3IULTIPLE MYELOMA A REPORTOF FIVECASES ERNEST SCOTT, M.D., F. M. STANTON, M.D., AND MARY OLIVER, MA. (From the Department of Pathology, Ohio State University) In 1848 Sir Henry Bence-Jones aiid Sir James Watson pre- sented a paper entitled, “On a New substance Occurring in the Urine of a Patient with Mollitis-ossium,” a “substance” now known as the Bence-Jones bodies, frequeiitly found in the urine of patients with multiple myeloma. The clinical discussion of this same case mas presented in 1850 by McIntyre. In 1873 von Rustizky, in his histological studies of the disease, recognized its involvement of the bone marrow and gave it the name of multiple myeloma. IGililer, in 1889, ~lsopresented a clinical description of the disease and inasmuch as he, rather than McIntyre, has often been credited with the first clinical presentation, the term “Kahler ’s disease” is frequently encountered in the older litera- ture. In 1920 Wallgren reported 120 cases with histological verifica- tion. In 1928 Geschickter and Copeland (l), from the surgical pathological material of the Johns Hopkins Hospital, reported a series of 13 cases, together with a complete review of all available cases in the literature, making a total of 425 cases. Since the publication of this comprehensive article with its discussion of the clinical and structural characteristics of the disease, we have been able to collect from the more recent literature 30 cases of multiple myeloma. To these we add 5 cases from among about 4400 au- topsies in our own series. Grouped by years, the additional cases are : 1927 : Lewis (2), Meyeriling (3), Kleine (4) ; 1928: Battaglia (5), Hcilmann (6), Barr (7),Durman (8), Short iind Crawford (9) ; 1929: Hewitt (10) (5 cases), Stone (ll), Cappel1 (12) (2 cases), Rogers (13), Hub- bard and Case (14) ; 1930: Perla aiid Hutner (15) (2 cases), Cabot (16), Geschickter (17), Freund (18) ; 1931: Cabot (19), Porchownik (20), Jackson et a1 (21) (5 cases). ETIOLOGY Multiple myeloma is a disease of later life. Eighty per cent of all cases, according to Geschickter and Copeland, occur be- tween the ages of forty aiid seventy, with the peak of incidence at 682 MULTIPLE MYELOMA 683 fifty-fiveyears. These authors find but three histologically proved cases under thirty-five years of age; while in the more recent literature are reported 4 cases below thirty-five years (Durman, Hubbard and Case, Rogers, Cabot). The incidence is more than twice as great among males as females. Of the 35 more recent cases, 26 or ‘75 per cent were in males, 9 in females. Wallgren found 68 per cent males among 98 cases, and Geschickter and Copeland in their study of 425 cases, 70 per cent. The latter also itate that in the Johns Hopkins records they found multiple myeloma in 0.03 per cent of all malignancies. CLINICALFEATURES Pain.: Pain, rheumatic and often intermittent, is a frequent first symptom. It occurs most often in the lumbar and sacral regions, next in frequency over the ribs and sternum. Sudden onset of pain with tenderness in the lumbar or dorsal regions was found in all of the present series. The severity of the pain may subside for some months, only to return with the greatest intensity. In the later stages of the disease neurologic symptoms may ap- pear. Forty per cent of the cases report paraplegias and other neurologic disturbances due to compression of the cord (1). In cases 1 and 4 of our series there is record of complete paralysis from the waist down, almost total loss of sensation, and incon- tinence of urine and feces. Multiplicity: Multiple tumor involvement of the bone marrow is characteristic. The lesions vary in size from that of a pin-head to that of an orange. We found in the literature but two cases in which the lesion was single : (a) Geschickter ’s in 1930, a plasma- cell tumor occurring in the femur, and (b) Rogers’ in 1929, a plasma-cell myeloma of the femur with a history of successful amputation. The question of future multiple recurrence arises here, in consideration of the fact that Geschickter and Copeland’s case 10, with a history of amputation for myeloma of the femur, developed within two years multiple myeloma of several bones. In 90 per cent of the cases the ribs, sternum, clavicle or spine in some combination are involved (1). Forty per cent of these have in addition involvement either of the skull or of the ex- tremities about the shoulder or pelvic girdle. Subpleural nodules, as in case 1of our series, are not infrequent. Involving the spine alone, Cabot (16) (1930) reports a case of myeloma in the fourth dorsal vertebra. The lesions of multiple myeloma are to be distinguished from giant-cell sarcoma by the occurrence of the former in the shafts of the long bones, of the latter in their epiphyses. hfultiple myeloma is to be differentiated from endothelial myeloma (Ewing’s tumor) 684 ERNEST SCOTT, F. M. STANTON, AND MARY OLIVER by the frequent occurrence of the latter in childhood and by its existence as one nodule in a bone, in contrast to the adult-age incidence and multiple lesions of the former. Multiple myeloma, moreover, rarely infiltrates soft tissue. The roentgenogram reveals a characteristic, " punchecl-out '' appearance of tlic bonc-small (li scrcte arcas of rarefaction with ragged, moth-eaten outlines and little attempt at boiic repair. The vascularity is grcat and frequently produces a pulsation of tlie mass. -4s was markedly illustrated in case 5, a mere shell of bone may remain over the tumor mass, which can be very easily sliattcred giving rise to spoiitancous fracturcs on tlie slightest movement. Fmctuws : Fractures are very commoii. Among 425 cases tlicre were 62 per cent with pathologic fructnres (1). The most usual sites are in the trunk, first in the ribs, thcw in the clavicle and sternum. Several fractures may ocmr in the same bone. No other tumor of tlie bone or hone-marrow displays such a high pcr- centagc of fractures. Upon the basis of this clinical observation and the apparent bone-resorptive power of tlie tumor cell, Wil- liams (35) in 1932 advanced the theory that the myeloma tumor cell is derived from the osteoblast ratlicr than from tlie plasma cell or myeloblast. If this be the case, however, we should expect to find some attempt at bone repair, whicli we failed to see in any of our cases and which authors state is characteristically absent. Beuzce-Jones Bodies: Tlie clemonstration of the Bence-Jones bodies, a protein distiiict from albumin and globulin, depends 011 the appearance, between 45" C. and 60" C., of a white precipitate in the urine and its disappearance upon further heating to 90'- 100" C. During thc course of the disease its appearance may be iiitermittcnt. It w'as fo~indin the wine of 16 of the 30 cases u7c collected from the literature and iii oiic of our own associated with c~lironicnephritis. It was not tested for in three of onr cases. On the other hand, Bencc-Jones bodies are found in a number of otlicr diseases involving the bone marrow (Boggs :uid Guthrie, 22) such as osteomalacia, mysedcma with bone clianges, lymphatic leukemia, aiid carcinoma of tlie stomach with bone metastases. Some authors consider it an intermediary metabolic substance wliicli may be due to a toxin from the tumor. Pcrlzwcig, Delruc, aiid Gescliickter (23) found a liypcrproteinuria associated with multiple myeloma, which they explain as a systemic respoiisc to tlie foreign-body proteins prescnt in tlie Bence-Jones bodies. Perla and Hutiier (15) found in their studies an association of Hence-Jones proteinuria and arteriosclerotic nephritis. They cx- plain the variable occurrence of Bence-Jones bodies in tlie urine as dependent on the presence of kidney lesions which may mist in MULTIPLE MYELOMA 685 the older age groups independently of tlie myeloma. It is not yet certainly known wlietlier Rcnce-Jones proteins can pass through the normal kidney. Metastases: Metastases are said to be rare in multiple myeloma. Hemopoietic tissues, as tlic spleen, liver, and lymph glands, are the most frequent sites, but metastases have been reported in other organs. Several authors have taken the position tliat these arc not true metastases, but evidences of a systemic disease of the hemopoietic organs, as Syrnmers (24), Hoffman, Heilmann, Barr, Jackson et al. In the hlood vessels of many of the bone-marrow growths, however, and in tlie liver sinusoids and kicliiey capillaries of Case 4, free tumor cells were found. It is to be expected that, if the tumor cell is a derivative of licmopoietic tissue and multiple myeloma is, therefore, a specific tumor of the bone marrow and general hemopoietic tissues in which the plasma cell is the neo- plastic element, the neoplasm will display a predilection for the marrow rather tlian for the epipliyses of tlic bones and will occur in multiple foci in tlie same aiid other bones through clircct ex- tension in the vascular tissue and through metastases. In view of the occurrence of tumor cells in kidney capillaries aiid liver sinusoids as well as in the marrow blood vessels, it seems to us that genuine metastasis is uiidoubteclly one method of dissemina- tion, and that by this means and by direct extension the multiple occurrence of tliese growths can be explained. On the contrary, it cannot be denied that the theory of a generalized hemopoietic origin has as yet not been entirely disproved. Bow Defornzities: Skeletal deformities were found in GO per cent of the cases (1). They are chiefly confined to the thorax and rarely involve the extremities, in this respect differing from the deformities of Paget’s disease aiid osteomalacia.