INTERFERON THERAPY IN MYELOMATOSIS

245 TABLE I-LABORATORY FINDINGS IN PATIENT

INTERFERON THERAPY IN MYELOMATOSIS

1

(IgA-x myeloma)

A. AHRE G. HOLM H. STRANDER

H. MELLSTEDT M. BJÖRKHOLM

B. JOHANSSON

Radiumhemmet, Karolinska Hospital, and Department of Medicine, Seraphimer Hospital, Stockholm, Sweden

Summary

Four patients with myelomatosis (one IgG-x-type, two IgA-x, and one Bencegiven human leucocyte interferon as the

Jones-x) were only treatment for from 3 to 19 months. Remission was complete in two patients and partial in the other two. Normal bone-marrow hæmatopoiesis was slightly inhibited. The disease has not so far progressed in any of the patients.

April, 1977, the patient was referred to our hospital pneumonia and anxmia and for consideration for antimyeloma therapy. Initially he received antibiotics and blood-transfusions. The pneumonia healed and his general condition improved. Laboratory investigations: E.S.R. 144 mm/h, Hb 62 g/1, white cells 3-3xl0’’/l, total lymphocytes 1-2x10/1, thrombocytes 110xlO"/I. Serum-creatinine 340 p.mol/1, serum-calcium 2-18 mmol/1. An IgA-xM-component was present in serum (table I). Urine contained free x-lightchains and the daily excretion was estimated at 2.1g/24 h. A bone-marrow specimen showed 30% well-differentiated plasma cells, some of which were typical "flaming" cells. No osteolytic lesions were seen on X-ray examination (skull, vertebrx, pelvis). Interferon therapy was started on April 27, 1977. During the first four months, he required blood-transfusions, but not In

because of INTRODUCTION

THE interferons are potent antiviral glycoproteins. other biological effects they inhibit multiplication of tumour cells in experimental systems.l The mechanisms underlying their antitumour properties remain unknown. Since 1969 the antitumour potency of exogenous leucocyte interferon has been evaluated in patients with osteosarcoma or with other malignancies treated at the Karolinska Hospital.23 Interferon has been tried in one patient with a melphalan-resistant IgGmyeloma with temporary response.4 The multiplication of a myeloma cell line was also inhibited by interferon in vitro.s We describe here the effects of human leucocyte interferon in patients with plasma-cell myeloma, who had not had previous antitumour therapy.

Among

METHODS

.

M-components in serum and/or urine

were identified by imfixation after agarose electrophoresis.6 Serum immunoglobulins were determined by the rocket technique7 (normal values: IgG 6.6-18.5 g/1, IgA 0.6-4.5 g/l, IgM 0.4-3.0 g/1). Urinary free light-chains were determined semi-quantitatively by comparison with the known content of albumin, or in urine not containing albumin with a known amount of albumin added. The ratio between monoclonal free light-chains and the known amount of albumin was estimated by densiometry after agarose electrophoresis.8 Blood chemistry estimations were made in an ’AutoAnalyzer’ (Technicon Instrument, Tarrytown, U.S.A.) (normal values: serum-creatinine 50-110 moM) serum-calcium 2.20-2-60 mmol/1, alkaline phosphatase <5.3 kat/1, serum-albumin 37-52 g/1). Partially purified human leucocyte interferon was obtained from the Finnish Red Cross Blood Transfusion Service, Helsinki. It was prepared according to the methods of Cantell et al,In all cases a dose of 3 x 106 standard units of interferon was given intramuscularly each day throughout the period of mune

treatment.

CASE-REPORTS

Patient1 An 85-year-old man was admitted to hospital in June, 1976, because of difficulties in taking care of himself at home. Laboratory findings: E.S.R. 138 mm/h (Westergren), Hb 109 g/1, white cells 46x 109/1. Serum-creatinine 141 mol/l, serum-calcium 2.36 mmol/l. Serum electrophoresis: IgA-x M-component. Immunoglobulins: IgG 4.8g/1, IgA 13 g/1, IgM 0.33 g/1. Urine electrophoresis revealed free x-chains (not measured). Bone-marrow biopsy: 20% plasma cells. No therapy was felt to be necessary at that time.

.

thereafter. The course of the disease is shown in table i. He has now been treated with interferon for 19-months. During this period IgA concentration decreased from 20.5to 4-1g/l. Urinary Bence-Jones protein excretion after 19 months of treatment was calculated at 0.4g/24 h. Only a scanty M-component was visible on serum as well as on urine electrophoresis. IgG has increased to 10.4 g/1 while serum IgM is unchanged. Bone-marrow plasma cells have decreased to 4% and E.S.R. to 70 mm/h. The haemoglobin concentration has remained low (90 g/1), but transfusion has not been necessary during the past 15 months. Renal function improved and serum-creatinine has fallen to 230 jmol/1. White cells, total lym-

phocytes, and thrombocytes have decreased during the treatment period (table i). The patient’s general condition is good. Patient 2 woman was admitted to hospital because of high E.S.R. (55 mm/h). Her history was noncontributory. Laboratory findings: Hb 131 g/1, white cells 4-4xl09/1, thrombocytes 280xl09/1. Serum-calcium 2.60 mmol/1, alkaline phosphatase 5.33 kat/1. Serum electrophoresis : M-component of IgG-x type. Immunoglobulins: IgG 34 g/1, IgA 1.33 g/1, IgM 1.11 g/1. Bone marrow: 10-15% mature plasma cells. On X-ray a compression fracture of Tll was seen, but no signs of destruction by tumour. Myelomatosis was suspected but not regarded as confirmed and she was followed regularly during the following months. Six months later her condition deteriorated. Her back pains became more severe and she was again admitted. E.S.R. 83 - mm/h, Hb 136 g/l, white cells 6.7xl09/1, total lymphocytes 3.4 x 09/1, and thrombocytes 294 x 109/1. Serum-creatinine 80

A 67-year-old back pain and a

mol/1, serum-calcium 2.86 mmol/1. Alkaline phosphatase 6.99 p.kat/1. Serum electrophoresis showed a monoclonal peak that identified as IgG-x (table n). No Bence-Jones protein was found in concentrated urine. Bone-marrow biopsy demonstrated 50% atypical plasma cells of varying maturity. X-ray revealed compression fractures of Til and T12 and osteolytic lesions of the ribs.

was

246 TABLE II-LABORATORY FINDINGS IN PATIENT 2

(IgG-xmyeloma)

mm/h. White cells, total lymphocytes, and thrombocytes decreased. Moreover, non-monoclonal immunoglobulins increased. The patient is in a good clinical condition and has gained 3 kg in weight and the episodes of respiratory infection are less frequent.

Patient 4 A 75-year-old woman had had 3 months of increasing pain in the lumbar region and left pelvis. She was referred to hospital after a fall and difficulty in walking. X-ray examination of the pelvis and femur revealed multiple sites of osteolytic destruction. Laboratory investigations: E.S.R. 21 mm/h, Hb 94 g/1 white cells 9.3 x 109/1, total lymphocytes 1-lxlOV, and thrombocytes 196 x 109/1. Serum-creatinine 70 p.mol/1, serum-calcium 3-05 mmol/1. Alkaline phosphatase 7.4 kat/1. Serum

made and daily interThe diagnosis of IgG-x-myeloma feron was started on Sept. 13, 1977. Serum-calcium was normal within one week and remained so, though alkaline phosphatase was slightly raised and did not return to normal until after eight months. The back pains disappeared after six months’ treatment. Laboratory findings are shown in table II. After 15 months of interferon treatment the serum-IgG fell to 40 g/1. No Bence-Jones proteins have been demonstrated in urine. Bone-marrow plasma cells decreased from 50% to 18% and E.s.R. to 64 mm/h. No further destruction has taken place in the skull, vertebrse, or pelvis. X-rays of the ribs (after 15 months’ treatment) showed callus formation in some lesions and an intact cortex, indicating healing. Owing to incomplete pretreatment examination of the ribs, the costal lesions could not be accurately estimated. Haemoglobin, thrombocytes, and non-monoclonal immunoglobulins remained essentially unchanged during treatment; and the total white count and total lymphocyte count decreased. was

electrophoresis showed striking hypogammaglobulinaemia (table Iv) but no M-component. Urine electrophoresis showed a massive M-component composed of free x-chains (13 g/24 h). Bone-marrow biopsy showed diffuse infiltration of plasma cells, which constituted 30% of the nucleated cells. Further X-rays of the skeleton revealed osteolytic lesions in the skull, vertebrae, and ribs. TABLE IV-LABORATORY FINDINGS IN PATIENT

4

(Bence-Jones x

myeloma)

,

Patient 3 A

67-year-old woman was admitted to hospital because of weight loss (10 kg) and recurrent upper respiratory infection. Laboratory tests: E.S.R. 121 mm/h, Hb 119 g/l, white cells 3.6 X 109/1, total lymphocytes 1.3 x 109/1, thromobocytes 248x109/1. Serum-creatinine 50 ,mol/1, serum-calcium 2-60 mmol/l. Serum electrophoresis and immune fixation showed an IgA-x M-component (table III). No Bence-Jones protein was found in concentrated urine. Skeletal X-rays revealed no osteolytic lesions. A bone-marrow specimen showed well-differentiated plasma cells, constituting 40% of all nucleated cells. Interferon therapy began on March 13, 1978. Table III shows the changes in laboratory variables during the 9 months’ observation. IgA decreased from 18.0to 1.2g/l and no M-component could be detected in serum. Plasma cells decreased from 40%

to

5% and

E.S.R.

from 121 mm/h

TABLE III-LABORATORY FINDINGS IN PATIENT

3

to

(IgA-x

myeloma)

14

*At this time the patient received 2 units of packed red cells, but later required no transfusion.

Interferon therapy began on Sept. 18, 1978. After 9 days the serum-calcium level was normal and has remained so, while alkaline phosphatase fell to normal after 8 weeks. A dramatic improvement was noted after 4 weeks (table iv): urinary lightchain excretion had decreased to 4 g/24 h and bone-marrow plasma cells to 3%. The laboratory status is still improving. She is considered to have achieved complete remission. The skeletal lesions have remained unchanged after 13 weeks’ therapy. From being bed-ridden she can now walk with sticks and she spends every weekend at home.

DISCUSSION

*No visible M-component on serum agarose-electrophoresis.

Four patients with previously untreated highly differentiated myelomas (one IgG-x, two IgA-x and one BenceJones-x) have received daily interferon injections as their only treatment for periods ranging from 3 to 19 months. All four improved clinically. The M-component disappeared almost completely in two patients (IgA-x) and bone-marrow plasma cells fell to normal numbers. The clinical effect was dramatic in the patient with x-light-chain disease: hypercalcxmia disappeared within a week and urinary protein excretion and the proportion of bone-marrow plasma cells decreased considerably

247 month. The effect was less impressive in the woman with IgG-x myeloma: over 15 months, paraprotein and E.S.R. decreased slightly, while the reduction of bone-marrow plasma cells was more evident; and callus formation was also noted in some of the osteolytic lesions. We regard patients 3 and 4 as having achieved complete remission, while patients 1 and 2 are in partial remission.’° The most remarkable finding is the almost complete disappearence of signs of myelomatosis in two cases. Full remission during conventional therapy of human myelomatosis is rare." Furthermore, the tendency for non-monoclonal immunoglobulins to return to normal is also noteworthy. In all four cases interferon treatment is continuing. Interferon preparations may cause fever and-other side-effects.12 In all four patients temperature increased by 1°-2° during the first few days. The decrease in white cells, total lymphocytes, and thromobocytes (tables i-iv) may probably be explained as a slight inhibitory effect on normal bone-marrow. These decreases did not necessitate interruption of the interferon treatment. Any anti-myeloma effect of interferon cannot be explained by inhibition of immunoglobulin production per se since other clinical indications of tumour regression appeared. Several interpretations may be offered. 12 Interferon may have direct effects on tumour-cell membranes and/or on tumour-cell multiplication. In line with this, an anti-proliferative effect of interferon on human myeloma cells and other B-cell lines has been described in vitro.35 Interferons may also act on the host response to tumour cells. The spontaneous cytotoxicity of peripheral lymphocytes is increased after an injection of interferon. 133 Little progress has been made in the therapy of myeloma over the past 20 years.14 The promising results in this pilot study justify an extended trial, and we have started a prospective randomised study comparing interferon with intermittent high-dose melphalan and prednisolone in myelomatosis. within

a

This study was supported by grants from the Swedish Cancer Sothe Cancer Society in Stockholm, and the County Council of Stockholm. The trial reported here was approved by the committee on ethics of the Karolinska Hospital and the Karolinska Institute. We appreciate the advice of Prof. K. Cantell, Prof. J. Einhorn, Prof. E. Osserman, and Prof. J. Waldenstrom.

ciety,

Requests for reprints should be addressed to: H. met, Karolinska Sjukhuset, S-104 01 Stockholm 60.

M., Radiumhem-

REFERENCES 1

Gresser, L. in Cancer: A Comprehensive Treatise (edited by F. Becker); vol. 5, p.521. New York, 1977. 2. Cantell, K., Strander, H. in Blood Leukocytes: Function and Use in Therapy (edited by C. P. Högman, K. Lindahl-Kiessli, and H. Wigzell); p. 73. Uppsala, 1977. 3. Strander, H. Blut, 1977, 35, 277. 4 Ideström, K., Cantell, K., Killander, D., Nilsson, K., Strander, H., Willems, J Acta med. scand. (in the press). 5. Einhorn, S., Strander, H. in Human Interferon: Production and Clinical Use (edited by W. Stinebring and P. J. Chapple); p. 159. New York, 1978. 6 Carlström, A., Johnsson, B. Unpublished. 7. Laurell,C B. Analyt. Biochem. 1966, 15, 45. 8. Bergström, K. Unpublished. 9. Mogensen, K. E., Cantell, K. J. Pharmac. Ther. C. 1977, 2, 369. 10 Committee of the Chronic Leukemia-Myeloma Task Force. Cancer Chemother. Rep 1973, 4, 145. 11 Waldenström, J. in Diagnosis and Treatment of Multiple Myeloma. New York, 1970. 12 Ingimarsson, S , Cantell, K., Strander, H. J. infect. Dis. (in the press). 13 Einhorn, S., Blomgren, H., Strander, H. Acta med. scand. (in the press). 14 See Br. med. J. 1975, i, 1653.

Reviews of Books Cancer: A Problem of Developmental Biology G. BARRY PIERCE, ROBERT SHIKES, and Louis M. FINK, University of Colorado Medical Center. Hemel Hempstead: PrenticeHall. 1978. Pp. 256. D1.65.

THIS eminently readable and most enjoyable short treatise examines tumours from the point of view of aberrations of celldifferentiation. The introductory chapter describes the classification and nomenclature of tumours, and the last two provide illustrations of the morphology of typical cases, together with the principles of current treatment regimens. The remaining chapters discuss different aspects of neoplasia including the genesis and early development of tumours, their genetic and immunological aspects, and their biochemistry. Ample references are provided to substantiate the concepts proposed by the authors; these concepts are presented logically and clearly. However, not everyone will agree wholly with their proposal that tumours arise from stem cells. While such a process may be true for epidermal, haematological, and some gonadal tumours, other cell-types must be involved in the origin of commoner tumours such as those of the bronchus and, possibly, breast. It is also a pity that in the discussions about selective advantage and progression, there is no mention of the recently described growth factors and their possible importance in this context. Unfortunately, also, the sections dealing with metastases and gene control make little reference to some of the recent exciting and relevant data. Notwithstanding these minor points, this book forms a very good basis for the medical student and the scientist embarking upon oncological studies’ for the first time.

Chronic Obstructive Lung Disease Clinical Treatment and

Management. Edited by

RICHARD E.

BRASHEAR, M.D., and MITCHELL L. RHODES, M.D., Division of Pulmonary Medicine, Indiana University School of Medicine. St. Louis:

Mosby. London: Kimpton.

1978. Pp. 264. 10.

Tms American multiauthor text describes chronic obstruclung disease in its widest sense, from pathology and physi-

tive

ology through management of acute and chronic respiratory failure to such matters as training, reconditioning, and stopping smoking. Most of the eighteen chapters are clearly written, detailed, and well-balanced accounts, often with 100 or more references. Some are justifiably critical of currently popular treatments--e.g., domiciliary oxygen treatment, intermittent positive-pressure ventilation, and long-term corticosteroids. These chapters come as a refreshing change, and may help offset the temptation to clinicians to prescribe ineffective, expensive, and sometimes harmful treatment. On the other hand, due weight is given to the importance of general education and to learning to live within respiratory limitations. More might have been devoted to the treatment of depression, which so often accompanies chronic chest disease. Less welcome aspects of the book include a certain amount of repetition, particularly in drug descriptions. The section on pulmonary-function testing scarcely mentions peak-flow rate, but concentrates enthusiastically on the flow-volume loop without drawing attention to the essential need for careful calibration of the apparatus. In an otherwise helpful chapter on evaluation of patients before surgery, nothing is said about simple exercise testing. The peculiar American attitude to cromoglycate is evident, the drug here being described alongside mucolytics and expectorants. The price of the book cannot have been helped by the many photographs of spirometers and oxygen-delivery systems. Nevertheless, this text can be recommended to moderately affluent physicians, principally because it neatly brings together so many diverse aspects of manage-