19 April 1969
`
`MepieneOURNAL
`
`163
`
`Current Practice
`
`
`
`Management of Multiple Myeloma
`
`J. S. MALPAS,* D-PHIL., M.R.C.P.
`
`British Medical Journal, 1969, 2, 163-165
`
`Considerable progress has been made in the therapy of multiple
`myeloma, and it is now possible not only to alleviate symptoms
`but to prolong survival. Patients may be enabled to resume
`full activity—or at
`least
`to lead a limited but comfortable
`existence.
`
`Multiple myeloma is a malignant disease of plasma cells,
`occurring usually in middle-aged and elderly people, and
`characterized by a proliferation of plasma cells throughout the
`bone marrow and lymphoreticular tissue. Occasionally it may
`start as an isolated tumour mass, but generalization of the
`disease inevitably occurs in time. When the disease progresses
`bone marrow failure, bone destruction, increased susceptibility
`to infection, and metabolic disturbances such as hypercalcaemia,
`hyperuricaemia, and uraemia may arise as complications. The
`disease is invariably fatal.
`The diagnosis of multiple myeloma and the clinical and
`pathological
`features of
`the disease have been extensively
`reviewed,!~* and will not be considered in detail. The diag-
`nosis is based on the demonstration on serum electrophoresis
`of an homogeneous band of protein, the so-called paraprotein
`or “M” component, or the presence of plasmacytosis with
`bone destruction apparent on a radiological survey of the skele-
`ton, or the presence of a solitary tumour composed of myeloma
`tissue.
`Usually there is no difficulty in distinguishing the
`abnormal plasma cells seen in myelomatissue, but occasionally
`difficulty can be experienced, and care must then be taken that
`the plasmacytosis is not the result of drug sensitivities, diseases
`of collagen tissue, chronic infection, cirrhosis of the liver, or
`malignant disease such as carcinomatosis or Hodgkin’s disease.
`In the same way homogeneous bands or “M” components on
`serum electrophoresis do not necessarily denote myeloma:
`they
`may be seen in macroglobulinaemia or other more benign
`immunoglobulin disorders.
`
`Clinical Pathology
`
`Tests carried out on the serum and urine are an essential part
`of diagnosis, and they may also provide evidence which will be
`of value in management and prognosis.
`Serum and Urinary Proteins—Gitlin’ and Cohen® have
`reviewed the terminology of the immunoglobulins. Most para-
`proteins found in multiple myelomaare related to the yG and
`yA immunoglobulins. More rarely paraproteins related to
`yM and yD immunoglobulins are found, and in about 6%
`of a large series Hobbs’ found that the myeloma was producing
`only Bence Jones protein (B.J.P.)—that
`is,
`the light chain
`moiety of the immunoglobulins. The prognosis for patients
`producing yG and yA paraproteins does not seem to differ.
`Though very few cases of yD paraproteins have been recorded
`their survival appears to be short.
`
`* Senior Lecturer in Medicine, Medical Unit, St. Bartholomew’s Hospi-
`tal, dpondon E.C.1 ; Consultant Physician, St. Leonard’s Hospital,
`ondon
`N.1,
`
`Certain complications appear to be more common in the
`presence of certain paraproteins. Thus yG myelomais asso-
`ciated with a higher
`incidence of
`infection and with less
`frequent occurrence of hypercalcaemia.®
`The presence of Bence Jones protein is of considerable prog-
`nostic importance.
`The light chain moieties which form
`B.J.P. are of two types, kappa (x) or lambda (A) chains. Hobbs®
`investigated a series of patients with paraproteinaemia and
`showed that the presence of B.J.P. in excess of 1 mg./100 ml.
`in the urine indicated a bad prognosis. Earlier, Walden-
`str6m!® 12 had shown that the occurrence of B.J.P.
`together
`with a rising level of paraprotein in the serum was also a bad
`augury.
`The presence of B.J.P. is closely correlated with renal failure
`and with anaemia, both of which have an adverse effect on
`survival. 12 Bergsagel, Migliore, and Griffith'* reported a
`higher incidence of response to therapy in patients producing
`B.J.P. of type «x. Caggiano, Cuttner, and Solomon‘ were unable
`to confirm this, but further evidence is now available from the
`M.R.C.trial in which patients producing x light chains appear
`to have a somewhat better prognosis.‘4
`In a long-term study
`by the South-west Cancer Chemotherapy Group patients pro-
`ducing » chains have a higher incidence of renal failure, a
`poorer response to therapy, and a shorter survival.’*
`Renal Function.—Between a third and a half of the patients
`who die from multiple myeloma do so as a consequence of
`renal failure. Many mechanisms contribute to the failure, in-
`cluding pyelonephritis, nephrocalcinosis,
`intracellular tubular
`damage, and amyloidosis. Once renal failure has begun in
`myeloma current forms of therapy do not appear to be able to
`arrest it. A patient with a blood urea of over 80 mg./100 ml.
`has a poor prognosis. The median survival of patients in this
`group is about eight weeks.
`This compares with a median
`survival of over three years for the group with blood ureas of
`less than 80 mg./100 ml.®
`An elevated level of serum calcium has been noted in a fifth
`to a half of patients when they first presented.
`Though
`increased bone resorption is the main factor responsible, wide-
`spread bony erosions are not always present.
`The serum
`alkaline phosphatase is usually not raised in multiple myeloma.
`It does not appear
`that hypercalcaemia has any effect on
`prognosis.
`In common with many malignant processes hyperuri-
`caemia and secondary gout may be associated with multiple
`myeloma.
`frequently complicates
`Haematological Studies——Anaemia
`the disease. When the anaemia is severe and requires frequent
`blood transfusion for its correction the patient’s prognosis is
`poor. The mechanism for the production of anaemia in mye-
`loma is complex.
`In a comprehensive investigation Cline and
`Berlin’* showed that anaemia could be due to bone marrow
`failure, shortening of the red cell survival, and iron deficiency.
`The latter usually resulted from recurrent bleeding episodes
`associated with thrombocytopaenia, and was usually seen in
`the later stages. Megaloblastic changes have been found on
`
`ALVOGEN, Exh. 1046, p. 0001
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`ALVOGEN, Exh. 1046, p. 0001
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`

`

`164
`
`19 April 1969
`
`Multiple Myeloma—Malpas
`
`BRITISH
`MEDICAL JouRNAL
`
`bone marrow examination by a number of investigators. Thirty-
`two patients with myeloma were studied by Hoffbrand, Hobbs,
`Kremenchuzky, and Mollin,!’ and intermediate megaloblastic
`changes were noted in six.
`These changes were mainly due
`to folic acid deficiency. Addisonian pernicious anaemia is rare
`in myeloma ; the low vitamin B,, levels that have been recorded
`were related to a reduction in the normal circulating immuno-
`globulin levels.
`
`Treatment
`
`Waldenstrém!* has outlined the basic principles of therapy
`in myeloma. Firstly, the treatment of a generalized malignant
`disease must be systemic and should not be directed against
`local lesions.
`Secondly, he has drawn an analogy between the
`disease and an infection with a microorganism. The cytostatic
`drug,
`like an antibiotic, must be given initially in high con-
`centration and then a lower dose must be given continuously.
`The specific chemotherapy available and its administration will
`be discussed in detail
`later.
`Supportive care to prevent or
`relieve complications
`such as
`fractures,
`infections, hyper-
`calcaemia, hyperuricaemia, renal failure, and hyperviscosity will
`be dealt with first.
`
`Supportive Therapy
`
`Skeletal pain is often responsible for the patient leading a
`limited existence. Deep x-ray therapy of local skeletal deposits
`is often of great benefit.
`Though the rapid development of
`chemotherapy has done much to make long-term control of
`skeletal pain easier, deep x-ray therapy is very effective when
`pain originates from a myelomatous deposit.
`It has the great
`advantage of providing rapid relief. Relief is usually so com-
`plete that if pain persists it may be advisable to seek some other
`cause for its occurrence, such as an unrecognized pathological
`fracture. Deep x-ray therapy may also be particularly useful
`when a deposit within the spinal theca threatens damage to the
`spinal cord.
`Immobilization of pathological fractures and spinal support
`by corsets and steel braces may bring relief of pain. The use
`of sodium fluoride to produce subacute fluorosis with hardening
`of the skeleton is not justifiable because of the risk of retinal
`damage.?®
`Infections are frequent in myeloma, and chest infections seem
`particularly common.
`They require urgent and adequate
`therapy.
`Because of
`the reduction in the level of normal
`immunoglobulin that
`is seen as myeloma progresses,’
`these
`patients often show poor resistance to infection, but prophy-
`lactic
`administration
`of
`gammaglobulin
`seems
`to
`be
`disappointing.
`Slight hypercalcaemia may be treated by rehydration and
`specific chemotherapy. When hypercalcaemia is more pro-
`nounced and symptoms such as nausea, vomiting, or mental
`disturbances supervene,
`immediate administration of cortico-
`steroids is
`imperative.
`A dramatic improvement
`is usually
`seen,
`
`Hyperuricaemia may occur in the absence of renal failure.
`Treatment with allopurinol has been reported and is effective.”°
`The renal failure of myeloma is usually chronic and irrever-
`sible. Acute renal failure may also occur. This may happen
`spontaneously or follow periods of vomiting with consequent
`dehydration. Vomiting may be induced by specific therapy
`with urethane or melphelan.
`There are a number of reports of acute renal failure after
`pyelography. This may occur with recently introduced con-
`trast media as well as with established media.?} Renal failure
`occurs too frequently to be a coincidence, butit is still a rela-
`tively rare occurrence. Vix?* carried out 52 intravenous pyelo-
`
`gramsin 40 patients without any evidence of renal deterioration,
`even in those already suffering from chronic renal
`failure.
`Pyelography should nevertheless not be carried out without a
`good indication, and if an intravenous pyelogram is necessary
`it is wise to omit the period of dehydration that is part of the
`routine preparation.
`A marked increase in the viscosity of serum may be seen occa-
`sionally in patients with yG myeloma. Hyperviscosity may
`give rise to mental symptomsvery similar to those observed in
`hypercalcaemia, and,
`in addition, a retinopathy,
`recurrent
`bleeding, cardiac failure, and lassitude may occur.
`Smith,
`Kochwa, and Wasserman?’ were able to demonstrate the
`formation of aggregates of yG in vivo. As retinal damage
`may rapidly progress to blindness plasmaphoresis must be
`carried out urgently to reduce the circulating protein. Plasma-
`phoresis must be followed by specific chemotherapy.
`There are a number of causes for the bleeding diathesis seen
`in some patients with myeloma.
`Thrombocytopenia may
`result from bone marrow failure or from treatment with cyto-
`toxic agents. The platelets may become coated with abnormal
`protein,?4 and rarely a circulating anticoagulant may cause
`bleeding.
`Myeloma is a disease of late middle age, so that the manage-
`ment of pregnancy occurring with this condition is uncommon,
`Occasionally, however, myeloma occurs in children or young
`adults, and Kosova and Schwartz?> reported the case of a 35-
`year-old woman with myeloma who, following a remission in-
`duced with deep x-ray and urethane, had a normal pregnancy
`and delivery. Pregnancy did not seem to cause a deterioration
`of her condition.
`
`Specific Therapy
`
`Many drugs have been used in the treatment of myeloma.
`Some drugs such as stilbamidine, methotrexate, vinblastine, and
`hydroxyurea have been shown to be ineffective. Others, like
`urethane and corticosteroids, may produce both subjective and
`objective improvement, but have not been shown to increase
`the length of survival.
`In a study by Holland ef a/.!? urethane
`was shown to be of no greater benefit than a placebo in increas-
`ing survival, and patients treated with it survived for a shorter
`period than those treated with supportive therapy only.
`After extensive trials?! ** cyclophosphamide and melphalan
`have been shown to be effective in treatment and to produce
`a definite increase in survival.
`It is difficult to compare the
`length of survival seen in recent series of patients treated with
`these alkylating agents with the series reported more than a
`decade ago.
`Someof the early series reported a median survival
`of only three months ; Osgood?’ showed in 1960 that
`the
`median survival for patients treated with steroids, radioactive
`phosphorus, and urethane was 20 months. This improvement
`was probably related, however, to the earlier recognition of the
`disease in the later series.
`
`Korst e¢ al.2* reported a series of 165 patients treated with
`cyclophosphamide.
`The median survival of this group was
`32 months, compared with 9 months in an ancillary group
`treated without cyclophosphamide.
`In 82 patients treated with
`melphalan over a seven-year period Alexanian et al.*° showed
`a median survival time of 34 months. Furthermore those who
`responded to melphalan lived some 30 months longer than a
`group of non-responders.
`There seems to be no doubt that
`cyclophosphamide and melphalan do prolong survival.
`In
`the M.R.C.
`trial? comparing them no significant difference
`between them was shown.
`
`Dosage and Toxic Side-effects
`Cyclophosphar:ide
`
`It can be given
`This alkylating agent is activated in vivo.
`orally or intravenously, but when treating myeloma the oral
`
`ALVOGEN, Exh. 1046, p. 0002
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`ALVOGEN, Exh. 1046, p. 0002
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`

`

`19 April 1969
`
`Multiple Myeloma—Malpas
`
`Mepiene3ouRNAL
`
`165
`
`It produces improvement in about
`route is usually preferred.
`a third of patients treated? The dose is 2 mg./kg./day, but
`the daily dosage is varied to avoid bone marrow suppression.
`Besides marrow toxicity cyclophosphamide can cause alopecia
`and haemorrhagic cystitis.
`Continued chemotherapy should
`be attempted, and an examination of the white cell count and
`platelet count should be carried out every three to four weeks.
`
`Melphalan
`
`Phenylalanine mustard can also be given orally. When
`first introduced for the treatment of myeloma it was suggested
`that a dose of 0-15 mg./kg./day should be given for a week
`followed by a period in which the bone marrow recovered.
`Maintenance therapy was then continued with doses of 0-05
`mg./kg./day. Long-term therapy was carried on with doses
`not greater
`than 0-06 mg./kg./day.1°7°°°
`Toxic effects
`include nausea, vomiting, ulceration of
`the mouth, gastro-
`intestinal haemorrhage, and bone marrow depression. Mel-
`phalan should be given with great care in the presence of renal
`failure.
`
`The number of patients who show a response to either cyclo-
`phosphamide or melphalanis still disappointingly low. Efforts
`have been made therefore to improve the remission rate and
`prolong survival by altering the regimens of administration or
`using combination chemotherapy with corticosteroids as well
`as cytostatic drugs. Alexanian et al.1° have compared four
`treatment regimens, daily melphalan 0-025 mg./kg./day, inter-
`mittent melphalan ‘0-25 mg./kg./day for four days followed
`by an interval of six weeks, intermittent melphalan with predni-
`solone
`1:0 mg./kg. on alternate days,
`and intermittent
`melphalan with prednisolone 2:0 mg./kg./day on the days
`when melphalan is being administered.
`They found that
`objective responses to melphalan occurred more often when it
`was given intermittently, and that there was no indication of
`increased toxicity.
`The addition of prednisolone to the regimen resulted in an
`enhanced response, with some 70% of the patients responding,
`and the median survival of the group treated with melphalan
`and prednisolone was six months longer than the group treated
`with melphalan alone.
`It was also evident that some patients
`
`who had shown no signs of responding to melphalan would
`do so when prednisolone was added.
`Recent advances such as these in the therapy of myeloma
`may now perhaps form the basis for a more generally optimistic
`outlook in this condition.
`
`I am grateful to Professor Raymond Alexanian and to Dr. J. R.
`Hobbs for kindly allowing me to quote from unpublished data.
`
`REFERENCES
`
`w
`
`J.,
`
`aceswe
`
`a
`
`©
`
`Osserman, E. F., and Takatsuki, K., Medicine (Baltimore), 1963, 42,
`357
`Drivsholm, A., Acta Medica Scandinavica, 1964, 176, 509.
`Bergsage!l, D. E., Griffith, K. M., Haut, A., and Stuckey, W.
`Advances in Cancer Research, 1967, 10, 311.
`Caggiano, V., Cuttner, J., and Solomon, A., Blood, 1967, 30, 265.
`Gitlin, D., Annual Review of Medicine, 1966, 17, 1.
`Cohen, S., British Journal of Haematology, 1968, 15, 211.
`Hobbs, J. R., Scientific Basis of Medicine Annual Reviews, 1966,
`. 106.
`Galton, D. A. G., and Peto, R., British Journal of Haematology, 1968,
`» 319.
`Hobbs, J. R., British Medical Journal, 1967, 3, 699.
`1° Waldenstrém, J., Acta Medica Scandinavica, 1964, 176, 345.
`11 Waldenstrém, J., British Medical Journal, 1964, 1, 859,
`.
`12 Holland, J. F., et al., Blood, 1966, 27, 328.
`13 Bergsagel, D. E., Migliore, P. J., and Griffith, K. M., Science, 1965,
`3
`.
`48, 376
`14 Hobbs, J. R., British Journal of Haematology, 1969, in press.
`15 Alexanian, R., et al., Journal of
`the American Medical Association,
`1969, in press.
`.
`.
`16 Cline, M. J., and Berlin, N. I., American Fournal of Medicine, 1962,
`33, 510.
`17 Hoffbrand, A. V., Hobbs, J. R., Kremenchuzky, S., and Mollin, D. L.,
`Journal of Clinical Pathology, 1967, 20, 699.
`.
`18 Waldenstrém, J., British Fournal of Haematology, 1968, 15, 217.
`19 British Medical Fournal, 1967, 2, 128.
`»” Rundles, R. W., Annals of the Rheumatic Diseases, 1966, 25, 615.
`21 Gross, M., McDonald, H. M., and Waterhouse, K., Radiology, 1968,
`90, 780.
`22 Vix, V. A., Radiology, 1966, 87, 896.
`33 Smith, E., Kochwa, S., and Wasserman, L. R., American Fournal of
`Medicine, 1965, 39, 35.
`24 Vigliano, E. M., and Horowitz, H. I., Blood, 1967, 29, 823.
`25 Kosova, L. A., and Schwartz, S. O., Blood, 1966,28, 102.
`26 Speed, D. E., Galton, D. A. G., and Swan, A., British Medical Fournal,
`1964, 1, 1664.
`27 Osgood, E. E., Cancer Chemotherapy Reports, 1960, 9, 1.
`*§ Korst, D. R., Clifford, G. O., Fowler, W. M., Louis, J., Will, J., and
`Wilson, H. E., Journal of the American Medical Association, 1964,
`189, 758.
`29 Alexanian, R., Bergsagel, D. E., Migliore, P. J., Vaughn, W. K., and
`Howe, C. D., Blood, 1968, 31, 1.
`5° Hoogstraten, B., et al., Blood, 1967, 30, 74.
`
`TODAY’S DRUGS
`
`With the help of expert contributors we print in this section
`notes on drugs in common use.
`
`Androgens and Anabolic Steroids
`Several androgenic steroid hormones
`are secreted by the
`adrenal cortex and the testis ; the most powerful is testosterone.
`. The action of these hormones is most clearly seen in the changes
`that occur in boys at puberty. Under the stimulus of gonado-
`trophin secreted by the pituitary gland testosterone and other
`androgenic steroids are secreted in significant amounts for the
`first time. These hormones are responsible for changes in the
`larynx causing deepening of
`the voice,
`for growth of
`the
`external genitalia and the prostate, and for the appearance of
`body hair with the typical male distribution. They also pro-
`duce pronounced retention of nitrogen and the build-up of
`body protein which results in development of the musculature
`and also accounts for, at least in part, the spurt in growth at
`puberty.
`As well
`as
`stimulating growth the androgenic
`
`hormones cause maturation of the bones and, eventually, fusion
`of the epiphyses, which brings growth to a halt.
`It is the
`property of these hormones to produce nitrogen retention and
`encourage protein anabolism which has led to a large scale
`attempt
`to develop compounds that will retain these actions
`but not have the masculinizing effects. These anabolic steroids
`are tested by bioassays which separate the effect upon nitrogen
`metabolism from the androgenic effects. Many such com-
`pounds have now been produced in which the nitrogen retain-
`ing properties predominate over the androgenic effects. None,
`however, has yet been shown to be entirely free of androgenic
`actions when tested in man.
`
`Hypogonadism
`
`The most clear-cut indication for the use. of testosterone is
`as replacement therapy in patients with hypogonadism. This
`raay be due either to disease of the testis or to diminished
`
`ALVOGEN, Exh. 1046, p. 0003
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`ALVOGEN, Exh. 1046, p. 0003
`
`