D IA G N O SIS
The accum ulation of plasm a cells is the

Abstract
Myeloma is a malignancy o f plasma cells which are terminally differentiated B-lymphocytes.The diagnosis may he made incidentally at routine blood testing, when an abnormality is fo u n d in the plasma proteins on electrophoresis.More usually the patients are symptomatic, with bone pain, anaemia, evidence o f renal failure, or the metabolic abnormalities associated with increased plasma calcium and urate levels.Effective treatment will extend survival from 7 to approximately 30 months and at the same time improve the quality o f life.Treatment is multidisciplinary, prominently involves the professional nurse and may arbitrarily be divided into two stages.Firstly, reversible lesions, such as dehydration and plasma hyperviscosity must be corrected, hypercalcaemia and hyperuricaemia improved and, i f necessary, renal dialysis undertaken.Secondly, but o f equal importance, is the need fo r specific therapy to be directed against the tumour itself, and both cytotoxic agents and irradiation have an important role to play.More recently, newer approaches have included high dose chemotherapy and bone marrow transplantation.
end stage of uncontrolled overgrowth or clonal expansion of B-lymphocytes.The tum our cells have a distinctive m orphology, with an eccentric nucleus and often abundant cytoplasm containing a high concentration of protein, leading to intense blue staining when the Rom anowsky dyes are used (Figure 1).Normally, a wide range of antibodies is produced by cells of the immune system, thereby providing protection from invading organisms.However, when malignant change arises in a single cell and leads to myeloma, large am ounts of a particular im m unoglobulin are synthesized, in contrast to the situation in health.It is this change th at is recognised in the protein electrophoretic pattern (Figure 2).Yet an alternative feature is the presence of light-chains from the abnorm al imm unoglobulin, known as Bence Jones protein, in the urine.The com bination of an abnorm al concentration of plasma cells, as for example in the bone marrow, combined with the presence of a paraprotein peak in the plasma are the two cardinal features for diagnosis (Table 1).
A num ber of consequences follow disease progression, such as the development of lytic lesions in bone, bone m arrow failure with development of anaem ia and throm bocytopenia, marked increase in whole blood viscosity with disturbances in mental function and a variety of metabolic changes, of which elevation in plasm a calcium and uric acid levels are the most typical.A word of w arning is appropriate since many of these findings can occur in other diseases, with m etastatic cancer affecting the skeleton, hypercalcaemia in tuberculosis, and elevated uric acid in prim ary gout.It is therefore im portant th at as many of the individual features as possible are combined to make a positive diagnosis of myeloma.those with high bulk, or stage III, and to recognise that between these two extremes exists a group defined by their being unable to fulfill the above criteria (Table 2).

PR O G N O STIC FA C TO R S
A part from the need to establish an accurate diagnosis and then to define the extent of disease present in the patient, other features have been recognised that have an influence on outcome of treatm ent; these variables are called predictive or prognostic factors.In general terms, the younger the patient with myeloma the greater the likelihood of high bulk disease, extensive skeletal damage and associated metabolic disorders or renal failure.Furtherm ore, marked elevations in serum lactic dehydrogenase level and a particular serum protein known as beta-2microglobulin have significant correlation with poor outcome.In the laboratory there are other measurements useful in recognising poor risk patients that include cytogenetic abnorm alities and the fraction of dividing cells in the tum our, which can be determined with radioactive isotopes; this is known as the labelling index.
CLIN IC A L FEA T U R E S At the one extrem e are localised areas of tum our, known as plasmacytomas, and at the other is active widespread disease that gives rise to the characteristic symptoms and signs.An intermediate pattern may be recognised in which the neoplastic process advances slowly, and these individuals are said to have the indolent or smouldering form.At the benign end of this indolent variant are some individuals who have only an abnorm al im m unoglobulin pattern on serum electrophoresis, which remains stable for years.The latter entity is described as m onoclonal gam m opathy of undetermined significance, and while some of these patients progress to myeloma, others die without undue change in the protein pattern taking place.
The most striking symptom of active or advancing disease is that of bone pain.Typically, this occurs in the axial skeleton The amount o f disease bulk has a direct bearing on response to therapy and survival.I t follow s that all patients should be classified according to currently acceptable international criteria.Stages are subclassified as A or B according to renal function: and many patients com plain of it being worse at night.The underlying abnorm alities are usually found to be lytic lesions, sometimes with a pathological fracture through the involved area, although there may be diffuse loss of bone or osteoporosis resulting in compression fracture of the vertebral bodies.
Renal dysfunction may occur for a num ber of reasons, of which the most im portant is that of dehydration.Associated disturbances are attributable to increases in serum calcium and uric acid levels.The kidney may be directly infiltrated with plasma cells or deposition of a material known as amyloid.A particularly interesting disturbance arises when part of the imm unoglobulin molecule, the light-chains or Bence Jones proteins, is deposited in the tubules, and this occurs usually when these fragments are excreted in the urine.It is im portant to appreciate that many of the factors contributing to abnormalities in renal biochemistry can be reversed and the older concept that all such patients of necessity have a poor outlook is no longer acceptable.
Haematologic abnorm alities typically are the presence of mild to m oderate degrees of anaem ia, with norm ochrom ic normocytic red cells.The usual cause is bone m arrow infiltration by the tum our, but there may be associated shortening of red cell survival or haemolysis.
T hrom bocytopenia may occur, leading to haem orrhage from the gastrointestinal tract, and this may be aggravated by impaired platelet function in patients with severe degrees of urem ia and increase in the blood urea level.The marked decrease in norm al gam m aglobulin leads to immunologic incompetence, with bacterial infections that may be recurrent and most frequently involve the lungs.
Neurologic com plications follow vertebral collapse or extradural spinal cord deposits of the tum our cells.Less frequently, peripheral neuropathy may be associated with amyloid and on rare occasions solitary plasmacytomas are found within the brain substance.
The raised plasma protein levels give rise to hyperviscosity and accounts for the marked increase in erythrocyte sedimentation rate, com pounds the degree of renal dysfunction and typically leads to severe degrees of mental confusion.

^K j r s i n g a s p e c t s
There are a num ber of areas where the academically orientated nursing professional has an im portant role to play.
It is necessary to strongly emphasize that in the contem porary context there is emerging a recognition that contributions from these colleagues are seriously and significantly under-utilised.Strenuous efforts are being made, particularly in the United States of America, to harness this resource by developing career structures or ladders that will bring equivalence at senior faculty level to the more traditional routes for prom otion into adm inistration or education.This is the concept of the Clinical Nurse Specialist, and it is not only appropriate but im portant and somewhat overdue that similar consideration and efforts be made by local statutory bodies in this country.M ore specifically, and in the outpatient clinic, strong psychological support is derived by integrating medical and nursing services into a multidisciplinary health care team.Not infrequently the medical profession are inadequately sensitive to patient anxieties and many questions about treatm ent details, side effects and even survival are directed to the sister involved with mom ent-to-m om ent care.These concerns range from such simple procedures as red cell transfusions to adm inistration of the often highly complex chem otherapy programmes and, more recently, to irradiation or even bone m arrow transplantation.An ideal opportunity to generally reassure the patient or organise referral to the social worker on issues that range from loss of earning power to care for the family arise when blood or urine samples are being collected.As part of the modern treatm ent programmes, blood transfusions may be replaced by the adm inistration of recom binant human erythropoietin.Since these protocols are carried out in the outpatient clinics and involve regular data collection it is entirely appropriate that nursing colleagues are equal co investigators in such developmental work and share the recognition that is derived from presentation at meetings and publication of trial results.
At least in our departm ent there is yet a further area where the Professional Nurse plays an im portant role and is delegated direct responsibility for management decisions.This is in the use of therapeutic apheresis to reverse hyperviscosity by means of continuous-flow blood fraction separation (Figure 3), and this would exemplify academic expertise com m ensurate with the specialist or senior specialist in the medical hierarchy, corresponding to the Clinical Nurse Specialist referred to above.In this technique the sister establishes a closed vein-to-vein circuit that includes the centrifuge in the system.The circulating blood is split into its fractions, based on density, and the red cells simply return to the patient, while the abnorm al plasma containing the paraprotein is discarded.Shortly before the patient receives his own red cells back, an electrolyte solution containing album in is mixed so that approxim ately norm al blood viscosity is re-established.The symptoms attributable to poor perfusion of the microcirculation in the patient may result in striking improvement in cerebral function, sometimes whilst on the machine, but invariably within the first 24 hours.
A nother area of responsibility is nursing management of the hospitalised patient.Here, wide ranging responsibilities includes m onitoring of fluid balance during treatm ent of hypercalcaemia with forced diuresis, requiring an awareness of the need to replace potassium and magnesium, regular charting of responses in plasma calcium level and ensuring that neither dehydration nor fluid overload occur.
There are additional im portant aspects to nursing the patient with bone pain due to lytic lesions, and an understanding of the role played by local radiotherapy and the judicious use of analgesia go a long way tow ards ensuring patient comfort.Unlike the misconception that nurses exist simply to carry out medical instructions, we strongly hold the viewpoint that optim um care of patients, those with myeloma providing an excellent illustration, requires a multidisciplinary health care team.In this particular context it is difficult to overestimate the role of the academically orientated and trained nurse who has kept her expertise up-todate.We consider these individuals to be specialists in their own right and it is appropriate that their responsibilities extend to the adm inistration and monitoring of cytotoxic drug therapy.There is a need to have a thorough knowledge of the protocols currently in use, a familiarity with the effects and com plications of cytotoxic drugs and be able to supervise the adm inistration of an optim al anti-emetic regimen th at will markedly contribute to patient com fort and safety.
As though these challenges were not enough, the role of colleagues who remain at the forefront of nursing and medical advances should extend to the guidance of ju n io r medical and nursing staff, particularly registrars rotating through departm ents, whose knowledge of complex m anagem ent schedules is often woefully inadequate.There is a need to interact confidently with clinical and laboratory specialists in haematology and also to provide the effective co-ordination of support that may extend to the provision Fig. 3. BLOOD F R A C TIO N SEPA R A T O R This instrum ent -the Cobe 2997 -exemplifies the sophisticated technology that has made it possible to remove the patient's plasma with its high concentration of abnorm al im m unoglobulin and to replace this with an electrolyte solution con taining album in.This m ethodology is highly efficient and will return plasma and whole blood viscosity to norm al, with objective im provem ent in cerebral function often strikingly evident within 12 hours.of allogeneic platelets, therapeutic plasma exchange, haemodialysis or intubation and assisted ventilation.Superimposed upon these aspects of comprehensive m anagem ent is the additional need to be vigilant for the onset of serious and often life-threatening infections, shock, collapse in blood pressure, deterioration in renal failure and development of disseminated intravascular coagulation.
It is our cumulative experience that optim um patient care is most efficient and cost-effectively achieved where a multidisciplinary group exists that com fortably accom modates the academic aspirations of the professional nurse as well as paramedical professionals.We do not consider it any longer appropriate to view nursing colleagues, most specifically the academically-orientated professional nurse, as the handm aiden of the physician!CON V ENTIO NA L TH ER A PY Currently, most regimens would employ an alkylating agent in the form of melphalan in com bination with prednisone.This simple approach remains the cornerstone aganst which other treatm ent options are measured.In general terms, the addition of further drugs has done little to improve the median survival, which has been extended from 7 to about 30 m onths with the twodrug programme.
Response in patients can be monitored by improvement in the stage and most im portantly in the perform ance status or K arnofsky rating.However, a num ber of individuals will be completely resistant or refractory to chem otherapy, and such a situation is associated with short survival.A further alternative is that relapse may occur after initial response and in these circumstances the tum our cells may change their characteristics and are said to have undergone escape by m utation.In both of these situations the treatm ent options are now more restricted and involve secondline drugs, generally with less satisfactory disease control or survival.
O ur own experience, based on the undoubted benefits of irradiation to local lesions, has been to treat larger parts of the body with radiotherapy.The upper or the lower half could be treated sequentially, and this has been shown to be effective for patients who have relapsed on chem otherapy.It is currently not clear whether such systemic radiotherapy will offer any advantages over conventional chemotherapy.

CO M PL IC A T IO N S OF CON V ENTIO NA L TH ER A PY
A part from the failure to respond or relapse in some individuals, the use of either radiotherapy or chemotherapy is associated with significant side effects.Thus, worsening of bone marrow function may lead to degrees of neutropenia or throm bocytopenia, restricting the am ount of treatm ent that can be given and thereby com prom ising tum our kill.In addition, there may be adverse effects of the treatm ent itself, including the emergence of preleukaem ia or acute nonlymphoblastic leukaemia.

D EV ELO PM EN TA L A PPR O A C H E S TO M A N A G EM EN T
Because of the difficulties with chem otherapy, many studies have been undertaken exploring alternative options.
Two rather different approaches are currently the subject of investigation.In the first of these is the use of recom binant hum an alpha interferon.This interesting molecule is produced by viruses and one of the effects noted is suppression of cell division, including the bone marrow.Based on that observation, such biologic immune response m odulation has been attem pted in patients with myeloma.Initially, studies were carried out on patients who had late or end-stage disease, with poor results.M ore recently, it has been suggested that interferon used early, either alone or preferably in com bination with one of the established drug regimens, may achieve better results.Early reports are encouraging, but have not as yet been confirmed.
The other alternative is the use of escalating doses of single agent chem otherapy, usually in the form of m elphalan, th at would otherwise be lethal because of the way in which it produces irreversible bone marrow damage.With the wider availability of bone marrow transplantation, it has become practical to use the very large quantities of the alkylating agent, often in com bination with radiotherapy, and then to rescue the patient from the myelotoxicity with either allogeneic or autologous bone marrow transplantation.This treatm ent option is of undoubted benefit, but is limited somewhat by the scarcity of transplant centres and the fact that many of the patients are elderly so that the conditioning regimens needed to eradicate the disease are associated with substantial m orbidity and mortality.Nevertheless, particularly in the younger patients, this remains the single most interesting addition to the therapeutic options for treating patients with myeloma.
As with nursing in general, each of these programmes is critically dependent upon direct involvement of our professional colleagues.In biologic immune response modulation is the need to adm inister the agent, m onitor the influenza-like syndromes that occur, and constantly be on the look-out for serious central nervous system signs and symptoms.In bone marrow transplantation, nurses play a role in the theatre, collecting marrow and subsequently caring for the imm unocompromised patient in the protected environm ent.The latter units, whilst having sisters-in-charge, are best supervised by an academic colleague corresponding to the Clinical Nurse Specialist in the American system.

QUALITY OF LIFE
There is an im portant ethical and moral responsibility to fully inform the patient of the diagnosis and w hat the outcome of no treatm ent or the best conventional treatm ent is likely to be.Only against this background is it possible to obtain the informed consent and co-operation from the patient and family, without which comprehensive m anagem ent cannot be undertaken.Thus, with even the established tw o-drug com binations, patients may experience many years of good quality life, particularly when attending a multidisciplinary clinic where all the various problems with the disease itself and the treatm ent can be anticipated and to a large extent circumvented.There does, however, come a time when relentless disease progression and failure to respond to drugs raise a question about persisting with therapy, particularly in the face of extensive skeletal disease damage, increasing age or failure of the patient or his family to give consent for extending treatm ent.Under the circumstances a more conservative approach may be necessary.
At the other extreme is the need to recognise that highly aggressive tr e a tm e n t^^ options may be urgently needed.Here, increasing doses of melphalan in com bination with radiotherapy and then bone marrow transplantation exemplify current practice and will require some weeks in isolation, with the patient at risk from serious com plications, including death.The appropriateness of this therapy depends upon the perform ance status of the patient and, to a very large extent, age.In the younger patient whose outlook for survival would be poor and who is, in any event, better likely to tolerate an aggressive management regimen, the likelihood of improved quality and quantity of life after the risks of the transplantation have passed is a compelling reason to follow this route, particularly in the light of steadily improving results.SU M M A R Y AND CO N CLU SIO N S Two comments are appropriate.£ Firstly, there is the haematologic * observation that quality and quantity of life can be improved by conventional treatm ent.The best results are obtained from a multidisciplinary health care group and considerable experience is necessary to select the option most likely to be of greatest benefit to any particular individual.However, even under these circumstances survival is modestly prolonged and modern treatm ent options must be appreciated as extending to biological immune response m odulation and most particularly to the use of high doses of chemotherapy, often in com bination with radiotherapy, followed by bone marrow transplantation.
The second point is equally im portant.This is that there is an integral part for the professional nurse to play in the multidisciplinary health care team.We no longer consider it appropriate for these colleagues to occupy any position other than an active role in all aspects of management.M ost particularly is our viewpoint that the fulfillment of nursing ideals and academic aspirations must be recognised by establishing a specific career

Fig. 2 .
Fig. 2. PLA SM A E L E C T R O PH O R E S IS In contrast to the norm al pattern, shown in the left-hand panel, the large am ount of abnorm al imm unoglobulin, which is known as paraprotein, is strikingly evident in the right-hand panel (arrow).

TABLE 1 Diagnostic Criteria in Myeloma This malignancy is most reliably diagnosed when the accepted criteria are observed. It is noteworthy that a number o f the associated features occur in other diseases and care should be exercised before attributing them to this immunoproliferative dis order. A confident diagnosis will be supported by any two major criteria, one major and two minor criteria, or different combinations thereof MAJOR CRITERIA 1. Plasmacytoma on tissue biopsy 2. Bone marrow piasmacytosis > 30% 3. Monoclonal immunoglobulin peak -IgG > 35 g/L -IgA > 20 g/L -■ Urinary light chain excretion > 1 g /24 hours MINOR CRITERIA 1. Bone marrow piasmacytosis between 10 and 30% 2. M onoclonal immunoglobulin peak less than for major criteria 3. Lytic bone lesions 4. Residual normal or polyclonal immunoglobu lins reduced -lgM < ,5 g/L , -IgA < 1 g/L -I g G < 6 g/L
C urationis Vol. 12, Nos. 3 & 4, D ecem ber/D esem ber 1989