Scand J Haematol 1985;35:4-9

Key words: macroglobulinaemia - Bence Jones proteinuria - benign monoclonal gammapathy - myeloma

Some reflections on myeloma

Jan Waldenstrom

University of Lund, Allmanna Sjukhuset, Malmo, Sweden

History It is rather interesting that the history of myeloma should lead back to a single patient who, for one reason or another, provoked an interest in his disease that led to several publica- tions between 1846 and 1850. We know the name o f the patient, and that he was born in 1801 and died on the 8th of January, 1846. He was a well- to-do grocer and the cause of this death was certified as ‘atrophy from albuminuria’. Dr. Thomas Watson saw the patient for the first time in the autumn of 1845. He then called Dr. William Maclntyre, who examined the patient and noted that he had severe bone pain with pathological fractures. The patient suffered from oedema and MacIntyre studied the effect of heating his urine (1). He noted that on heating the precipitate redissolved and also that pre- cipitation started at lower temperatures than was necessary for albumin to coagulate. It is thus clear that Bence Jones’ protein should really be called MacIntyre’s protein. As a matter of fact, Bence Jones wrote in one of his papers (2) that MacIntyre, being in attendance on the case with Dr. Watson, had two days previously first observed the peculiar reactions of the urine, which really applies to the protein now called Bence Jones’ and is much more characteristic than the findings of Bence Jones and published by him. McIntyre described the post mortem examination in great detail and the condition of the bones fitted well with the diagnosis ‘mollities ossium’. Some material from vertebrae and a rib was sent for histological examination to Dr. Dalrymple, a surgeon at the Royal Ophthalmic

Hospital and a member ,o f the Microscopical Society. He gave a description of the microscopi- cal findings that fitted in very well with the diagnosis of malignant plasmocytoma (3). The two doctors believed that this was a malignant disease of the bone. Further work has discussed the death certificate (Figure 1). I have read the 3 detailed publications of the history and the pathology of this patient. The attendant physi- cians as well as the chemical pathologist and the haematologist who studied the miscroscopy must have realized the importance of their observa- tions. These were published in great detail and describe most of the fundamental symptoms of this disease. The observations make very interest- ing reading.

I have also studied a paper by the grandson of Otto Kahler (4). It is quite clear that Kahler, in 1889, really saw a patient with myeloma, but the discovery by the British doctors cannot be disputed.

Subsequent years saw many publications, chiefly casuistic. Perhaps the most important is a paper by Arvid Wallgren (9, who later became Sweden’s leading paediatrician. He collected a number of cases from Uppsala and found that the manifold histological types accepted at that time by the leading pathologists were useless and meaningless. His opinion that we should simply talk about myeloma cells has, of course, been accepted everywhere nowadays.

The disease Myeloma, or malignant plasmocytoma, is usually regarded as very well-defined and easy to recog-

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6 WALDENSTROM

nize. This is also true of the typical cases. An elderly person who consults the doctor for severe pain, usually in the back, and has an unex- plained, usually very much increased erythrocyte sedimentation rate should always be suspected of having myeloma. Some simple measures may confirm the diagnosis. An X-ray of the spine may be diagnostic, but it must be remembered that elderly patients, especially women, may have spontaneous fractures of the spine caused by osteopenia. This may be difficult to distinguish from myeloma and the osteolytic lesions in the spine may also be diffuse and therefore invisible. Focal lesions in the spine are sometimes difficult to observe. The most important radiographic examination is therefore a lateral picture of the skull and a picture of the pelvis. According to my experience, overdiagnosis is not uncommon. It is said that the rounded foci should not be bordered by sclerotic bone, and this distinguishes them from metastases of carcinoma. This is probably true, but according to my experience the usual finding in myeloma is a very large number of round holes of varying size. So-called venous lacunae (Pacchioni) are sometimes mis- taken for myeloma foci. It should also be remembered that the plasma cell proliferation may cause quite special pictures, even resembling Paget’s disease. In such instances bone marrow puncture gives the answer.

Already at an early stage, serum elec- trophoresis should be performed. Presence of an M component, i.e. a monoclonal IgG, IgA, IgD, is of great help. In the absence of other symptoms, such as back pain, anaemia or mark- ed bone marrow plasmocytosis, the presence of an M component should be judged very care- fully, as even quite large M components may be found in completely static ‘benign’ conditions. Present studies by Kyle and by Waldenstrom (6) and others have proved this. It is therefore impossible to give a certain upper limit above which malignant plasmocytoma must be diag- nosed. On the other hand we know from the work of Hallen (7) that in a consecutive series of patients from Malmo with myeloma no less than 18 of 73 had M-component levels below 20 g/l

and no urinary Bence Jones protein on admis- sion. In the same material, 20 out of 84 had a plasma cell count below 10%. Otherwise a high plasma cell count is usually, but not always, a strong indicator of myeloma. Kyle and Wal- denstrom have both found what Kyle calls ‘smoldering’ myeloma with a very slow pro- gression during several years before clearcut symptoms develop.

Perhaps the most bewildering finding has recently been published by Waldenstrom (6). We have seen patients with what could be called smoldering benign conditions. They have had a slow but steady increase in M components during the years and then died from intercurrent disease without being treated. At post mortem, no signs of myeloma were detected.

This brings up the question whether a post mortem may exclude the presence of myeloma. I am inclined to dispute this statement. We have seen patients who have died with evident clinical symptoms of myeloma, whereas nothing was mentioned about this diagnosis in the protocol from the post mortem, (see Waldenstrom, Acta Medica, 1984, in press).

In previous publications, Waldenstrom and many other authors have maintained that an increasing M component should be a sign of myeloma. This is not always true, even if exceptions are rare.

What about marked excretion of Bence Jones protein in the urine? If the amount of this substance is more than 100 mg/24 h, I think that myeloma should be the obvious diagnosis. Benign Bence Jones proteinuria of any magni- tude has been observed only on very rare occasions. I have followed a lady who started in 1971 to have no less than 400 mg/l of Bence Jones kappa chains and a very small amount of IgGK (3 g/l) in the serum. I last saw her 1 3 yr later. In the meantime she has had amounts of Bence Jones protein, varying between 400 and 1900 mg/l. She is still in excellent health, without any signs and symptoms, although it is possible that she is developing a very slight anaemia. There are several explanations why the finding of Bence Jones proteinuria without myeloma should

MYELOMATOSIS 7

be so rare. One is the fact that routine examina- tions for Bence Jones protein are seldom per- formed. The technique is rather complicated as the dip of AlbustixO does not react to Bence Jones protein. Other methods that also react to albumin must therefore be used. To me it does not seem improbable that the performance of the sulphosalicylic acid or the Heller’s test on some 10000 urine samples in wards with patients suffering from diseases belonging to internal medicine should detect some inexplicable Bence Jones proteinurias. It is to be regretted, however, that all the positive urines would have to be electrophoresed in order to find the light chain M component. This would hardly be worth while.

The cytology of the myeloma cell is difficult to judge. In many textbooks the authors speak about some plasma cells as atypical, undifferenti- ated, etc. We have to confess, however, that even in persons whose disease history remained benign for decades, plasma cells of an atypical nature could be detected already at an early stage. It is therefore advisable that we should not make a point of such findings. On the other hand, I would be inclined to think that a high percentage of cells showing well-defined nucleoli is a serious omen. This fits in well with Turesson’s studies (8). This author examined a large number of bone marrow slides from patients with an increased percentage of plasma cells in the bone marrow. He found that cells from persons who later developed clearcut myeloma had a higher ratio between area of nucleolus as compared to the nuclear area. Further testing of new methods would be highly desirable. Incorporation of tritiated thymidine has been studied.

All these discussions are of course only rele- vant if we believe that early diagnosis of myeloma is important. It is my firm belief that this is not the case. 1 believe that present-day medicine is ridden by the dogma that early treatment is always beneficial. The outcry about health control and health examinations on a regular basis is usually founded on very shaky ground. Prophylaxis (anti-smoking, anti-alcohol, anti-sedentary, anti-stress, anti-gluttony) is of course all important and cannot be too often

stressed. In disease where radical treatment can eradicate the evil, early treatment is of para- mount importance and this statement still has to be upheld, even if recent studies seem to show that the inherent characteristics of the diseased cell are the decisive factor. A small mammary carcinoma, radically operated upon, may have produced metastatic cells of high malignancy, whereas a large ‘neglected’ carcinoma may be comparatively benign. I regret to say that this also seems to be true of myeloma. Everyone with broad experience has seen patients who seem to have an early detected myeloma that still pro- gresses rapidly and fatally. Happily, the reverse is also common. A widespread myeloma with high plasmocytosis and a large M component already at detection may live a long time, but only under one condition: That he or she not be overtreated. It might be wise to follow the old English adage to ‘wait and see’, before embark- ing on an early treatment of myeloma patients.

This takes us to another heretical standpoint that is completely contrary to all our previous beliefs. I am still convinced that a radical reduction of the size of the M component is an excellent sign of therapeutic effect, but I am no longer of the opinion that we should try to reduce or, if possible, abolish the M component by all means. I have seen too many patients who have lived happily with rather large M compo- nents and I have also seen maximal reduction of the M component, in 1 case with lethal con- sequences because of aplastic anaemia after a standard course of cytostatics. In another patient, overdosage of melphalan gave a spec- tacular decrease of the M component but also an aplastic condition of the bone marrow. Only heroic measures helped the patient to recover and we are now much intrigued to see the further development.

In a previous study I gave a motto for ideal therapy: slow but sure. It will shock many of the more or less dogmatic oncologists that my ideas about responders and non-responders are rather heretical. We know that the natural development of the disease is a steady increase in the M component and in the percentage of plasma cells

8 WALDENSTROM

in the bone marrow. Even the change from increase to a static state is, of course, a result. We do not know whether, in the long run, this could be just as good for the patient as more spectacular and therefore - for the doctor’s ego - more stimulating rapid drops to very low values.

Regarding the acute leukaemias, we learned that eradication of the last diseased cell is a must. It is not self-evident that this also holds true of other neoplastic conditions. The military strategists talk about Cannae as a battle of annihilation, whereas a less dramatic retarding strategy may be better in the war against myeloma.

One of the great problems posed by medicine is: to treat or not to treat. Young doctors - and surgeons of most ages -.tend to be treatment- happy. This is of course desirable, but it is important to realize that some pathological conditions may be better left alone. This is especially true of what I have called benign monoclonal gammapathy. In a recent publication (6) I have tried to collect our experiences from Uppsala and Malmo in this field. Hallen (7) wrote the first comprehensive study and was able to show how common it is that people have M components and no other symptoms at the time of examination ( 3 % above the age of 60). These findings were considerably broadened when he and Axelsson (9) were able to examine an unselected population of 7000 healthy people above 25 yr of age in 1966. It was then found that almost exactly 1% had an M component without showing any signs of myeloma. Axelsson (10) followed up on this material 11 yr later. In most cases the levels had remained surprisingly stationary. With an observation time of almost 500 patient yr, malignant disease of immunocytes occurred in only 3 of 64 persons, and only one M component disappeared. Axelsson wrote: ‘It is reassuring that even in the long run the majority represent a benign condition’. This is certainly an understatement. Radl et a1 found, in individuals above the age of 95 yr, 19% with M compo- nents.

On the other hand, there definitely are developments indicating a malignant evolution of

the disease process. In the individual case it i s extremely difficult to decide at an early stage whether the patient has early myeloma or is going to develop myeloma from a seemingly benign initial stage. Kyle speaks about smolder- ing, slowly developing myeloma. We have also seen smoldering developments without produc- tion of any myeloma that could be diagnosed as such when the patient died from intercurrent disease.

My recommendations would be: If bone pain and bone destruction compatible with myeloma are present, active treatment should be started at once. If equivocal X-ray findings are present without pain, wait and see. If there is moderate or no increase in sedimentation rate and/or electrophoretic M component during 2-3 yr, the risk that the patient will develop myeloma is negligible, and no so-called prophylactic treat- ment should be given. An observation time of several months before treatment is usually advisable if pain and/or bone destruction are absent.

The future What should we expect? Hypercalcaemia is still one of the most serious problems in myeloma. The old idea, promoted by the morphological thinking of the pathologists, that bone meta- stases as such cause hypercalcaemia by ‘mobiliza- tion’ of bone is refuted by the fact that we may see widespread and rapid bone destruction with- out hypercalcaemia. The present-day functional and biochemical approach indicates that calcium metabolism is influenced by some calcium-mobi- lizing factors analogous to or possibly identical with PTH. This factor has up to now escaped all attempts at isolation. It is probable that the future will give us excellent methods, not only to bring hypercalcaemic levels down to normal but also to stabilize them at a normal level. The problem of whether or not the sulphones should be used is no nearer solution. Like calcitonin, these seem to have an excellent effect in Paget’s disease, but very probably, responsible authori-

ties have been so scared by the thalidomide catastrophe that they are inclined to see ghosts everywhere. Sir Derrick Dunlop, who was one of the leading British experts in the field, has said: ‘It is easy to count the number of people who would have died unnecessarily from pneumonia after the discovery of M & B 693, if the rules for release had been as strict a t that time as they are now’. This is an aspect that the administrator is apt to forget. Active sin is regarded as so much more abominable than a sin of omission.

I have only a few words to say about mac- roglobulinaemia. Practically all instances of monoclonal IgM in the plasma represent a benign condition. A small group among them develops into clinical macroglobulinaemia that has been called Waldenstrom’s macroglobulinae- mia. It is quite clear that the typical symptoms arise from very high values of one mac- roglobulin, usually above 40 g/l, with a marked syndrome of hyperviscosity as was described already in 1944 (12). Other patients suffer from symptoms caused by the lymphocytoid-cell pro- liferation that may appear as a malignant lym- phoma, for instance infiltrating the lung or metastasizing in the brain, although such patients are rare. The prognosis is bad. Certain physical properties of IgM (cold agglutinin or cryoglo- bulin) may cause circulatory disturbances etc.

A few monoclonal macroglobulins have an effect similar to antibodies causing severe disease (13). This holds true of some anticoagulants and of IgM active against certain components of the nervous system causing severe secondary disease. As a matter of fact, treatment of mac- roglobulinaemia should be even more con- servative than treatment of the conditions with increased monoclonal IgG or IgA. Even com- paratively high levels of macroglobulin may be compatible with fairly good health. Plas- mapheresis is of immense help when hyper- viscosity and hypervolaemia are found.

MYELOMATOSIS 9

This presentation has been intentionally pro- vocative. It is meant as a basis for a lively discussion and I can already feel that many have been sharpening their pencils.

References I .

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Maclntyre W. Case of mollities and fragilitas ossium accompanied with urine strongly charged with animal matter. Med Chir SOC Tr 1850;33:21 I . Bence Jones H. On a new protein occurring in the urine of a patient with mollities ossium. Proc Roy Soc 1848,673. Dalrymple J . On the microscopic character of ‘mollities ossium’. Dublin Quart J Med Sci 1848;2:85. Kahler 0. Zur Symptomatologie des multiplen Myeloms. Beobachtung von Albumosurie. Prager Med Wochenschr 1889;14:33 and 45. Wallgren A. Untersuchungen iiber die Myelomkrankheit. Acta Soc Med Upsal 1920;25:113. Waldenstrom J. Benign monoclonal gammapathy. Acta Med Scand 1984;216:435-47. Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med 1980;302:1347. Hallen J . Discrete gammaglobulin (M-) components in serum. Clinical study of 150 subjects without myelomatosis. Acta Med Scand 1966;suppl:462:84-7. Turesson I. Nucleolar size in benign and malignant plasma cell proliferation. Acta Med Scand 1975;197:7-14. Axelsson U, Hallen J. A population study on monoclonal gammapathy. Follow-up after 5’/2 yr on 64 subjects detected by electrophoresis of 6995 sera. Acta Med Scand 1972; 191 : 1 1 1-3. Axelsson U. An 11 yr follow-up on 64 subjects with M-components. Acta Med Scand 1977;201:173-5. Radl J , Sepers JM, Skvaril F, Morel1 A, Hijmans W. Immunoglobulin patterns in humans over 95 yr of age. Clin Exp Immunol 1975;22:84-90. Waldenstrom J . Incipient myelomatosis or ‘essential’ hyperglobulinemia with fibrinogenopenia - a new syn- drome? Acta Med Scand 1944;117:216-47. Waldenstrom J . The benign monoclonal gammapathies: a study of monoclonal antibodies. Ergeb Inn Med Kind- erheilk 1982;50:3 1-77.

Correspondence to: Prof. Jan Waldenstrom Dept. of Medicine Allmanna Sjukhuset Malmo Sweden