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 Multiple myeloma 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 proteinuria only) occurred in 25 percent and no bone marrow. 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 lymphocyte. 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- plasma cell tumors in both man and mouse. The sions, anemia, 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 inclusion bodies 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 thyroid 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 kidney will be capacity for antibody 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 plasma cell dyscrasias, The frequency of amyloidosis 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 amyloid 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