1513

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 my- eloma. Cases were classified as solitary plasmacytomas of bone (SPB) (32 cases) or extramedullary plasmacyto- mas (EP) (14 cases). There was an overall 93% response rate of the tumor to radiation therapy: 62% had a com- plete response after radiation therapy, whereas 31% had a partial response. Conversion to multiple myeloma was influenced by the type of plasmacytoma; 53% of the pa- tients 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 17 years. The median survival time for patients after conversion to my- eloma was 14.5 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 my- eloma. Adjuvant chemotherapy did not affect the inci- dence of conversion but did appear to delay conversion to myeloma. Seven patients in whom multiple sequential solitary plasmacytomas developed formed a distinct sub- set, with a median time to a second plasmacytoma of 63 months. In three of these patients, conversion to my- eloma occurred subsequently. This study supports the idea of EP having a lower incidence of conversion to my- eloma and a different natural history from SPB, with SPB likely to be multiple myeloma in evolution. Cancer 1992; 69:1513-1517.

Solitary plasmacytomas are tumors of plasma cell origin that constitute less than 10% of all plasma cell neo- plasms. 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, Mis- souri.

Address for reprints: Todd H. Wasserman, MD, Radiation Oncol- ogy Center, Mallinckrodt Institute of Radiology, 4939 Audubon Ave- nue, Suite 5500, St. Louis, Missouri 63110.

Accepted for publication June 3, 1991.

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 ap- pears to convert more readily to multiple myeloma. This suggests different natural b e h a v i ~ r . ~ - ~ This retro- spective analysis was performed to identify factors that might be used to predict conversion to multiple my- eloma 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 re- ferred to the Mallinckrodt Institute of Radiology, Wash- ington University School of Medicine, and Christian Northeast Hospital, St. Louis, Missouri, from 1961 to 1988. Criteria for inclusion in this study were as fol- lows: (1) biopsy evidence of a plasma cell neoplasm; (2) bone marrow biopsy specimen with negative findings (less than 10% plasma cells); and (3) absence of evi- dence of other lesions based on clinical examination or skeletal series. Forty-six patients met these criteria (Ta- ble 1). Four of 46 patients did not have initial bone marrow biopsies but have been included based on eval- uation of the course of their disease: 2 had conversion to myeloma only after a significant time interval (29 and 177 months) and 2 had not had conversions to my- eloma at last follow-up (9 and 190 months).

Thirty-three patients were male (72%) and 13 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 14 patients (30%) with no clinical or radiographic evidence of bone in- volvement. Initial work-up included a complete history and physical examination; a biopsy of the primary site; bone marrow biopsy (42 patients); serum protein elec- trophoresis (21 patients); complete blood count and platelet count; determination of blood urea nitrogen,

1514 CANCER March 25, 2992, Volume 69, No. 6

Table 1. Patient Characteristics Solitary plasmacytoma Extramedullary of bone Dlasmacvtoma

~~

No. of patients 32 14 Male:female 2.2:l 3.71 Median age (yr) 60 58

Response rate after

Conversion to multiple

Age range (yr) 21-81 20-85

radiation therapy (%) 94 93

mveloma (YO) 53 36

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 14 patients [57%]) (Table 2).

All patients received radiation therapy as primary treatment. The median dose was 4610 cGy (range, 1611 to 6200 cGy). In addition, 14 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: (1) 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 symp- tomatic relief that is less than complete; (3) conversion to multiple myeloma, which requires 10% 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 in- cluded the Pearson chi-square, Yates corrected chi- square, and Fisher's exact test (two-tailed), where ap- propriate. Survivals and survival functions were ana- lyzed 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 ther- apy 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 21% 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 con- version to multiple myeloma. Five of 14 (36%) patients with EP had conversions. Median time to conversion for SPB was 31 months, with a range of 3 to 204 months. Median time for conversion of EP was 13 months, with a range of 3 to 61 months. Time to con- version to myeloma showed no evidence of a plateau for the patients with SPB, who continued to have con- versions to myeloma even after 17 years (Fig. 1). Thir- teen of 17 (76%) patients with SPB in whom conversion to myeloma occurred died. Median time from SPB con- version to death was 24 months. Three of five (60%) patients with EP converting to myeloma died: one pa- tient 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 depen- dent on radiation dose. The median dose for those hav- ing a complete response was 4600 cGy (range, 1611 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 ob- served 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 re- ceived a median dose of 4620 cGy.

Size of the lesion at diagnosis, total serum protein level, and a monoclonal spike observed on protein elec- trophoresis 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

Head and neck Mesentery Axilla Pleura Pelvic Stomach

Extramedullary plasmacytoma (n = 14)

11 (34%) 6 (19%) 4 (13%) 5 (16%) 3 (10%) 3 (10%)

8 (57%) 2 (14%) 1 1 I

1

PlasmacytomalHolland et al. 1515

" 0 + 0 2 4 6 8 0 1 2 1 4 1 6 1 8

MYELOMA FREE SURVIVAL (years)

Figure 1. 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 my- eloma free. Of those with conversion to myeloma, 9 of 11 (82%) had lesions that were 5 cm or larger, whereas only 5 of 18 (28%) myeloma-free patients had lesions that were 5 cm or larger (17 lesions could not be as- sessed for size) (P = 0.0078). 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 11 patients with a monoclonal spike had conversions, whereas 4 of 10 pa- tients who had negative results on protein electrophore- sis had conversions (P = 0.2). Hematocrit, alkaline phosphatase level, and serum calcium level did not pre- dict for conversion to multiple myeloma.

The use of adjuvant chemotherapy did not affect the rate of conversion to myeloma. Nine of 14 patients (64%) who received adjuvant chemotherapy had con- version to multiple myeloma, whereas 13 of 32 patients (41%) who did not receive chemotherapy had conver- sion. Adjuvant chemotherapy delayed the time to con- version. 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-

apy alone. The survival time after development of my- eloma 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 61 months from diagno- sis (range, 55 to 110 months). Median time to conver- sion to myeloma after the appearance of a second soli- tary plasmacytoma was 25 months (range, 15 to 36 months). The four patients in whom conversion did not occur have been observed for 22, 27, 30, and 136 months since the appearance of their second solitary plasmacytoma.

Discussion

Solitary plasmacytomas are rare tumors of plasma cell origin, categorized as EP or SPB. EP most commonly originate in head and neck sites. Woodruff et ~ 1 . ' ~ re- ported 16 patients, Corwin and Lindberg6 12 patients, and Knowling et a1.' 25 patients with El'. All but two EP developed in head and neck locations. Six of these 53 patients (12%) had metastatic involvement of cervical lymph nodes.

Our findings differ slightly from these previous re- ports, with only 8 of 14 (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 14 (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 in- frequently 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 1 of 12 and Bataille and Sany3 reported 1 of 18 SPB occurring in the extremities, the Princess Margaret Hospital series2 reported a slightly higher in- cidence of 5 of 25.

Chak et d.," from Stanford University, published a study of 20 patients with SPB and analyzed an addi- tional 45 cases from the literature. Overall median sur- vival time was 47 months after progression of disease. Overall survival time was 10.7 years. They did not find sex, age, site, or paraprotein presence to be a prognostic factor.

1516 CANCER March 15, 2992, Volume 69, No. 6

Frassica et ~ 1 . ’ ~ 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 1 1 % . No patient who received 4500 cGy or more to a solitary lesion had local failure. Abnormal serum protein levels did not influ- ence disease-free survival or overall survival. Median survival time was 96 months.

Delauche-Cavallier et ~1.’’ 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 multi- ple myeloma even after 17 years. In our review, median survival time of patients with SPB after conversion to myeloma was 24 months, which is similar to the sur- vival time of patients in whom myeloma is diagnosed initially. The continued conversion of SPB to myeloma suggests that these tumors are actually multiple my- eloma in evolution.

The different rates of EP and SPB for conversion to multiple myeloma have been observed previously. Knowling et a1.’ 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 17% of the patients with EP. It is interesting that, al- though our analysis supports the concept of SPB behav- ing 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 non- head 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 13 months, compared with 31 months for SPB.

Table 3. Study Comparison

A primary goal of our analysis was to identify fac- tors that might aid in identifying those patients with plasmacytoma at greater risk for development of my- eloma. Lesion size, total serum protein levels, and the presence of a monoclonal spike on serum protein elec- trophoresis 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 find- ings. Similar tumor burden data have been reported as a prognostic factor for myeloma.” Serum beta-2 micro- globulin 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 pa- tients) had a total of 16 solitary plasmacytomas. Three of these patients had subsequent conversion to multiple myeloma, with a median time from diagnosis to con- version of 61 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 ap- pearance of a second plasmacytoma and will be ob- served with great interest to determine whether the de- velopment of a second solitary plasmacytoma is a har- binger 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 15% of their patients, and myeloma developed later in 75% of these patients.

Radiation therapy is the primary modality of treat- ment 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

Corwin and Knowling et al.’ Lindberg6

Current study (MIR) (Princess Margaret) (M. D. Anderson) Characteristics SPB EP SPB EP SPB EP

No. of patients 32 14 25 25 12 12 Male/female 2/ 1 3/1 2/1 5/1 3/1 3/1

Response (%) 94 93 92 96 92 83

Median survival (mo) 50+ 63+ 86 101 43+ 124 % Conversion to myeloma 53 36 48 8 50 17

SPB: Solitary plasmacytoma of bone; EP: exhamedullary plasmacytoma; MIR: Mallickrodt Institute of Radiology.

Plasmacytoma/HolIand et al. 1517

in addition to local therapy for solitary plasmacytomas in an attempt to prevent progression to multiple my- eloma. Fourteen patients in the current series received adjuvant chemotherapy, but this did not affect the rate of conversion (64% receiving chemotherapy had con- version to myeloma, whereas 4 1 % of those not receiv- ing chemotherapy had conversion). Chemotherapy may delay the time to conversion; median time to con- version was 59 months with chemotherapy and 29 months without. Median time to death after develop- ment of myeloma was similar in the patients with plas- macytoma initially treated with chemotherapy (1 7 months) and those not receiving initial chemotherapy (12 months). Of course, any advantage incurred by a delay in conversion to myeloma must be balanced with the side effects of chemotherapy involving an alkylat- ing 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 ulti- mately will convert to myeloma. A definitive analysis of prognostic and therapeutic factors will require more pa- tients, and an attempt is being made to accomplish this with a multiinstitutional registry of patients with plas- macytoma.

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