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Long Survival in Multiple Myeloma
Long Survival in Multiple Myeloma EDWIN D. BA YRD
SINCE the outlook for survival in multiple myeloma is so uniformly disheartening, instances of unusual duration warrant recognition. Most authors would undoubtedly agree with Snapper and co-workers when they say, "The average period of survival was 20 months, but most of the patients lived less than one and a half years." Adams and associates found the average to be 21 months, Brownell 12 months, Fowler and Gordon 172 to 2 years, and Coley 18 months. All are in accord with our own findings 4 of an average survival of 18 months after onset of symptoms. Of 55 patients followed until they died, Snapper and co-workers found that eight died in the fifth to seventh year of the disease and one lived with her disease for more than 8 years. It is significant that the last-mentioned patient was observed to have mature plasma cells in her marrow. Longest survival in Fowler's series of 52 patients was 3 years. Others1, 5, 12, 14 have reported occasional survivals of 5 to 572 years. Gross and Vaughan reported on two patients who lived for 6 and 10 years respectively. The first of these, a 66-year-old man, was shown to have multiple lesions on x-ray examination and the diagnosis was proved by biopsy. There was no Bence Jones proteinuria, and serum globulins were normal. The lesions were radiosensitive. The patient was first seen in 1931 and was living in 1936. The second patient, a woman 65 years of age, had a plasma cell tumor of the mandible removed in 1926. There was no recurrence until 1934 when she was again operated upon. There was no Bence Jones proteinuria or aspiration of the bone marrow and it was not shown that the myelomatous process was more than a solitary lesion during this time. The patient died in 1936. Geschickter and Copeland stated in 1949 that the longest survival in a proved case was 7 years. They gave no details and may well have been quoting the literature. Kesterson and McSwain recorded a survival of 9 years in a patient whose initial lesion in 1941 was a sacral plasmacytoma. Not until 1946 or 1947 were multiple areas of involvement noted. The patient died in 1951. This case resembles cases of sacral myeloma which also appeared to be solitary at the outset with survival of 872 and 9 years.4 1163
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Garland and Kennedy reported on a patient with "myeloblastic" myeloma who was alive 8~ years after the onset of symptoms in 1939. This patient did not have anemia, Bence Jones proteinuria or aspiration of the bone marrow. The initial lesion was limited to the eighth thoracic vertebra (T-8) and contiguous areas. Roentgen therapy was given and symptoms of transverse myelitis were relieved. Follow-up x-ray examination 1 and 2 months after admission showed the "development of new areas of rib destruction elsewhere" and "apparent progression of the left 8th rib lesion." The patient was not seen for a year and a half and then returned with further involvement of adjacent areas, namely T-7 and T-9. Nothing then was said about "new areas of rib destruction elsewhere." More roentgen therapy was given over the area of T-7 to T-9. It was not until December, 1946, that definite evidence of multiple lesions appeared. The patient was still alive in November, 1947. Multiple or generalized myelomatosis was not proved in this case until the eighth year of the disease, and it seems probable that this case is similar to those reported by Svien and co-workers (in one of which there was a survival of 84 months) of initial solitary myeloma associated with transverse myelitis and relieved surgically by decompression of the cord. Earlier2, 4 reports from the Clinic mentioned survivals of more than 7 years in multiple myeloma. Two of these early cases, reported here in detail, and two others, observed since, are the basis for this paper. With the exception of these patients, a patient treated with radiophosphorus (previously reported and still alive),3 and a patient of Snapper and associates, it would appear that no patient with multiple or systemic myeloma has been known to survive the seventh year. The pmblem of multiple myeloma in general and of diagnosis and treatment in particular has been reviewed within recent years in this periodicaP2 and elsewhere 1 , 4-7,14,15 and will not be discussed here. REPORT OF CASES
CASE 1. A 53-year-old physician was seen at the Clinic in May, 1940, because of backache. He had first experienced pain in the back in December, 1938, when compression of T-12 and 1-1 was noted following an accident. Fourteen months later, in February, 1940, he again hurt his back. X-ray examination then revealed "multiple myeloma." Except for limited motion in the spinal column, physical examination was not remarkable. The laboratory findings were as follows: grade 2 albuminuria but no Bence Jones proteinuria; hemoglobin, 13.5 gm. per 100 cc. of blood; erythrocytes, 5,120,000, and leukocytes, 9,900, per cubic millimeter of blood; smears oflperipheral blood, rouleau formation; serologic reaction for syphilis, negative; and serum calcium, 9.7 mg. per 100 cc. The serum protein was not determined. Roentgenograms of the skull revealed "multiple, small, punched out areas of destruction throughout the calvarium." Roentgenograms of the thoracic and lumbar portions of the spinal column showed destructive changes throughout with narrowing of vertebrae suggesting fracture. Roentgenograms of the ribs were reported as showing osteoporosis affecting all bones and, in addition, osteolytic lesions.
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Aspiration of the bone marrow disclosed many myeloma plasma cells. The patient was given roentgen therapy periodically thereafter for relief of pain, and on at least one occasion he was given p32 and stilbamidine. He suffered frequent fractures of his ribs and ultimately died, on May 12, 1947, which was 7 years after admission to the Clinic and 8Yz years after backache and compression fracture of the spinal column first developed.
LThis patient's roentgen findings, onset and course were characteristic of multiple myeloma except for duration. Bence Jones proteinuria was not present, but it is likely, in view of rouleau formation in the peripheralblood smears, that he had altered globulins. Examination of the bone marrow (Fig. 151) revealed a uniformly well-differentiated myeloma
Fig. 151. Well-differentiated myeloma plasma cells constituted 28 per cent of myeloid elements in this marrow. Also, 21 per cent were lymphocytes (Wright's stain; X600).
plasma cell which made up 28 per cent of the cells in the aspirated specimen of bone marrow. CASE 2. A 40-year-old unemployed single woman was admitted to the Clinic on July 12, 1941. She had had backache since the preceding January, when something "gave way" in her back during a coughing spell. She asserted that she had had pneumonia at that time. She felt better by May, 1941, but again a cough caused recurrence of pain in the back. On examination the patient was noted to breathe with difficulty because of pain. There was tenderness over the lower thoracic and upper lumbar portions of the spinal column, and motion was restricted. The liver was palpable at the costal margin, but the spleen was not. There was pallor of the skin and mucous membranes. The laboratory findings were as follows: grade 3 albuminuria and Bence Jones
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proteinuria; hemoglobin, 8.4 gm. per 100 cc. of blood; erythrocytes, 3,410,000, and leukocytes, 11,000, per cubic milliIi1eter; sedimentation rate, 95 mm. in 1 hour (Westergren method); blood urea, 38 mg. per 100 cc.; serum calcium, 9.6 mg. per 100 cc.; and flocculation reaction for syphilis, negative. Roentgenograms of the thoracic and ·. lumbar portions of the spinal column disclosed osteoporosis and compression fracture, while those of the head showed osteolytic lesions. Aspirated bone marrow presented the characteristics of multiple myeloma. The patient's brother, a veterinarian, gave her calcium gluconate intravenously which he said relieved her of pain for about 6 months at a time. She finally died, on May 10, 1948, which was 772 years after onset of her symptoms and very nearly 7 years after the diagnosis was made .
• Fig. 152. Sixty per cent of the myeloid elements in this marrow were mature myeloma plasma cells (Wright's stain; X750).
The sudden onset of backache in association with respiratory infection and cough is typical of multiple myeloma, as was the subsequent course of repeated pathologic fractures. Bence Jones proteinuria, as well as a very high sedimentation rate, was noted. The latter suggests that hyperglobulinemia of some degree might have been found if it had been sought for. It is of interest to observe that the patient already had significant anemia at this early date in her disease. Smears of bone marrow (Fig. 152) showed abundance of plasmacytes (60 per cent) of a well-differentiated type. Long survival in this case was not associated with any of the usual forms of therapy for this disease. CASE 3. A 61-year-old housewife was admitted to the Clinic on August 22, 1945. She had had pain in the back since she fell in December, 1944. In addition, she had noticed occasional hemoptysis for the past 4 or 5 months.
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Examination was remarkable principally for tenderness of the lumbar portion of the spinal column. The patient was wearing a brace. The laboratory findings were as follows: urinalysis, negative except for Bence Jones proteinuria; hemoglobin, 11.9 gm. per 100 cc. of blood; erythrocytes, 3,550,000, and leukocytes, 6,900, per cubic millimeter; platelets, 105,000 per cubic millimeter; differential count in per cent: lymphocytes 30, monocytes 6, neutrophils 62, eosinophils 1 and basophils 1; serum calcium, 10.2 mg. per 100 cc.; serum phosphorus, 3 mg. per 100 cc.; total serum proteins, 7.5 gm. per 100 cc.; albumin-globulin ratio, 2.5: 1.0; and sedimentation rate, 5 mm. in 1 hour (Westergren). Roentgenograms of the head and thorax did not disclose any abnormality. Those of the lumbar and thoracic portions of the spinal column were interpreted as showing extensive osteoporosis with compression fracture of T-12. The patient was seen again in 1946,1947,1948 and 1953. Bence Jones proteinuria was constantly present. Serum proteins, serum calcium and serum phosphorus remained normal. Anemia gradually developed, and the concentration of hemoglobin in August, 1953, was 8,4 gm. per 100 cc. of blood. The erythrocyte count was 2,500,000 and the leukocyte count 3,300 per cubic millimeter of blood at that time. The erythrocyte sedimentation rate in August, 1953, was 10 mm. in 1 hour (Westergren) and the value for blood urea was normal-38 mg. per 100 cc. The total serum proteins at that time measured 5.6 gm. per 100 cc., with 4.3 gm. of albumin and 1.3 gm. of globulin. Aspiration of the bone marrow in 1948 and in 1953 revealed "a low grade myeloma with a fair amount of normal marrow remaining." Roentgenograms of the spinal column showed gradual progression of osteoporosis and compression fracture of T-10 and L-1, as well as of T-12. Roentgen therapy to the spinal column was administered on at least two occasions, in 1948 and 1953. Subsequently, urethane was also prescribed. The patient died on October 4, 1954, at the age of 70, more than 9 years after her first admission to the Clinic and very nearly 10 years after the onset of symptoms. Once more, back pain was the presenting complaint, and compression fracture in the spinal column was the cause of it. Again Bence Jones proteinuria was a constant finding; however, the concentration of serum globulins was low rather than high. Osteolytic bone lesions did not appear. Smears of bone marrow (Fig. 153) showed a mature type of myeloma plasma cell, which comprised 12 per cent of the cells present. CASE 4. In January, 1943, a 63-year-old farmer was admitted to the Clinic with a history of hoarseness of 2 years' duration which followed a severe sore throat. He felt well otherwise. Physical examination was not remarkable except for fixation of the left vocal cord. The blood pressure was 126 mm. of mercury systolic and 80 mm. diastolic. Laboratory examination disclosed the following: albuminuria, grade 3, and Bence Jones proteinuria; hemoglobin, 11.6 gm. per 100 cc. of blood; erythrocytes, 4,390,000, and leukocytes, 9,700, per cubic millimeter; differential count in per cent: lymphocytes 29.5, monocytes 17, neutrophils 51.5, eosinophils 1.5 and basophils 0.5; peripheral-blood smears, marked rouleau formation suggesting multiple myeloma; flocculation test for syphilis, negative; blood urea, normal (32 mg. per 100 cc.); total serum proteins, 9.9 gm. (3.3 gm. of albumin and 6.6 gm. of globulin) ; and sedimentation rate, 35 mm. in 1 hour (Westergren), but as repeated in subsequent years it was 114, 112 and 137 mm. respectively.
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Fig. 153. Mature myeloma plasma cells may again be noted in the marrow (Wright's stain; X750) .
Fig. 154. The sharp, high gamma peak is characteristic in electrophoretic patterns in mUltiple myeloma. Roentgenograms of the head, thorax, spinal column and pelvis showed only hypertrophic changes. Sternal aspiration revealed what was considered to be an early plasma cell myeloma. The patient was seen again in 1949, 1952, 1953 and December, 1955, the last date being 12 years and 11 months after the first admission. He continued to show Bence Jones proteinuria, and the concentration of serum proteins was continually elevated to levels as high as 10.2 gm. per 100 cc. Electrophoresis (Fig. 154) showed the main peak to be in the gamma globulin fraction. This was also
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true of the urinary proteins which migrated wholly in the gamma range. Repeated stl'lrnal aspiration showed no change in the basic bone-marrow picture. The concentration of blood urea was still normal, 42 mg. per 100 cc., in 1955. The sedimentation rate, 137 mm. in 1 hour (Westergren), was at its highest. When seen in December, 1955, the patient felt well but had had a recurrence of hematemesis which he had had previously in 1953. No intrinsic gastrointestinal lesion could be demonstrated to account for this, but it was not considered to be secondary to the myelomatous process as he had never bled abnormally from the nose or gums or any other site. Except for some osteoporosis, x-ray examination of the skeleton has continued to give negative results.
'. Fig. 155. Well-differentiated myeloma plasma cells were a constant finding in this case. There was also lymphocytosis (Wright's stain; XSOO):
The patient has never had any treatment specifically for his myeloma, and when last seen, at the age of 76 years, he still seemed to be fully as vigorous and healthy as most men of that age.
This patient was alive and essentially well 13 years, lacking 1 month, after the first examination. During this period there was consistent elevation of serum globulins and persistent Bence Jones proteinuria. Osteolytic bone lesions have not developed and the concentration of blood urea has remained normal. Smears of the bone marrow (Fig. 155) showed a mature type of plasma cell which accounted for 11 per cent of the cellular elements present. There were, in addition, a lymphocytosis and an increase in mast cells. COMMENT
It is of interest that, although Bence Jones proteinuria is commonly associated with renal failure, which is a leading cause of death in mul-
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tiple myeloma, three of these patients should have survived for recordbreaking lengths of time with Bence Jones protein in their urine. It is even more surprising when one considers that Bence Jones protein was present from the time of first admission in each of these three cases, a finding that occurs in no more than 50 per cent of the cases of multiple myeloma, on an average. Unfortunately, more is not known about the nature of Bence Jones protein in these cases as compared with those in which renal insufficiency is present. Case 4 was the only case in this group in which electrophoresis was performed on urinary proteins. In that case, all of theW protein present exhibited the mobility of gamma globulin, reflecting the abnormal peak in the serum. Hyperglobulinemia was shown to be absent in Case 3, known to be present in Case 4, and suggested by the finding of excessive rouleau formation in blood smears or an exceptionally high sedimentation rate in Cases 1 and 2. All four cases were characterize(by the finding o(well-differentiated myeloma plasma cells in the bone marrow, in keeping with the case reported by Snapper and co-workers and the observations previously made 2 regarding the relative benignancy of mature cells. Much normal marrow was present in all cases, with plasma cell percentages of only 28, 12 and 11 being noted on examination in Cases 1, 3 and 4 respectively, while approximately 40 per cent of normal elements remained in Case 2. Appropriately, Case 2 was the only case presenting with an appreciable anemia. Each of the first three cases followed the classic, if drawn out, course of multiple myeloma with the development of osteolytic bone lesions or pathologic fracture or both, gradual progression and death. Case 4 differed from the first three in this and other important respects, and needs additional consideration. In Case 4, significant bone lesions were persistently absent. There was no apparent progression after nearly 13 years of disease. The blood urea continued at normal values. The only anemia was that noted immediately following episodes of hematemesis. The spleen and lymph nodes were not palpable, while the marrow conversely was more notable for lymphocytes than plasma cells. Thus, this case, of the four, was the only one in which the bone marrow exhibited lymphocytes in excess of plasma cells. It was further distinguished in respect to the bone marrow by numerous tissue basophils or mast cells. Age, sex, long duration, absence of osteolytic bone lesions, and presence of lymphocytes and mast cells in the bone marrow suggest macroglobulinemia of Waldenstrom. Missing in this case from the syndrome as presented by Waldenstrom were anemia, bleeding from the nose and gums, dyspnea, a sense of illness, and adenopathy. Present in this case,though not usually seen in macroglobulinemia, were a persistent Bence Jones
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proteinuria, normal platelets and an appreciable number of plasma cells in the bone marrow (virtually as many as noted in Case 3). The presence or"absence of macroglobulins, not determined, might be regarded as the point of final distinction upon which the diagnosis of myeloma would turn. This is an open question. The age and sex favor myeloma as well as macroglobulinemia. Bone lesions may be absent in otherwise classic multiple myeloma in one-eighth of the cases, while osteoporosis alone may be noted in another 12 per cent. Lymphocytosis was present in approximately a quarter of more than 50 myeloma marrows previously reviewed. Mast cells, too, are not uncommonly noted. Thus, it is apparent that the presence or absence of bone lesions, lymphocytosis, and mast cells in the marrow is not specific. Against the diagnosis of "macroglobulinemia" in this case, though not the presence of macroglobulins, were constant Bence J ones proteinuria and the absence of anemia, bleeding from the nose and gums, any feeling of illness, and adenopathy even after 13 years of disease. Mandema considers "macroglobulinemia" to be a variant of multiple myeloma, so perhaps a distinction is being made in this case where none is needed. The patient, it is obvious, had combined features in common with both conditions in an almost benign disease, and, while it seems that the case may best be classed with the chronic myelomas at present, its ultimate position must await further clarification of this group of plasma cell disorders. SUMMARY
Four cases of multiple myeloma are presented with survival periods ranging from 7Y2 to nearly 13 years. Bence Jones proteinuria was present in three cases, and in three there were osteolytic bone lesions or compression of vertebrae and pathologic fracture. All the patients had plasmacytosis consistent with myeloma on aspiration of the bone marrow. One had hyperglobulinemia, one did not, and two probably did. One patient was anemic from the outset. Treatment included roentgen therapy, use of radiophosphorus, stilbamidine therapy, urethane therapy, intravenous use of calcium salts, and nothing at all. REFERENCES 1. Adams, W. S., Ailing, E. L. and Lawrence, J. S.: Multiple Myeloma: Its Clinical 2. 3. 4. 5.
and Laboratory Diagnosis with Emphasis on Electrophoretic Abnormalities. Am. J. Med. 6:141-161 (Feb.) 1949. Bayrd, E. D.: Bone Marrow on Sternal Aspiration in Multiple Myeloma. Blood. 3:987-1018 (Aug.) 1949. Bayrd, E. D. and Hall, B. E.: Unusual Remission After Radiophosphorus Therapy in a Case of "Acute Plasma Cell Leukemia." Blood. 3:1019-1024 (Aug.) 1948. Bayrd, E. D. and Heck, F. J.: MUltiple Myeloma: Review of Eighty-three Proved Cases. J.A.M.A. 133:147-157 (Jan. 18) 1947. Brownell, E. G.: Multiple Myeloma: Review of Sixty-one Proved Cases. A.M.A. Arch. Int. Med. 95:699-704 (May) 1955.
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6. Coley, B. L.: Neoplasms of Bone and Related Conditions: Their Etiology, Pathogenesis, Diagnosis and Treatment. New York, Paul B. Hoeber, Inc., 1949, 765 pp. 7. Fowler, W. M. and Gordon, J. D.: Multiple Myeloma. Am. Pract. & Digest Treat. 1 :449--460 (May) 1950. 8. Garland, L. H. and Kennedy, B. R.: Roentgen Treatment of Multiple Myeloma. Radiology. 50:2!:J7-317 (March) l!:J48. 9. Geschickter, C. F. and Copeland, M. M.: Tumors of Bone. Ed. 3, Philadelphia, J. B. Lippincott Company, 1949, 810 pp. 10. Gross, R. E. and Vaughan, W. W.: Plasma Cell Myeloma: Report of Two Cases with Unusual Survivals of Six and Ten Years. Am. J. Roentgenol. 39:344-352 (March) 1938. 11. Kesterson, John and McSwain, Barton: Myeloma of Bone. J. Bone & Joint Surg. 34A:224-228 (March) 1952. 12. Limarzi, L. R.: Diagnostic and Therapeutic Aspects of Multiple Myeloma. M. CLIN. NORTH AMERICA. 35:189-226 (Jan.) 1951. 13. Mandema, E.: Waldenstrom's Macroglobulinemia. Nederl. tijdschr. geneesk. 98:2109-2118 (July) 1954. 14. Meacham, G. C.: Plasma Cell Myeloma. Ann. Int. Med. 38:1035-1047 (May) 1953. 15. Snapper, Isadore, Turner, L. B. and Moscovitz, H. L.: Multiple Myeloma. New York, Grune & Stratton, Inc., 1953, 168 pp. 16. Svien, H. J., Price, R. D. and Bayrd, E. D.: Neurosurgical Treatment of Compression of the Spinal Cord Caused by Myeloma. J.A.M.A. 153:784-786 (Oct. 31) 1953.
SINCE the outlook for survival in multiple myeloma is so uniformly disheartening, instances of unusual duration warrant recognition. Most authors would undoubtedly agree with Snapper and co-workers when they say, "The average period of survival was 20 months, but most of the patients lived less than one and a half years." Adams and associates found the average to be 21 months, Brownell 12 months, Fowler and Gordon 172 to 2 years, and Coley 18 months. All are in accord with our own findings 4 of an average survival of 18 months after onset of symptoms. Of 55 patients followed until they died, Snapper and co-workers found that eight died in the fifth to seventh year of the disease and one lived with her disease for more than 8 years. It is significant that the last-mentioned patient was observed to have mature plasma cells in her marrow. Longest survival in Fowler's series of 52 patients was 3 years. Others1, 5, 12, 14 have reported occasional survivals of 5 to 572 years. Gross and Vaughan reported on two patients who lived for 6 and 10 years respectively. The first of these, a 66-year-old man, was shown to have multiple lesions on x-ray examination and the diagnosis was proved by biopsy. There was no Bence Jones proteinuria, and serum globulins were normal. The lesions were radiosensitive. The patient was first seen in 1931 and was living in 1936. The second patient, a woman 65 years of age, had a plasma cell tumor of the mandible removed in 1926. There was no recurrence until 1934 when she was again operated upon. There was no Bence Jones proteinuria or aspiration of the bone marrow and it was not shown that the myelomatous process was more than a solitary lesion during this time. The patient died in 1936. Geschickter and Copeland stated in 1949 that the longest survival in a proved case was 7 years. They gave no details and may well have been quoting the literature. Kesterson and McSwain recorded a survival of 9 years in a patient whose initial lesion in 1941 was a sacral plasmacytoma. Not until 1946 or 1947 were multiple areas of involvement noted. The patient died in 1951. This case resembles cases of sacral myeloma which also appeared to be solitary at the outset with survival of 872 and 9 years.4 1163
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Garland and Kennedy reported on a patient with "myeloblastic" myeloma who was alive 8~ years after the onset of symptoms in 1939. This patient did not have anemia, Bence Jones proteinuria or aspiration of the bone marrow. The initial lesion was limited to the eighth thoracic vertebra (T-8) and contiguous areas. Roentgen therapy was given and symptoms of transverse myelitis were relieved. Follow-up x-ray examination 1 and 2 months after admission showed the "development of new areas of rib destruction elsewhere" and "apparent progression of the left 8th rib lesion." The patient was not seen for a year and a half and then returned with further involvement of adjacent areas, namely T-7 and T-9. Nothing then was said about "new areas of rib destruction elsewhere." More roentgen therapy was given over the area of T-7 to T-9. It was not until December, 1946, that definite evidence of multiple lesions appeared. The patient was still alive in November, 1947. Multiple or generalized myelomatosis was not proved in this case until the eighth year of the disease, and it seems probable that this case is similar to those reported by Svien and co-workers (in one of which there was a survival of 84 months) of initial solitary myeloma associated with transverse myelitis and relieved surgically by decompression of the cord. Earlier2, 4 reports from the Clinic mentioned survivals of more than 7 years in multiple myeloma. Two of these early cases, reported here in detail, and two others, observed since, are the basis for this paper. With the exception of these patients, a patient treated with radiophosphorus (previously reported and still alive),3 and a patient of Snapper and associates, it would appear that no patient with multiple or systemic myeloma has been known to survive the seventh year. The pmblem of multiple myeloma in general and of diagnosis and treatment in particular has been reviewed within recent years in this periodicaP2 and elsewhere 1 , 4-7,14,15 and will not be discussed here. REPORT OF CASES
CASE 1. A 53-year-old physician was seen at the Clinic in May, 1940, because of backache. He had first experienced pain in the back in December, 1938, when compression of T-12 and 1-1 was noted following an accident. Fourteen months later, in February, 1940, he again hurt his back. X-ray examination then revealed "multiple myeloma." Except for limited motion in the spinal column, physical examination was not remarkable. The laboratory findings were as follows: grade 2 albuminuria but no Bence Jones proteinuria; hemoglobin, 13.5 gm. per 100 cc. of blood; erythrocytes, 5,120,000, and leukocytes, 9,900, per cubic millimeter of blood; smears oflperipheral blood, rouleau formation; serologic reaction for syphilis, negative; and serum calcium, 9.7 mg. per 100 cc. The serum protein was not determined. Roentgenograms of the skull revealed "multiple, small, punched out areas of destruction throughout the calvarium." Roentgenograms of the thoracic and lumbar portions of the spinal column showed destructive changes throughout with narrowing of vertebrae suggesting fracture. Roentgenograms of the ribs were reported as showing osteoporosis affecting all bones and, in addition, osteolytic lesions.
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Aspiration of the bone marrow disclosed many myeloma plasma cells. The patient was given roentgen therapy periodically thereafter for relief of pain, and on at least one occasion he was given p32 and stilbamidine. He suffered frequent fractures of his ribs and ultimately died, on May 12, 1947, which was 7 years after admission to the Clinic and 8Yz years after backache and compression fracture of the spinal column first developed.
LThis patient's roentgen findings, onset and course were characteristic of multiple myeloma except for duration. Bence Jones proteinuria was not present, but it is likely, in view of rouleau formation in the peripheralblood smears, that he had altered globulins. Examination of the bone marrow (Fig. 151) revealed a uniformly well-differentiated myeloma
Fig. 151. Well-differentiated myeloma plasma cells constituted 28 per cent of myeloid elements in this marrow. Also, 21 per cent were lymphocytes (Wright's stain; X600).
plasma cell which made up 28 per cent of the cells in the aspirated specimen of bone marrow. CASE 2. A 40-year-old unemployed single woman was admitted to the Clinic on July 12, 1941. She had had backache since the preceding January, when something "gave way" in her back during a coughing spell. She asserted that she had had pneumonia at that time. She felt better by May, 1941, but again a cough caused recurrence of pain in the back. On examination the patient was noted to breathe with difficulty because of pain. There was tenderness over the lower thoracic and upper lumbar portions of the spinal column, and motion was restricted. The liver was palpable at the costal margin, but the spleen was not. There was pallor of the skin and mucous membranes. The laboratory findings were as follows: grade 3 albuminuria and Bence Jones
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proteinuria; hemoglobin, 8.4 gm. per 100 cc. of blood; erythrocytes, 3,410,000, and leukocytes, 11,000, per cubic milliIi1eter; sedimentation rate, 95 mm. in 1 hour (Westergren method); blood urea, 38 mg. per 100 cc.; serum calcium, 9.6 mg. per 100 cc.; and flocculation reaction for syphilis, negative. Roentgenograms of the thoracic and ·. lumbar portions of the spinal column disclosed osteoporosis and compression fracture, while those of the head showed osteolytic lesions. Aspirated bone marrow presented the characteristics of multiple myeloma. The patient's brother, a veterinarian, gave her calcium gluconate intravenously which he said relieved her of pain for about 6 months at a time. She finally died, on May 10, 1948, which was 772 years after onset of her symptoms and very nearly 7 years after the diagnosis was made .
• Fig. 152. Sixty per cent of the myeloid elements in this marrow were mature myeloma plasma cells (Wright's stain; X750).
The sudden onset of backache in association with respiratory infection and cough is typical of multiple myeloma, as was the subsequent course of repeated pathologic fractures. Bence Jones proteinuria, as well as a very high sedimentation rate, was noted. The latter suggests that hyperglobulinemia of some degree might have been found if it had been sought for. It is of interest to observe that the patient already had significant anemia at this early date in her disease. Smears of bone marrow (Fig. 152) showed abundance of plasmacytes (60 per cent) of a well-differentiated type. Long survival in this case was not associated with any of the usual forms of therapy for this disease. CASE 3. A 61-year-old housewife was admitted to the Clinic on August 22, 1945. She had had pain in the back since she fell in December, 1944. In addition, she had noticed occasional hemoptysis for the past 4 or 5 months.
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Examination was remarkable principally for tenderness of the lumbar portion of the spinal column. The patient was wearing a brace. The laboratory findings were as follows: urinalysis, negative except for Bence Jones proteinuria; hemoglobin, 11.9 gm. per 100 cc. of blood; erythrocytes, 3,550,000, and leukocytes, 6,900, per cubic millimeter; platelets, 105,000 per cubic millimeter; differential count in per cent: lymphocytes 30, monocytes 6, neutrophils 62, eosinophils 1 and basophils 1; serum calcium, 10.2 mg. per 100 cc.; serum phosphorus, 3 mg. per 100 cc.; total serum proteins, 7.5 gm. per 100 cc.; albumin-globulin ratio, 2.5: 1.0; and sedimentation rate, 5 mm. in 1 hour (Westergren). Roentgenograms of the head and thorax did not disclose any abnormality. Those of the lumbar and thoracic portions of the spinal column were interpreted as showing extensive osteoporosis with compression fracture of T-12. The patient was seen again in 1946,1947,1948 and 1953. Bence Jones proteinuria was constantly present. Serum proteins, serum calcium and serum phosphorus remained normal. Anemia gradually developed, and the concentration of hemoglobin in August, 1953, was 8,4 gm. per 100 cc. of blood. The erythrocyte count was 2,500,000 and the leukocyte count 3,300 per cubic millimeter of blood at that time. The erythrocyte sedimentation rate in August, 1953, was 10 mm. in 1 hour (Westergren) and the value for blood urea was normal-38 mg. per 100 cc. The total serum proteins at that time measured 5.6 gm. per 100 cc., with 4.3 gm. of albumin and 1.3 gm. of globulin. Aspiration of the bone marrow in 1948 and in 1953 revealed "a low grade myeloma with a fair amount of normal marrow remaining." Roentgenograms of the spinal column showed gradual progression of osteoporosis and compression fracture of T-10 and L-1, as well as of T-12. Roentgen therapy to the spinal column was administered on at least two occasions, in 1948 and 1953. Subsequently, urethane was also prescribed. The patient died on October 4, 1954, at the age of 70, more than 9 years after her first admission to the Clinic and very nearly 10 years after the onset of symptoms. Once more, back pain was the presenting complaint, and compression fracture in the spinal column was the cause of it. Again Bence Jones proteinuria was a constant finding; however, the concentration of serum globulins was low rather than high. Osteolytic bone lesions did not appear. Smears of bone marrow (Fig. 153) showed a mature type of myeloma plasma cell, which comprised 12 per cent of the cells present. CASE 4. In January, 1943, a 63-year-old farmer was admitted to the Clinic with a history of hoarseness of 2 years' duration which followed a severe sore throat. He felt well otherwise. Physical examination was not remarkable except for fixation of the left vocal cord. The blood pressure was 126 mm. of mercury systolic and 80 mm. diastolic. Laboratory examination disclosed the following: albuminuria, grade 3, and Bence Jones proteinuria; hemoglobin, 11.6 gm. per 100 cc. of blood; erythrocytes, 4,390,000, and leukocytes, 9,700, per cubic millimeter; differential count in per cent: lymphocytes 29.5, monocytes 17, neutrophils 51.5, eosinophils 1.5 and basophils 0.5; peripheral-blood smears, marked rouleau formation suggesting multiple myeloma; flocculation test for syphilis, negative; blood urea, normal (32 mg. per 100 cc.); total serum proteins, 9.9 gm. (3.3 gm. of albumin and 6.6 gm. of globulin) ; and sedimentation rate, 35 mm. in 1 hour (Westergren), but as repeated in subsequent years it was 114, 112 and 137 mm. respectively.
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Fig. 153. Mature myeloma plasma cells may again be noted in the marrow (Wright's stain; X750) .
Fig. 154. The sharp, high gamma peak is characteristic in electrophoretic patterns in mUltiple myeloma. Roentgenograms of the head, thorax, spinal column and pelvis showed only hypertrophic changes. Sternal aspiration revealed what was considered to be an early plasma cell myeloma. The patient was seen again in 1949, 1952, 1953 and December, 1955, the last date being 12 years and 11 months after the first admission. He continued to show Bence Jones proteinuria, and the concentration of serum proteins was continually elevated to levels as high as 10.2 gm. per 100 cc. Electrophoresis (Fig. 154) showed the main peak to be in the gamma globulin fraction. This was also
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true of the urinary proteins which migrated wholly in the gamma range. Repeated stl'lrnal aspiration showed no change in the basic bone-marrow picture. The concentration of blood urea was still normal, 42 mg. per 100 cc., in 1955. The sedimentation rate, 137 mm. in 1 hour (Westergren), was at its highest. When seen in December, 1955, the patient felt well but had had a recurrence of hematemesis which he had had previously in 1953. No intrinsic gastrointestinal lesion could be demonstrated to account for this, but it was not considered to be secondary to the myelomatous process as he had never bled abnormally from the nose or gums or any other site. Except for some osteoporosis, x-ray examination of the skeleton has continued to give negative results.
'. Fig. 155. Well-differentiated myeloma plasma cells were a constant finding in this case. There was also lymphocytosis (Wright's stain; XSOO):
The patient has never had any treatment specifically for his myeloma, and when last seen, at the age of 76 years, he still seemed to be fully as vigorous and healthy as most men of that age.
This patient was alive and essentially well 13 years, lacking 1 month, after the first examination. During this period there was consistent elevation of serum globulins and persistent Bence Jones proteinuria. Osteolytic bone lesions have not developed and the concentration of blood urea has remained normal. Smears of the bone marrow (Fig. 155) showed a mature type of plasma cell which accounted for 11 per cent of the cellular elements present. There were, in addition, a lymphocytosis and an increase in mast cells. COMMENT
It is of interest that, although Bence Jones proteinuria is commonly associated with renal failure, which is a leading cause of death in mul-
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tiple myeloma, three of these patients should have survived for recordbreaking lengths of time with Bence Jones protein in their urine. It is even more surprising when one considers that Bence Jones protein was present from the time of first admission in each of these three cases, a finding that occurs in no more than 50 per cent of the cases of multiple myeloma, on an average. Unfortunately, more is not known about the nature of Bence Jones protein in these cases as compared with those in which renal insufficiency is present. Case 4 was the only case in this group in which electrophoresis was performed on urinary proteins. In that case, all of theW protein present exhibited the mobility of gamma globulin, reflecting the abnormal peak in the serum. Hyperglobulinemia was shown to be absent in Case 3, known to be present in Case 4, and suggested by the finding of excessive rouleau formation in blood smears or an exceptionally high sedimentation rate in Cases 1 and 2. All four cases were characterize(by the finding o(well-differentiated myeloma plasma cells in the bone marrow, in keeping with the case reported by Snapper and co-workers and the observations previously made 2 regarding the relative benignancy of mature cells. Much normal marrow was present in all cases, with plasma cell percentages of only 28, 12 and 11 being noted on examination in Cases 1, 3 and 4 respectively, while approximately 40 per cent of normal elements remained in Case 2. Appropriately, Case 2 was the only case presenting with an appreciable anemia. Each of the first three cases followed the classic, if drawn out, course of multiple myeloma with the development of osteolytic bone lesions or pathologic fracture or both, gradual progression and death. Case 4 differed from the first three in this and other important respects, and needs additional consideration. In Case 4, significant bone lesions were persistently absent. There was no apparent progression after nearly 13 years of disease. The blood urea continued at normal values. The only anemia was that noted immediately following episodes of hematemesis. The spleen and lymph nodes were not palpable, while the marrow conversely was more notable for lymphocytes than plasma cells. Thus, this case, of the four, was the only one in which the bone marrow exhibited lymphocytes in excess of plasma cells. It was further distinguished in respect to the bone marrow by numerous tissue basophils or mast cells. Age, sex, long duration, absence of osteolytic bone lesions, and presence of lymphocytes and mast cells in the bone marrow suggest macroglobulinemia of Waldenstrom. Missing in this case from the syndrome as presented by Waldenstrom were anemia, bleeding from the nose and gums, dyspnea, a sense of illness, and adenopathy. Present in this case,though not usually seen in macroglobulinemia, were a persistent Bence Jones
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proteinuria, normal platelets and an appreciable number of plasma cells in the bone marrow (virtually as many as noted in Case 3). The presence or"absence of macroglobulins, not determined, might be regarded as the point of final distinction upon which the diagnosis of myeloma would turn. This is an open question. The age and sex favor myeloma as well as macroglobulinemia. Bone lesions may be absent in otherwise classic multiple myeloma in one-eighth of the cases, while osteoporosis alone may be noted in another 12 per cent. Lymphocytosis was present in approximately a quarter of more than 50 myeloma marrows previously reviewed. Mast cells, too, are not uncommonly noted. Thus, it is apparent that the presence or absence of bone lesions, lymphocytosis, and mast cells in the marrow is not specific. Against the diagnosis of "macroglobulinemia" in this case, though not the presence of macroglobulins, were constant Bence J ones proteinuria and the absence of anemia, bleeding from the nose and gums, any feeling of illness, and adenopathy even after 13 years of disease. Mandema considers "macroglobulinemia" to be a variant of multiple myeloma, so perhaps a distinction is being made in this case where none is needed. The patient, it is obvious, had combined features in common with both conditions in an almost benign disease, and, while it seems that the case may best be classed with the chronic myelomas at present, its ultimate position must await further clarification of this group of plasma cell disorders. SUMMARY
Four cases of multiple myeloma are presented with survival periods ranging from 7Y2 to nearly 13 years. Bence Jones proteinuria was present in three cases, and in three there were osteolytic bone lesions or compression of vertebrae and pathologic fracture. All the patients had plasmacytosis consistent with myeloma on aspiration of the bone marrow. One had hyperglobulinemia, one did not, and two probably did. One patient was anemic from the outset. Treatment included roentgen therapy, use of radiophosphorus, stilbamidine therapy, urethane therapy, intravenous use of calcium salts, and nothing at all. REFERENCES 1. Adams, W. S., Ailing, E. L. and Lawrence, J. S.: Multiple Myeloma: Its Clinical 2. 3. 4. 5.
and Laboratory Diagnosis with Emphasis on Electrophoretic Abnormalities. Am. J. Med. 6:141-161 (Feb.) 1949. Bayrd, E. D.: Bone Marrow on Sternal Aspiration in Multiple Myeloma. Blood. 3:987-1018 (Aug.) 1949. Bayrd, E. D. and Hall, B. E.: Unusual Remission After Radiophosphorus Therapy in a Case of "Acute Plasma Cell Leukemia." Blood. 3:1019-1024 (Aug.) 1948. Bayrd, E. D. and Heck, F. J.: MUltiple Myeloma: Review of Eighty-three Proved Cases. J.A.M.A. 133:147-157 (Jan. 18) 1947. Brownell, E. G.: Multiple Myeloma: Review of Sixty-one Proved Cases. A.M.A. Arch. Int. Med. 95:699-704 (May) 1955.
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6. Coley, B. L.: Neoplasms of Bone and Related Conditions: Their Etiology, Pathogenesis, Diagnosis and Treatment. New York, Paul B. Hoeber, Inc., 1949, 765 pp. 7. Fowler, W. M. and Gordon, J. D.: Multiple Myeloma. Am. Pract. & Digest Treat. 1 :449--460 (May) 1950. 8. Garland, L. H. and Kennedy, B. R.: Roentgen Treatment of Multiple Myeloma. Radiology. 50:2!:J7-317 (March) l!:J48. 9. Geschickter, C. F. and Copeland, M. M.: Tumors of Bone. Ed. 3, Philadelphia, J. B. Lippincott Company, 1949, 810 pp. 10. Gross, R. E. and Vaughan, W. W.: Plasma Cell Myeloma: Report of Two Cases with Unusual Survivals of Six and Ten Years. Am. J. Roentgenol. 39:344-352 (March) 1938. 11. Kesterson, John and McSwain, Barton: Myeloma of Bone. J. Bone & Joint Surg. 34A:224-228 (March) 1952. 12. Limarzi, L. R.: Diagnostic and Therapeutic Aspects of Multiple Myeloma. M. CLIN. NORTH AMERICA. 35:189-226 (Jan.) 1951. 13. Mandema, E.: Waldenstrom's Macroglobulinemia. Nederl. tijdschr. geneesk. 98:2109-2118 (July) 1954. 14. Meacham, G. C.: Plasma Cell Myeloma. Ann. Int. Med. 38:1035-1047 (May) 1953. 15. Snapper, Isadore, Turner, L. B. and Moscovitz, H. L.: Multiple Myeloma. New York, Grune & Stratton, Inc., 1953, 168 pp. 16. Svien, H. J., Price, R. D. and Bayrd, E. D.: Neurosurgical Treatment of Compression of the Spinal Cord Caused by Myeloma. J.A.M.A. 153:784-786 (Oct. 31) 1953.