Multiple myeloma: An overview for the clinician

JOSEPH R. KLOS, n.o. Portsmouth, Virginia JONATHAN W. BORTZ, DD. Allentown, Pennsylvania

11.7 per million and in the white population 9.7 per usually affects million. The approximate frequencies of occurrence persons past 40, but occurs even in of the various immunoglobulins, derived from re- children. It has numerous clinical ports of several authors, 4" 5•7"8 have been 53 percent manifestations related to tumor for IgG, 20 percent IgA, and less than 1 percent IgD formation, abnormal proteins in and IgE. Light-chain disease (with Bence-Jones serum or urine, and infiltration of only) occurred in 25 percent and no . Chemotherapy at abnormal protein in urine or serum in 1 percent. present employs alkylating agents and Franklins disease, or IgG heavy-chain disease, steroids and leads to survival for an with proteinuria or alpha chain disease is rare. average of 48 months. The prognosis Etiology depends on the clinical stage, which is based on the number of neoplastic The cause of the disease is unknown. The cells and other characteristics of the homogeneous immunoglobulin produced by the tumor that affect its response to neoplastic plasma cells suggests malignant treatment. transformation of a single clone of cells derived from a solitary B . Since many of these immunoglobulins are specific and their structural determinants are identical to those of the normal immunoglobulins of normal persons, the possibility that proliferation of neoplastic cells Multiple myeloma is a lymphoreticular disorder might represent an inappropriate response to an characterized by a neoplastic proliferation of initial antigenic stimulus has been suggested.9" to plasma cells with abnormal immunoglobulin syn- Virus-like particles have been identified 4 in thesis. Characteristically there are lytic bone le- tumors in both man and mouse. The sions, , and a homogeneous elevation of possibility that a chronic hypersensitivity reaction globulin in serum and/or urine. The disease has and chronic inflammation, virus infection, and he- been known to medical science since 1845, when reditary factors may lead to evolution of plas- Bence-Jones protein was discovered in the urine by macytomas exists. No characteristic karyotypic Maclntyre and Watson and described by Bence- abnormalities have been identified in association Jones. 1 The disease has carried the name multiple with myeloma. myeloma since the pathologic studies of Rustizky2 A variety of inconsistent karyotypic abnor- in 1873. The presence of abnormal, tall, narrow malities have been observed: These include aneu- peaks on serum electrophoresis was described first ploidy, pseudodiploidy, polyploidy, and such struc- in 1939 by Longsworth and associates.3 tural abnormalities as translocations, deletions, Approximately 80 percent of patients with mul- chromatid breaks, and giant chromosomes. The tiple myeloma „ are past 40.4 The disease is rare wide variety of aberrations suggests that they are before age 30, but occurs even in children. Early secondary to the neoplasm rather than causative studies reported a sex ratio of 3 male to 1 female according to Osserman and Farhangi.5 patient, but this sex distribution apparently no longer exists.5 Clinical picture A recent study5 showed a greater frequency and Pain, tumors, deformities, pathologic fractures, earlier age of onset in the black than in the white and neurologic symptoms are common presenting population. MacMahon and Clark s reported the complaints of multiple myeloma. Less frequent are mean annual death rate from 1949 through 1952 to anemia, abnormal bleeding tendency, and ne- be 8.9 per million population. For 1951 and 1952 phritis. Fever may occur early in the disease, but is only the death rate in the nonwhite population was of low grade and intermittent. Weight loss is

Multiple myeloma 113/101 moderate at first but becomes severe. Back pain is coagulation factors V, VII, and VIII, platelets, fi- the most common presenting symptom of multiple brinogen, and prothrombin. myeloma and should suggest the possibility of Cold sensitivity is present as a result of the pathologic fracture, especially in persons past 30. presence of cryoglobulins. The symptoms of cryo- Destruction of cortical bone results in pain, swel- globulinemia include a Raynaud type phenomenon ling, and pathologic fracture. The pain is fre- and circulatory impairment, occasionally leading quently rheumatic and often wandering and in- to occlusion and gangrene after only mild exposure termittent at presentation. Often it is referred to to cold. There may be extensive purpura and occa- the back and less often to the chest or extremities. sional thromboses of retinal veins. Generally. the onset of pain is attributed to There may be hyperviscosity syndrome, usually pressure or motion. Rarely is pain not present. associated with intrinsic high viscosity monoclonal The turners are usually multiple and confined to IgG myeloma and occasionally with IgA myeloma. areas of red marrow, including the ribs, sternum, This syndrome is associated with circulatory im- spine, skull, and extremities about the shoulder pairment, but this is more often seen in Wal- and pelvic girdles. Tumors occasionally are palpa- denstróms macroglobulinemia than in myeloma.5 ble, are tender, and vary in size from that of a pea to It is due to either the high molecular weight of the that of a hazel nut. They are elastic and yielding, protein or an increase in its intravascular concen- parchment-like crepitation may be observed over tration. the remaining cortex. The relation between renal disease and Bence- As the disease progresses, there may be classic Jones proteinuria has been assumed for many osseous deformities such as the progressive depres- years. Immunohistochemical studies have iden- sive deformity of pectus cavum or diffuse os- tified Bence-Jones proteins in the cytoplasm of teoporosis with progressive collapse of vertebral the tubular cells but not in the casts, per se. Specific bodies and codfish deformity. Multiple osteolytic defects in the tubulartransport resorption mecha- "punched-out" lesions may be present at the initial nisms may lead to an adult Fanconis syndrome x-ray examination." The roentgenograms are not (aminoaciduria, glycosuria, hyperchloremic aci- wholly reliable in diagnosis of multiple myeloma, dosis, and hyperphosphaturia with needlelike since 13 percent of patients have no significant cytoplasmic in the epithelium of osseous lesions at diagnosis. 12 Occasionally, in- the proximal tubules) in association with Bence- stead of osteolytic lesions, there is diffuse os- Jones proteinuria. This suggests that at least some teoporosis. Moreover, when there are multiple, Bence-Jones proteins have a specific nephrotoxic small, discrete, osteolytic lesions, the possibility of effect, while others appear to have no specific ne- metastatic carcinoma from the breast or phrotoxicity but cause damage by precipitation of must be considered. proteins and obstruction of the tubular lumina. Patients with multiple myeloma are highly sus- This causes a foreign body reaction leading to atro- ceptible to infections, especially with Diplococcus phy of the affected nephron. Rarely does nephron pneumoniae.8"5" 1$ Osserman and Farhangi5 said atrophy progress to diffuse renal atrophy with this is due at least in part to impairment of the renal insufficiency, but if it does, the will be capacity for formation, and Fahey and small and finely granular. Other factors besides associates1° said there is a significant relation be- Bence-Jones proteins contribute to development of tween such impairment and the susceptibility to the renal lesion known as myeloma kidney. These infection. The frequency of herpes zoster and gen- include hypercalciuria, hyperuricosuria, and de- eralized varicella infections is increased with mul- hydration. tiple myeloma and other , The frequency of appears to be in- but apparently is no higher with Hodgkins disease creased with IgD myeloma.5 Approximately 80 or lymphosarcoma.5 Susceptibility to other viral percent of patients with systemic amyloidosis were infections is not increased. Studies of homograft reported by Maldohado and associates e to have rejections have shown a significant prolongation plasmacytosis of marrow. In most cases, according of rejection time, indicating immunologic deficien- to White and colleagues, 16 the protein compo- cies in myeloma that may include cell-mediated nent of is homogeneous and "consists mechanisms. of either an intact light polypeptide chain or an A hemorrhagic diathesis is a rare presenting aminoterminal fragment of a light chain." Kappa sign of myeloma. This results from throw= and lambda paraproteins occur in a ratio ap- bocytopenia or a coagulation defect. Williams and proaching 3 to 5 with myeloma-related amyloido- associates5 have expressed the opinion that these sis, but in a ratio of 3 to 2 with myeloma not asso- defects are directly related to a protein-protein ciated with amyloidosis. 7.16 Clinically, patients complex interaction of a specific M-protein to with amyloidosis manifest macroglossia, cutaneous

114/102 Oct. 1979/Journal of AOA/vol. 791no. 2 hemorrhages (resulting from infiltration of a vessel aspiration or needle biopsy, is essential for the wall), cardiac failure (myocardial infiltration), pe- diagnosis of multiple myeloma. The marrow usu- ripheral neuropathy, carpal tunnel syndrome, ally will contain from 5 to 10 percent plasma cells, nephrotic syndrome, hepatosplenomegaly, or occa- often in sheets,5 and at times may be in excess of 50 sionally malabsorption syndrome. percent of cells, with large, immature and multinu- Neurologic manifestations develop in a signifi- cleated forms. Flame cells, or Undritz type, which cant number of cases. Confusion and delirium are are a form of a storage cell with a cytoplasm mark- associated with multiple myeloma, as with other edly distended by accumulation of proteins, usually serious dyscrasias. There is occasional direct occur with IgA myelomas. 5,18 Hayhoe and Neu- pressure by myeloma on the spinal cord, nerve man s state that they are not confined to IgA roots, cranial nerves, or peripheral nerves, or there type but are common also with IgG and Bence- may be pathologic fracture of vertebral bodies or Jones types. Electron microscopy has shown these other bones. Compression of the spinal cord result- cells to contain distended endoplasmic cisternae.5 ing in partial paralysis and ultimately paraplegia Release of proteins from these flame cells may re- is an extremely serious complication, which re- quire dissolution and disintegration of the cyto- quires emergency laminectomy and decompres- plasm via clasmatosis.5 sion. It should be followed by radiation therapy. The typical myeloma cell 11 is moderately large, Occasionally, infiltration of peripheral nerves from 15 to 30 microns, and round or ovoid, with a and nerve roots by amyloid causes peripheral nucleus between 5 and 7 microns. The nucleus is neuropathy or root syndromes. These are usually round and eccentrically placed, with one or occa- symmetric and associated with other evidence of sionally two nucleoli. Chromatin is not as fine as in amyloidosis, including macroglossia, cardiac man- the myeloblast or as coarse as in the normal plas- ifestations, and/or carpal tunnel syndrome. macyte, and the wheel-spoke arrangement of the Gastrointestinal symptoms may include chromatin is not present." The cytoplasm may be diarrhea, nausea, vomiting, and colic. Hema- basophilic, bright blue, or lighter blue, but does not temesis and melena have been described rarely. show the typical bluish green of the plasmacyte." Epistaxis, ecchymosis, and bleeding about the A perinuclear clear zone is unusual. The myeioma gums and lips also have been described in occa- cell does not take specific stains of plasmacytes. sional cases. The reaction to oxidase is negative. Electron mi.- Palpable splenomegaly is present in 10 per- .croscopy occasionally shows virus-like inclusion cent of cases; hepatomegaly in .30 percent, and bodies in both nucleus and cytoplasm, but there is hepatosplenomegaly in 23 percent. These usually no evidence that they are etiologic. Plasma cells of are due to extramedullary hematopoiesis. 9" 17 multiple myeloma and macroglobulinemia often In from 2 to 10 percent of cases, there may be a contain intranuclear inclusion bodies which have solitary , usually a cystic lesion re- been shown to contain both a specific immuno- sembling a soap bubble but much larger and more globulin secreted by the myeloma and a carbohy- irregular than the usual discrete lesions of multi- drate, probably a part of the myeloma-unique pro- ple myeloma. The diagnosis of solitary plas- tein. Also, intracytoplasmic crystals are relatively macytoma should be based on a careful search for frequent in disorders affecting plasma cell prolifer- additional lesions over 10 years. ation. Cutaneous manifestations are rare, but occa- Peripheral blood often exhibits anemia, usually sionally nodules in the skin may contain isolated normocytic and normochromic. Occasionally, ma- . crocytic anemia with megaloblastic marrow is ob- served. The anemia is refractory to treatment with Laboratory diagnosis iron, vitamin B12, folate, and liver and is due to Hyperproteinemia, hyperglobulinemia, elec- marrow replacement, accelerated erythrocyte de- trophoretic evidence of an abnormal protein com- struction, blood loss, renal insufficiency, effects of ponent in the serum, Bence-Jones protein in the radiotherapy and chemotherapy, intercurrent in- urine, electrophoretic evidence of an abnormal fections, and/or nutritional factors. In rare cases globulin component in the urine with or without secondary polycythemia is associated with multi- Bence-Jones protein, cryoglobulinemia, pyro- ple myeloma and appears to decrease the progress globulinemia, macroglobulinemia, identification of the myeloma. A leukoerythroblastic picture and quantitation of excess globulins by im- (immature granulocytes and nucleated erythro- munoelectrophoresis, and the presence of multiple cytes) may be present. plasmacytomas in the bone marrow are diagnostic Rouleau formation due to an increase in globulin signs of multiple myeloma. resulting in a decrease in zeta potential leads to Examination of bone marrow, obtained by either sludging of blood in the capillary beds and causes

115/103 Multiple myeloma technical difficulty in immunohematologie and of M-spikes are located in the gamma range of hematologic studies. The direct Coombs reaction globulin and from 15 to 30 percent in the beta normally is negative. The sedimentation rate fre- globulin region." There is an occasional M-spike in quently is considerably elevated. Approximately a the transitional region between gamma and beta; third of patients have leukopenia and/or associated rarely there is an M-spike in the alpha-2 region." If thrombocytopenia prior to treatment. The differen- the quantities of IgG, IgA, and IgM are decreased tial leukocyte count frequently will show relative with a monoclonal spike, IgD myeloma should be lymphocytosis ( from 40 to 50 percent) with variable suspected. If the quantities of IgG, IgA, and IgM are numbers of immature and plasma- decreased and there is little or no monoclonal spike, cytes and occasionally myeloma cells. IgE myeloma or light chain disease should be sus- With regard to the protein abnormality, approx- pected. imately 1 percent of patients with multiple Other dysproteinemias occasionally occur with mveloma have no demonstrable protein abnormal- multiple myeloma. The first, cryoglobulinemia, is ity in serum or urine, e• 19 but have only multiple characterized by precipitation of the protein below plasmacytomas of bone marrow. Approximately 25 37 C. It is associated with extensive purpura, pr rcent of patients with multiple myeloma have Raynauds phenomenon, and occasional throm- only Bence-Jones protein in the urine. 4,5.8 Elec- boses of retinal vein. The precipitate is characteris- trophoresis of serum of these patients usually tically a yellowish gray gel. If this is present in shows only a decrease in gamma globulins. 5 A large quantities, the diagnosis is almost certainly rapid screening test for Bence-Jones protein in multiple myeloma. If it occurs in small quantities, urine consists of heat precipitation at from 50 to 60 chronic lymphocytic leukemia, kala-azar, lym- C., with re-solution between 90 and 95 C. and re- phosarcoma, systemic lupus erythematosus, precipitation after cooling. It may be necessary to rheumatoid arthritis, polyarteritis nodosa, Sjóg- concentrate the urine twentyfold when significant rens syndrome, subacute bacterial endocarditis, amounts of protein are not present. The Albustix coronary artery disease, polycythemia vera, portal test often gives a false-negative result when a sig- cirrhosis, and certain malignant tumors are nificant amount of Bence-Jones protein is present.5 possibilities. The second dysproteinemia is pyro- For this reason the urine should be tested with 20 globulinemia, in which the proteins differ from percent solution of sulfosalicylic acid. Approxi- Bence-Jones proteins in being irreversibly pre- mately 50 percent of myeloma patients have cipitated by heating to 56 C. Bence-Jones protein demonstrable in the urine by Hypercalcemia has been observed in about 40 the heat precipitation method. 20 From 50 to 60 per- percent of patients with multiple myeloma.23 cent have Bence-Jones proteinuria demonstrable Levels from 12 to 15 mg./100 ml. are not unusual. by electrophoresis. 21 Bence-Jones protein appears The increase in calcium has been attributed24 to as a sharply defined band between the alpha and the resorption of bone which takes place in gamma globulins on urinary electrophoresis. myeloma. Calcium is increased also as a result of Rarely is Bence-Jones protein seen in any other secondary hyperplasia of the parathyroid glands disease, but it has been reported in myelocytic and because of renal insufficiency. There usually is no lymphocytic leukemia, polycythemia vera, meta- associated increase in inorganic phosphorus in static carcinoma of bone, senile osteomalacia, mul- serum. The alkaline phosphatase concentration in tiple fractures of bone, and inactive tuberculosis.22 the serum is normal or occasionally minimally in- Electrophoresis of serum shows a characteristic creased. This distinguishes the condition from pri- monoclonal protein spike in approximately 75 per- mary hyperparathyroidism. cent of cases. Hyperproteinemia may be mild or Uric acid in the serum frequently is increased." extreme. The highest level of total protein In many cases nitrogen retention" has resulted recorded, according to Wintrobe," was 23.3 from renal insufficiency because of precipitation of grams/100 ml. The average is closer to 8 or 9 Bence-Jones proteins in the cells and other proteins grams/100 ml. There is a reversal of the albumin- in the tubular lumina. globulin ratio as a result of hyperglobulinemia. The diagnostic work-up for multiple myeloma The characteristic serum spike on electrophoresis may include protein electrophoresis of serum, is a tall, narrow, sharply defined peak due to the quantitation of immunoglobulins, urinary elec- presence of large amounts of a relatively trophoresis, tests for Bence-Jones proteins, total homogeneous abnormal protein. This is called a protein, albumin, a complete blood count, determi- monoclonal spike in contrast to the polyclonal nation of the sedimentation rate, bone marrow as- spike found in certain chronic inflammatory pro- piration and needle biopsy, immunoele c cesses. The monoclonal spike is called the M-spike, -trophoresis, metastatic survey, bone scan, mea- not to be confused with IgM. From 55 to 60 percent surement of calcium, inorganic phosphorus, and

116/104 3 Oct. 1979/Journal of AOA/vol. 79/oo. alkaline phosphatase in serum, tests for cryoglobu- 1. Osteolytic lesions when other causes lins and occasionally pyroglobulins, and the Sia have been excluded water test. 2. Absence of other diseases, charac- It is important to search for other sources of os- terized by marrow plasmacytosis teolytic lesions, such as metastatic carcinoma, and other causes of plasmacytosis, including hepatitis, Treatment hepatic cirrhosis, chronic infections such as inac- Studies of cell kinetics 25 have shown that approxi- tive tuberculosis, Hodgkins disease, and occa- mately 20 grams of plasmacytes are needed to pro- sional neoplasms such as hypernephromas. duce a detectable (0.2 grams/100 ml.) monoclonal In differential diagnosis of multiple myeloma the spike on protein electrophoresis. By Gompertzian following conditions, some mentioned by Osserman growth equations, Salmon26 calculated that the and Farhangi,5 should be considered: clone originates approximately 5 years before the Macroglobulinemia cell mass reaches diagnostic size. With such slow Heavy chain disease proliferation of cells, it is obvious that few are in Light chain disease the S phase. For this reason resistance to drugs Amyloidosis specific for S phase is high. Most of the chemo- Benign therapeutic agents currently used in the treatment Franklins disease of multiple myeloma are alkylating agents which Solitary plasmacytomas are not cycle dependent. Lichen myxedematosus or papular mucinosis Melphalan (Alkeran) is given in a high dose, 0.25 Occult plasmacytomas due to: mg. per kilogram body weight per day for 4 days, a. Chronic inflammatory and infectious pro- intermittently at intervals of from 4 to 6 weeks.4 cesses, including osteomyelitis, tuber- Hoogstraten and associates 27 reported that pa- culosis, chronic biliary tract disease, tients who responded to continuous Alkeran pyelonephritis, rheumatoid arthritis and therapy had a significantly increased median chronic pyoderma survival in comparison with nonresponders. b. Nonreticular neoplasms, including car- Alexanian and associates28 reported that the re- cinoma of bowel, breasts, and biliary tract sponse rate to a regimen of 0.25 mg. per kilogram c. Lipodystrophies, including Gauchers dis- per day for 4 days every 6 weeks was approximately ease, familial hypercholesteremia and twice the response rate to a daily dose of 0.025 mg. xanthomatosis per kilogram per day. In another study Hoogstra- d. Hypersensitivity to drugs such as sul- ten and colleagues29 reported that there was no fonamides apparent increase in median survival when con- e. Viral infections tinuous rather than intermittent Alkeran medica- f. Valve prostheses tion was used, but there was a significant im- Coleman and Silver" suggested the follow- provement in function with continuous treatment. ing diagnostic criteria for plasma cell Cyclophosphamide (Cytoxan) given orally (0.25 myeloma: gram per square meter of body surface per day for 4 I. Myeloma cells in excess of 20 percent or days) or intravenously (1.0 gram per square meter sheet-like replacement by myeloma cells for 4 days) at intervals of 3 or 4 weeks theoretically Plus should spare hematopoietic stem cells, since the II. Abnormality of immunoglobulin production drug is more toxic for regenerating than for resting A. Any of the following: hematopoietic cells.4"13 Steroids seem to increase the response rate to 1. Monoclonal spike greater than 4 alkylating agents. Steroids should be used inter- grams/dl. mittently at a dose of 1 or 2 mg. per kilogram of 2. Rising monoclonal spike followed an- body weight per day for 4 days at intervals of 4 to 6 nually weeks concomitantly with alkylating agents.4•13 3. Bence-Jones protein in excess of 0.5 The use of a combination of Alkeran and steroids gram/24 h. increased the response rate from 35 percent on Or Alkeran alone to 70 percent with the combina- B. Any of the following: 28 In a study reported by Coleman and 1. Monoclonal spike less than 4 grams/dl. tions. 13 symptomatic and objective clinical im- with reciprocal depression of normal Silver, provement was increased when prednisone with or immunoglobulins without testosterone enanthate was given along 2. Panhypogammaglobulinemia 13 The dose of Alkeran in this study And with Alkeran. was modified according to changes in platelet and C. Any of the following:

117/105 Mulitiple myeloma (1) 50 percent regression in size of plas- TABLE I. MULTIPLE MYELOMA STAGING SYSTEM. ADAPTED FROM macytoma; DURIE AND SALMON?" (2) reduction of serum immunoglobulin to 50 I. All of the following: percent of pretreatment level and/or reciprocal im- Hemoglobin - 10 gm./100 ml. Serum calcium normal 12 mg./100 ml.) provement of normal immunoglobulina by 50 per- X-ray evidence of normal bone structure or cent; solitary bone plasmacytoma reduction of urinary light chain to 50 per- Low M-spike (3) IgG .5 gm /100 ml. cent of pretreatment level; or (4) evidence of recalcification on skeletal sur- IgA 3 gm./100 ml. or vey; Urine light chain M component 4 gm./24 hr. (5) reduction of plasmacytosis of bone marrow Low tumor cell mass by 20 percentage points or to normal; II- Neither I nor III. Intermediate tumor cell mass (6) increase of hemoglobin by 2 grams/100 ml.; III. One or more of the following: (7) return to normal of urea nitrogen level of Hemoglobin < 8.5 gm /100 ml. blood; Serum calcium ? 12 mg./100 ml. Advanced lytic bone lesions (8) return of calcium to normal or reduction by 2 High M-spike mg./100 ml.; IgG > 7 gm./100 ml. (9) improvement in performance and decrease in or IgA ? 5 gm./100 ml. pain. or Periods of remission have ranged from 6 months Urine light chain M component 12 gm./100 ml. to 7 years. 5 The median survival period has been 3 High tumor cell mass Subclassification years. The survival period is decreased by compli- A. Normal renal function (serum creatinine cations such as plasma cell leukemias, myelo- 2 mg./ 100 ml.) monocytic and myelocytic leukemias, and B. Abnormal renal function (serum creatinine ,2 mg /100 nil.) amyloidosis, especially when it involves the kid- neys. Multiple myeloma has a variety of complica- leukocyte counts. tions. The goal of supportive care is to maintain Radiotherapy is effective for relief of local bone physical and mental well-being. One of the most pain. The complications of intensive and extensive common, and serious, complications is infection by radiation treatment include hypercalcemia. This the usual pathogenic and occasionally by oppor- may be treated by hydration and administration of tunistic organisms (both viral and bacterial). diuretics, corticosteroids, and oral phosphates. Another important and serious complication is Mithramycin, a cytotoxic antibiotic, may be life renal insufficiency and failure. Renal function is saving if conservative treatment fails and the cal- probably one of the most important factors in the cium level continues to rise. prognosis of multiple myeloma. 32 Renal disease may be due to a direct nephrotoxic effect of Bence- Prognosis Jones proteins or to the intratubular precipitation Multiple myeloma can terminate as an acute of proteins. For this reason the patient should be myeloblastic or myelomonocytic leukemia after adequately hydrated to prevent both the renal variable periods of therapy with alkylating agents, complications and the added complications of especially Alkeran, and/or radiation therapy. Such hypercalcemia and possible hyperviscosity. Since leukemia is generally unresponsive to classic an- hydration is important, the patient should not be tileukemic regimens. There is an increased inci- subjected to unnecessary surgery, catheterization, dence of plasma cell leukemia in IgD and IgE or elective biopsy, especially when it involves the myeloma. urinary tract.32 Recently there have been attempts3°,31 to stage Clinical emphasis should be placed on the pre- multiple myeloma on a clinical basis in relation to vention of infectious, metabolic, orthopedic, and tumor cell mass. Dune and Salmon30 classified the neurologic complications. If signs or symptoms of disease in three stages according to the criteria any of these complications appear, treatment listed in Table 1. should be initiated early. The patient with multiple The patients prognosis is directly related to the myeloma, as with any other malignant disease, and clinical stage. For example, Stage 3 disease has a his family require all the patience and physical and worse prognosis than Stage 2, and Stage 2A has a psychologic support that the physician and the better prognosis than Stage 2B. Coleman and paramedical persons can provide. Silver13 listed the following criteria of response to chemotherapy on the basis of their review of vari- ous studies: 1. Jones, H.B.: On a new substance occurring in the urine of a patient with Mollities ossium. Philos Trans R Soc Lond (Biol Sci) 1:55-62, 1848

118/106 Oct. 1979/Journal of AOA/vol. 79/no. 2 2. Rustizky, J.: Multiples myelom. Dtsch Z Chir 3:162-72, 12 Sep 1873 Azar, H.A., et al.: "Nonsecretory" plasma cell myeloma. Observations on 3. Longsworth, L.G., Shedlovsky, T., and Maclnnes, D.A.: Electrophore- seven cases with electron microscopic studies. Am J Clin Pathol 58:618- tic patterns of normal and pathological human blood serum and plasma. J 29, Dec 72 Exp Med 70:399-413, 1 Oct 39 Bergsagel, D.E.: Total body irradiation for myelomatosis. Br Med J 2:325, 4. Bakemeier, R.F.: The malignant lymphomas. In Clinical oncology for 8 May 71 medical students and physicians. A multidisciplinary approach, edited by Bergsagel, D.E.: Plasma cell myeloma. An interpretive review. Cancer P. Rubin. Ed. 4. American Cancer Society, New York, 1974 30:1588-94, Dec 72 5. Osserman, E.F., and Farhangi, M.: Plasma cell myeloma. In Hematol- Bergsagel, D.E.: The treatment of plasma cell myeloma. Br J Haematol ogy, edited by W.J. Williams, et al. McGraw-Hill Book Co., New York, 33:443-9, Aug 76 1972 Bloch, K.J., and Maki, D.G.: Hyperviscosity syndromes associated with 6. MacMahon, B., and Clark, D.W.: The incidence of multiple myeloma. J immunoglobulin abnormalities. Semin Hematol 10:113-24, Apr 73 Chronic Dis 4:508-15, Nov 56 Bonnet, J.D.: Myeloma and other paraproteinernias. Postgrad Med 7. Jancelewicz, Z., et al.: IgD multiple myeloma. Review of 133 cases. 61:216-20, Feb 77 Arch Intern Med 135:87-93, Jan 75 Conklin, R., and Alexanian, R.: Clinical classification of plasma cell 8. Maldonado, J.E., et al.: Pathophysiology of the monoclonal gam- myeloma. Arch Intern Med 135:139-43, Jan 75 mopathies. Postgrad Med 53:102-6, Jun 73; 54:139-45, Jul 73 Davidsohn, I., and Henry, J.: Todd-Sanford clinical diagnosis by labora- 9. DeVita, V.T., and Cannellos, G.P.: Treatment of the lymphomas. tory methods. Ed. 15. W.B. 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J Pa Os- teopath Med Assoc 20:36-7, Summer 77 College of Osteopathic Medicine. Dr. Klos is now a resident in the Department of Pathology, U.S. Naval Hospital, Portsmouth, 32. Cohen, H.J., and Rundles, R.W.: Managing the complications of plasma cell myeloma. Arch Intern Med 135:177-84, Jan 75 Virginia. Dr. Bortz is attending physician at Allentown Os- teopathic Hospital, Allentown, Pennsylvania. Alexanian, R., et al.: Prognostic factors in multiple myeloma. Cancer 36:1192-201, Oct 75 Dr. Klos, U.S. Naval Hospital, Portsmouth, Virginia 23708.

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