Plasmacytoma. Treatment Results and Conversion to Myeloma. John Holland, MD, David A. Trenkner, MD, Todd H. Wasserman, MD, and Barbara Fineberg, BA

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1 53 Plasmacytoma Treatment Results and Conversion to Myeloma John Holland, MD, David A. Trenkner, MD, Todd H. Wasserman, MD, and Barbara Fineberg, BA Forty-six cases of solitary plasmacytoma were reviewed for response to radiation and progression to multiple myeloma. Cases were classified as solitary plasmacytomas of bone (SPB) (32 cases) or extramedullary plasmacytomas (EP) (4 cases). There was an overall 93% response rate of the tumor to radiation therapy: 62% had a complete response after radiation therapy, whereas 3% had a partial response. Conversion to multiple myeloma was influenced by the type of plasmacytoma; 53% of the patients with SPB converting to myeloma versus 36% of the patients with EP. Time from diagnosis to conversion for patients with SPB showed no evidence of plateau, with conversion continuing to occur even after 7 years. The median survival time for patients after conversion to myeloma was 4.5 months and was not affected by time to conversion. Serum protein level, presence of monoclonal gammopathy, and size of primary lesion were of some prognostic significance in predicting conversion to myeloma. Adjuvant chemotherapy did not affect the incidence of conversion but did appear to delay conversion to myeloma. Seven patients in whom multiple sequential solitary plasmacytomas developed formed a distinct subset, with a median time to a second plasmacytoma of 63 months. In three of these patients, conversion to myeloma occurred subsequently. This study supports the idea of EP having a lower incidence of conversion to myeloma and a different natural history from SPB, with SPB likely to be multiple myeloma in evolution. Cancer 992; 69: Solitary plasmacytomas are tumors of plasma cell origin that constitute less than 0% of all plasma cell neoplasms. The rarity of this tumor and its long natural history make determination of prognostic factors diffi- From the Radiation Oncology Center, Mallinckrodt Institute of Radiology, Washington University Medical Center, St. Louis, Missouri. Address for reprints: Todd H. Wasserman, MD, Radiation Oncology Center, Mallinckrodt Institute of Radiology, 4939 Audubon Avenue, Suite 5500, St. Louis, Missouri 630. Accepted for publication June 3, 99. cult. These tumors are categorized as extramedullary plasmacytomas (EP) or solitary plasmacytoma of bone (SPB).'** EP frequently remain localized and can be controlled with radiation therapy, whereas SPB appears to convert more readily to multiple myeloma. This suggests different natural behavi~r.~-~ This retrospective analysis was performed to identify factors that might be used to predict conversion to multiple myeloma and to document the control of plasmacytoma by radiation therapy. Materials and Methods This study is a retrospective review of the records of all patients with a diagnosis of solitary plasmacytoma referred to the Mallinckrodt Institute of Radiology, Washington University School of Medicine, and Christian Northeast Hospital, St. Louis, Missouri, from 96 to 988. Criteria for inclusion in this study were as follows: () biopsy evidence of a plasma cell neoplasm; (2) bone marrow biopsy specimen with negative findings (less than 0% plasma cells); and (3) absence of evidence of other lesions based on clinical examination or skeletal series. Forty-six patients met these criteria (Table ). Four of 46 patients did not have initial bone marrow biopsies but have been included based on evaluation of the course of their disease: 2 had conversion to myeloma only after a significant time interval (29 and 77 months) and 2 had not had conversions to myeloma at last follow-up (9 and 90 months). Thirty-three patients were male (72%) and 3 were female (28%). Median age was 60 years (range, 20 to 85 years). Thirty-two patients were classified as having SPB (70%), and EP was diagnosed in 4 patients (30%) with no clinical or radiographic evidence of bone involvement. Initial work-up included a complete history and physical examination; a biopsy of the primary site; bone marrow biopsy (42 patients); serum protein electrophoresis (2 patients); complete blood count and platelet count; determination of blood urea nitrogen,

2 ~~ 54 CANCER March 25, 2992, Volume 69, No. 6 Table. Patient Characteristics Solitary plasmacytoma of bone Extramedullary Dlasmacvtoma No. of patients 32 4 Male:female 2.2:l 3.7 Median age (yr) Age range (yr) Response rate after radiation therapy (%) Conversion to multiple mveloma (YO) creatinine, alkaline phosphatase, serum calcium, and urine protein levels; and skeletal radiographic series. Twenty of 32 SPB (63%) occurred in the axial skeleton, with vertebral bodies being the most common site. Most EP occurred in head and neck sites (8 of 4 patients [57%]) (Table 2). All patients received radiation therapy as primary treatment. The median dose was 460 cgy (range, 6 to 6200 cgy). In addition, 4 patients (30%) received adjuvant chemotherapy. The median follow-up was 66 months (range, 3 to 286 months). The end points used in this study are the following: () complete response, which is defined as total eradication of tumor based on symptomatic relief or radiographic evidence; (2) partial response, defined as clinical or radiographic diminution of tumor greater than 50% in any dimension or symptomatic relief that is less than complete; (3) conversion to multiple myeloma, which requires 0% or more plasma cells on bone marrow biopsy or multiple sites of involvement on skeletal series; (4) development of a second solitary plasmacytoma; or (5) death. This study was analyzed on a VAX 8600 computer (Digital Equipment Corp., Maynard, MA) with the use of BMDP Statistical Software.24 Statistical tests included the Pearson chi-square, Yates corrected chisquare, and Fisher's exact test (two-tailed), where appropriate. Survivals and survival functions were analyzed with the use of the actuarial life table as applied by Cutler and Ederer," and statistical tests were the generalized Wilcoxon (Breslow), generalized Savage (Mantel-Cox), and Tarone-Ware tests." Results Solitary plasmacytoma responded well to radiation therapy over the entire range of radiation doses used in this analysis. Ninety-four percent of the SPB responded to treatment: 56% with a complete response and 38% with a partial response. Ninety-three percent of the El' responded to radiation therapy: 72% had a complete response and 2% had a partial response. There was no evidence of a radiation dose-response effect over the dose range used. Seventeen of 32 (53%) patients with SPB had conversion to multiple myeloma. Five of 4 (36%) patients with EP had conversions. Median time to conversion for SPB was 3 months, with a range of 3 to 204 months. Median time for conversion of EP was 3 months, with a range of 3 to 6 months. Time to conversion to myeloma showed no evidence of a plateau for the patients with SPB, who continued to have conversions to myeloma even after 7 years (Fig. ). Thirteen of 7 (76%) patients with SPB in whom conversion to myeloma occurred died. Median time from SPB conversion to death was 24 months. Three of five (60%) patients with EP converting to myeloma died: one patient died l month after the diagnosis of myeloma and one after 5 months; in one the diagnosis was made at autopsy. The complete response rate was not dependent on radiation dose. The median dose for those having a complete response was 4600 cgy (range, 6 to 6200 cgy), compared with a median dose of 4620 cgy (range, 2478 to 5600 cgy) for those with incomplete responses. Patients with plasmacytoma ultimately converting to myeloma received slightly less irradiation than those who remained myeloma free; the median dose for those with conversion to myeloma was 4550 cgy, compared with 4725 cgy for those who remained myeloma free. For patients with SPB, a similar difference was observed between those in whom myeloma developed and those remaining myeloma free; patients with SPB in whom myeloma developed had a median dose of 4450 cgy, whereas myeloma-free patients with SPB received a median dose of 4620 cgy. Size of the lesion at diagnosis, total serum protein level, and a monoclonal spike observed on protein electrophoresis appeared to predict conversion to multiple Table 2. Local Site of Solitary Plasmacytoma ~~ ~~ ~ Solitary plasmacytoma of bone (n = 32) Vertebra Pelvic girdle Shoulder girdle Skull Pelvic Extremities Extramedullary plasmacytoma (n = 4) Head and neck Mesentery Axilla Pleura Pelvic Stomach (34%) 6 (9%) 4 (3%) 5 (6%) 3 (0%) 3 (0%) 8 (57%) 2 (4%) I

3 PlasmacytomalHolland et al. 55 " apy alone. The survival time after development of myeloma was essentially the same for both groups. A unique pattern of progression was observed in seven patients in whom multiple, sequential, solitary plasmacytomas developed before any manifestation of myeloma. The median time to development of a second plasmacytoma was 63 months. Three of these patients had subsequent conversions to multiple myeloma, with a median time to conversion of 6 months from diagnosis (range, 55 to 0 months). Median time to conversion to myeloma after the appearance of a second solitary plasmacytoma was 25 months (range, 5 to 36 months). The four patients in whom conversion did not occur have been observed for 22, 27, 30, and 36 months since the appearance of their second solitary plasmacytoma. + Discussion MYELOMA FREE SURVIVAL (years) Solitary plasmacytomas are rare tumors of plasma cell Figure. Actuarial progression-free survival of patients with extramedullary plasmacytomas compared with patients with solitary plasmacytomas of bone. Conversion to multiple myeloma is the end point. myeloma. The median lesion size was 7 cm for those in whom conversion to myeloma occurred, compared with a median size of 3.75 cm for those remaining myeloma free. Of those with conversion to myeloma, 9 of (82%) had lesions that were 5 cm or larger, whereas only 5 of 8 (28%) myeloma-free patients had lesions that were 5 cm or larger (7 lesions could not be assessed for size) (P = ). The median serum protein level in patients with conversion to myeloma was 7.55 mg/dl, compared with 6.9 mg/dl for those in whom conversion did not occur. Patients with a monoclonal spike on serum electrophoresis were more likely have conversion to myeloma. Eight of patients with a monoclonal spike had conversions, whereas 4 of 0 patients who had negative results on protein electrophoresis had conversions (P = 0.2). Hematocrit, alkaline phosphatase level, and serum calcium level did not predict for conversion to multiple myeloma. The use of adjuvant chemotherapy did not affect the rate of conversion to myeloma. Nine of 4 patients (64%) who received adjuvant chemotherapy had conversion to multiple myeloma, whereas 3 of 32 patients (4%) who did not receive chemotherapy had conversion. Adjuvant chemotherapy delayed the time to conversion. The median time to conversion for the patients receiving chemotherapy was 59 months, whereas it was 29 months for the patients treated with radiation ther- origin, categorized as EP or SPB. EP most commonly originate in head and neck sites. Woodruff et ~. ' re- ~ ported 6 patients, Corwin and Lindberg6 2 patients, and Knowling et a.' 25 patients with El'. All but two EP developed in head and neck locations. Six of these 53 patients (2%) had metastatic involvement of cervical lymph nodes. Our findings differ slightly from these previous reports, with only 8 of 4 (57%) EP occurring in the head and neck. One patient had a primary tumor in the base of the tongue with extension to cervical nodes. The most common site within the head and neck was the nasal cavity, consistent with other serie~.'~''-'~ Unlike those in other series, almost half of our patients with EP had tumors not located in the head and neck region. Six of 4 (43%) had extramedullary tumors originating in diverse locations, including mesenteric nodes,' axillary nodes, pelvic nodes, pleura, and stomach. SPB frequently occur in the axial skeleton and infrequently in the bones of the extremities. Only 3 of 32 patients in our series had primary lesions develop in either the humerus or femur. Although Woodruff et reported of 2 and Bataille and Sany3 reported of 8 SPB occurring in the extremities, the Princess Margaret Hospital series2 reported a slightly higher incidence of 5 of 25. Chak et d.," from Stanford University, published a study of 20 patients with SPB and analyzed an additional 45 cases from the literature. Overall median survival time was 47 months after progression of disease. Overall survival time was 0.7 years. They did not find sex, age, site, or paraprotein presence to be a prognostic factor.

4 56 CANCER March 5, 2992, Volume 69, No. 6 Frassica et ~. ~ reported a Mayo Clinic study of 47 patients with SPB. Overall, myeloma developed in 54%, sequential solitary bony lesions developed in 2%, and local recurrence developed in %. No patient who received 4500 cgy or more to a solitary lesion had local failure. Abnormal serum protein levels did not influence disease-free survival or overall survival. Median survival time was 96 months. Delauche-Cavallier et ~. found that an M-protein was a prognostic factor in SPB of the spine. EP appears to have a different natural history than SPB, with a lower incidence of conversion to multiple myeloma. In contrast, SPB continues to convert to multiple myeloma even after 7 years. In our review, median survival time of patients with SPB after conversion to myeloma was 24 months, which is similar to the survival time of patients in whom myeloma is diagnosed initially. The continued conversion of SPB to myeloma suggests that these tumors are actually multiple myeloma in evolution. The different rates of EP and SPB for conversion to multiple myeloma have been observed previously. Knowling et a. reported a 48% conversion rate for SPB, compared with 8% for EP. Convin and Lindberg, from the M. D. Anderson Hospital, reported a similar difference (Table 3).6 Fifty percent of the patients with SPB had conversion to myeloma, compared with only 7% of the patients with EP. It is interesting that, although our analysis supports the concept of SPB behaving as myeloma in evolution with a greater conversion rate than EP, our EP conversion rate of 36% is higher than that reported by the groups at Princess Margaret or M. D. Anderson. Perhaps, the higher frequency of nonhead and nonneck EP sites in our review is related to this increase in conversion to myeloma. However, two of six nonhead and nonneck EP converted (33%), a rate of conversion similar to that of the three of eight head and neck EP (38%). Our patients with EP did seem to have quicker conversions than our patients with SPB. Median EP conversion time was 3 months, compared with 3 months for SPB. A primary goal of our analysis was to identify factors that might aid in identifying those patients with plasmacytoma at greater risk for development of myeloma. Lesion size, total serum protein levels, and the presence of a monoclonal spike on serum protein electrophoresis appear to correlate with risk of conversion to multiple myeloma. These factors all indicate a greater initial tumor burden. Unfortunately, the small patient population in this series, because of the rarity of these tumors, precludes statistical significance of some findings. Similar tumor burden data have been reported as a prognostic factor for myeloma. Serum beta-2 microglobulin may be a useful prognostic indicator in the future.? A unique group of patients were identified in whom multiple solitary plasmacytomas developed without evidence of conversion to multiple myeloma. These seven patients (SPB: four patients; EP: three patients) had a total of 6 solitary plasmacytomas. Three of these patients had subsequent conversion to multiple myeloma, with a median time from diagnosis to conversion of 6 months. Three of the four patients in whom conversion has not occurred have been observed for less than 3 years (22,27, and 30 months) since appearance of a second plasmacytoma and will be observed with great interest to determine whether the development of a second solitary plasmacytoma is a harbinger of ultimate conversion to myeloma. It is interesting that the fourth patient in our series in whom conversion has not occurred has had three sequential SPB, with a follow-up of 89 months since appearance of the third lesion. Bataille and Sany3 reported that new solitary lesions developed in 5% of their patients, and myeloma developed later in 75% of these patients. Radiation therapy is the primary modality of treatment in the management of solitary plasmacytomas. The recommended dose of radiation is 5000 to 6000 cgy in 5 to 7 Chemotherapy has been found to prolong survival time effectively in patients with multiple myel~ma. ~ As a result, adjuvant chemotherapy has been administered Table 3. Study Comparison Corwin and Knowling et al. Lindberg6 Current study (MIR) (Princess Margaret) (M. D. Anderson) Characteristics SPB EP SPB EP SPB EP No. of patients Male/female 2/ 3/ 2/ 5/ 3/ 3/ Median survival (mo) % Conversion to myeloma Response (%) SPB: Solitary plasmacytoma of bone; EP: exhamedullary plasmacytoma; MIR: Mallickrodt Institute of Radiology.

5 Plasmacytoma/HolIand et al. 57 in addition to local therapy for solitary plasmacytomas in an attempt to prevent progression to multiple myeloma. Fourteen patients in the current series received adjuvant chemotherapy, but this did not affect the rate of conversion (64% receiving chemotherapy had conversion to myeloma, whereas 4 % of those not receiving chemotherapy had conversion). Chemotherapy may delay the time to conversion; median time to conversion was 59 months with chemotherapy and 29 months without. Median time to death after development of myeloma was similar in the patients with plasmacytoma initially treated with chemotherapy ( 7 months) and those not receiving initial chemotherapy (2 months). Of course, any advantage incurred by a delay in conversion to myeloma must be balanced with the side effects of chemotherapy involving an alkylating agent. In conclusion, extraosseous plasmacytomas display a lower incidence of conversion to myeloma than do SPB and appear to have a different natural history. SPB actually may be myeloma in evolution. Lesion size, total serum protein levels, and the presence of a monoclonal spike on serum electrophoresis may be of prognostic significance in identifying those solitary lesions that ultimately will convert to myeloma. A definitive analysis of prognostic and therapeutic factors will require more patients, and an attempt is being made to accomplish this with a multiinstitutional registry of patients with plasmacytoma. References Osserman EF. Plasma-cell myeloma:. Clinical aspects. N Engl j Med 959; 26: Knowling MA, Harwood AR, Bergsagel DE. Comparison of extramedullary plasmacytomas with solitary and multiple plasma cell tumors of bone. j Clin Oncol 983; : Bataille R, Sany. Solitary myeloma: Clinical and prognostic features of a review of 4 cases. Cancer 98; Mill WB, Griffith R. The role of radiation therapy in the management of plasma cell tumors. Cancer 980; 45: Wiltshaw E. The natural history of extramedullary plasmacytoma and its relationship to solitary myeloma of bone and myelomatosis. Medicine 976; Corwin J, Lindberg RD. Solitary plasmacytoma of bone versus extramedullary plasmacytoma and their relationship to multiple myeloma. Cancer 979; 43: Meis JM, Butler JJ, Osbome BM et al. Solitary plasmacytomas of bone and extramedullary plasmacytomas. Cancer 987; 59: Wasserman TH. Diagnosis and management of plasmacytomas. Oncology 987; (2): Greenberg P, Parker RG, Fu Y-S et al. The treatment of solitary plasmacytoma of bone and extramedullary plasmacytoma. Am ] Clin Oncol 987; 0: Cutler SJ, Ederer F. Maximum utilization of the life table method in analyzing survival. j Chronic Dis 958; 8: Miller RG Jr. Survival Analysis. New York: John Wiley and Sons, Woodruff RK, Whittle JM, Malpas JS. Solitary plasmacytoma: I. Extramedullary soft tissue plasmacytoma. Cancer 979; 43: Poole AG, Marchetta FC. Extramedullary plasmacytoma of the head and neck. Cancer 968; 22: Mendenhall CM, Thar TL, Million RR. Solitary plasmacytoma of bone and soft tissue. Int ] Radiat Oncol Biol Phys 980; 6: Tong D, Griffin TW, Laramore GE et al. Solitary plasmacytoma of bone and soft tissue. Radiology 980; 35: Petrovich Z, Fishkin B, Hittle RE et al. Extramedullary plasmacytoma of the upper respiratory passages. Znt ] Radiat Oncol Biol Phys 977; 2~ Woodruff RK, Malpas JS, White FE. Solitary plasmacytoma:. Solitary plasmacytoma of bone. Cancer 979; 43: Chak LY, Cox RS, Bostwick DG et al. Solitary plasmacytoma of bone: Treatment, progression, and survival. ] CIin Oncol 987; 5: Frassica DA, Frassica FJ, Schray MF et al. Solitary plasmacytoma of bone: Mayo Clinic experience. Int j Radiat Oncol Biol Phys 989; 6~ Delauche-Cavallier MC, Laredo JD, Wybier M et al. Solitary plasmacytoma of the spine: Long-term clinical course. Cancer 988; 6: Bataille R, Dune BGM, Grenier J ef al. Prognostic factors and staging in multiple myeloma: A reappraisal. j Clin Oncol 986; 4~ Mayr NA, Wen B-C, Hussey DH et al. The role of radiation therapy in the treatment of solitary plasmacytomas. Radiother Ond 990; 7: Spom JR, McIntyre DR. Chemotherapy of previously untreated multiple myeloma patients: An analysis of recent treatment results. Sernin Oncol 986; 3: Dixon WJ. BMDP Statistical Software. Los Angeles: University of California Press, 988.