79

Chapter 79

Plasma Cell Myeloma and Plasmacytoma

David C. Hodgson

Joseph Mikhael

Richard W. Tsang

Epidemiology and Etiology

Plasma cell neoplasms account for 22% of all mature B-cell neoplasms in the Surveillance, Epidemiology, and End Results (SEER) program in the United States (85). The majority of plasma cell neoplasms are multiple myeloma, with solitary plasmacytoma accounting for ≤6% of cases and rarely plasma cell leukemia. Although the incidence of multiple myeloma has gradually increased in the 1970s through the 1990s (100), recently there has been a downward trend, with an annual decrease of 0.3% from 1992 to 2002 (101). Data from SEER indicate an incidence rate of 5.5/100,000 per year and mortality rate of 3.8/100,000 per year during the period 1998 to 2002 (101). For 2007, it is estimated that there will be 19,900 new cases and 10,790 deaths due to multiple myeloma in the United States (5). The incidence rate exceeds that of Hodgkin's lymphoma and is about one-quarter that of non-Hodgkin's lymphoma. The incidence rate rises with advancing age, with a median age at diagnosis of 70 years (101), and <1% of cases are diagnosed in persons <35. Nonregistry studies usually report a lower median age ranging from 60 to 66 years (50,68). There is a slight male predominance, and for black Americans, the incidence and mortality rates are approximately double that of whites. The 5-year relative survival rates have increased, from 26% in 1975 to 1977, to 33% in 1996 to 2002 (p <.05) (5). The etiology of multiple myeloma is not known, but there are studies reporting association with prior exposure to radiation (e.g., atomic bomb survivors in Hiroshima) (88), certain chemicals such as petroleum products (18,29), and monoclonal gammopathy of unknown significance (MGUS) (69). The previously reported association with herpes simplex virus type 8 does not appear to be causally related (113).

Natural History, Genetic Mechanisms

Multiple myeloma is a disease with a wide clinical spectrum, ranging from the condition known as MGUS to the most aggressive form, plasma cell leukemia (Table 79.1). In all cases, a plasma cell clone exists but to varying degrees. The secretion of a monoclonal protein by these plasma cells, along with their interaction with the bone marrow environment, is the source of organ damage in patients with this illness (54). These concepts have become particularly important as the molecular mechanisms by which the disease progresses through these “stages” provide essential information that may help to better understand the disease and its potential therapies.

Monoclonal Gammopathy of Unknown Significance

MGUS has traditionally been considered a benign or a premalignant condition in which only a small proportion of patients will progress to multiple myeloma or related diseases (see Table 79.1). In MGUS, the monoclonal protein is ≤3 g/dL and the bone marrow clonal plasma cells are <10% with no related organ damage. This condition is likely much more common than initially thought, as it has been documented in 3% of the overall population and 5% in those over the age of 70 (70). The risk of transformation to myeloma and related diseases (such as amyloidosis or Waldenstrom's macroglobulinemia) has been estimated at 1% per year, based on a 30-year follow-up of 1,384 patients at the Mayo Clinic (69).

Asymptomatic Multiple Myeloma (Smoldering Myeloma)

Asymptomatic multiple myeloma represents an intermediate form of myeloma whereby patients meet serological monoclonal protein and bone marrow criteria for the diagnosis of myeloma (in excess of 10% clonal plasmacytosis) but have yet to develop evidence of end organ damage (see Table 79.1). These patients are not significantly anemic, do not have renal insufficiency, and do not have bony disease. Although the risk of transformation to multiple myeloma is much higher than in MGUS (5–10% per year), some patients may “smolder” for many years. These patients generally do not require therapy but should be followed closely to monitor for progression.

Pathophysiology

Multiple myeloma arises from malignant transformation of a late-state B cell. Although the seminal event has yet to be defined, one of the earliest genetic events is the illegitimate switch recombination of partner oncogenes into the immunoglobulin heavy (IgH) chain (65). Other events may occur such as cytogenetic hyperploidy and upregulation of cell cycle control genes. The result of these genetic abnormalities is the development and propagation of a clonal population of B cells within the bone marrow; this, however, is common and can be seen in up to 5% of the general population over the age of 70 (70). Most of these will not go on to develop myeloma, so there must be additional events to create the malignant phenotype of multiple myeloma. These secondary events may include mutations of kinases, deletions of chromosomes, and up-regulation of enzymes such as c-myc (43). Having sustained a secondary event, the malignant plasma cells begin to proliferate in the bone marrow microenvironment, producing monoclonal proteins and causing osteolytic bone disease. The slow accumulation of these malignant cells gradually results in the characteristic clinical features of myeloma of anemia, bone resorption, hypercalcemia, renal failure, and immunodeficiency. Established myeloma is dependent and sustained on a number of microenvironment features, including the bone marrow stroma itself and the cytokines interleukin-6 and insulinlike growth factor-1 (54). The bone disease that arises in myeloma appears to be mediated in part by RANK ligand/osteoprotegerin and the Wnt-signaling antagonist dickkopf 1 (DKK1) (114).

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Clinical Presentation

Solitary Plasmacytomas

The median age at diagnosis of solitary plasmacytoma (SP) is 55 to 65 years, on average about 10 years younger than patients with multiple myeloma (90,110,117). Males are affected predominately (male:female ratio 2:1) (90). A diagnosis of SP is made if all the following criteria are satisfied at presentation: a histologically confirmed single lesion with negative skeletal imaging outside the primary site, normal bone marrow biopsy (<10% monoclonal plasma cells), and no myeloma-related organ dysfunction (37). A monoclonal protein is present in 30% to 75% of cases (particularly for an osseous presentation), the level is usually minimally elevated (IgG <3.5 g/dL, IgA <2.0 g/dL, and urine monoclonal kappa or lambda <1.0 g per 24 hours) (37,121).

The disease more commonly presents in bone (80%). Such cases are considered stage I multiple myeloma according to the Durie and Salmon (38) staging system. The most common location is the vertebra (90). Patients with bone involvement often present with pain, neurologic compromise, and occasionally pathologic fracture. A lytic lesion is typical, with or without adjacent soft tissue mass. Less commonly SP presents in an extramedullary site (20%), usually as a mass in the upper aerorespiratory passages that produces local compressive symptoms (4,90,110,116). The histologic diagnosis of extramedullary plasmacytoma (EMP) can be difficult, with the main differential diagnosis being extranodal marginal zone lymphoma (MALT type), where there can be extensive infiltration by plasmacytoid cells (4,58).

Multiple Myeloma

Bone pain and symptoms due to anemia, such as easy fatigability, are the most common (68). Because of the myriad effects of the disease, other insidious symptoms can result from a combination of hypercalcemia, renal impairment, infection, neurologic compression, and occasionally, hyperviscosity. Bone disease manifesting as generalized osteopenia and multiple lytic bone lesions can frequently lead to pathologic fractures. In the vertebral column, this often results in a diminished height. Sclerotic lesions at presentation are rare.

Laboratory evaluation generally confirms anemia, high erythrocyte sedimentation rate, and a variable degree of granulocytopenia and thrombocytopenia. An abnormal monoclonal immunoglobulin (M-protein) in the blood and/or urine is characteristic (68), most commonly immunoglobulin G (IgG) or immunoglobulin A (IgA). Biclonal disease is also recognized, and, rarely, nonsecretary disease. Occasionally only monoclonal light chains are detected. It is important to assess for hypercalcemia, renal dysfunction, and integrity of the skeleton because these complications require appropriate management. A constellation of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes characterize a rare plasma cell dyscrasia known as polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome (33,89).

Plasma Cell Leukemia

Plasma cell leukemia is a very rare variant of multiple myeloma, where the proliferation of plasma cells is not confined to the bone marrow but may be detected in the peripheral blood. It carries a very poor prognosis with median survival of only 3 to 6 months (123). There is currently no standard therapy for this condition, but patients are usually treated with high-dose, multiagent chemotherapeutic regimens or with experimental therapies.

Diagnostic Work-Up and Staging

The recommended tests for the diagnosis of plasma cell neoplasms are outlined in Table 79.2. The most important components relate to the measurement and quantification of the M-protein, bone marrow examination with ancillary

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studies, serum β2 microglobulin and albumin, and diagnostic imaging of involved bony sites. The M-protein should be measured with serum protein electrophoresis (SPEP). Quantification of the monoclonal immunoglobin with immunofixation techniques is also acceptable and especially useful if the M component is at a low level. If no M-protein is detectable, assays for free light chains should be performed in the serum and in the urine (Bence-Jones proteinuria). The standard imaging is the skeletal survey, as radionuclide bone scan usually does not detect lytic disease and has limited value (37). For localized areas of concern, both computed tomography (CT) or magnetic resonance imaging (MRI) should be liberally utilized. MRI is preferred to assess the extent of vertebral disease and the presence of spinal cord or nerve root compression. With advances in diagnostic imaging, it is likely that “stage migration” has occurred (41). It has been documented that some patients with presumed solitary plasmacytoma of bone will be upstaged following the detection of multiple vertebral lesions or bone marrow disease by MRI (74,76,118) or by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) (105). The staging criteria for the widely used Durie and Salmon staging system are detailed in Table 79.3 (38). The newer International Myeloma staging system is simple, validated, and of importance particularly for present and future clinical trials (see Table 79.3) (50). Criteria for the diagnosis of MGUS and asymptomatic (smoldering) myeloma are also well established (37,51).

Prognostic Factors

Solitary Plasmacytoma

Age is a factor affecting the risk of progression to myeloma in some series (14,24,117) but not in others (20,56,77,90,106). A bony presentation has been consistently demonstrated to have a significantly higher risk of subsequent development of myeloma with a 10-year rate of 76%, compared with an extramedullary presentation where the 10-year rate was 36% (Fig. 79.1) (90). Subclinical bone disease, either detected as generalized osteopenia (45) or through abnormal MRI scan of the spine (76,86,118), predicts for rapid progression to symptomatic multiple myeloma. A suppression of the normal immunoglobulin classes, also known as immunoparesis, has been shown to correlate with a higher risk of progressing to myeloma (45,59). Where there was an elevation of M-protein pretreatment, the persistent of the M-protein following radiation therapy (RT) predicts for progression to myeloma (74,121). Many of these factors reflect the presence of occult myeloma. Therefore, it is not surprising that generalized disease becomes manifest once the local disease is controlled. Pathologic factors have been examined in some studies, with the finding that anaplastic plasmacytomas (those with a higher histologic grade) (112), and those tumors expressing a high level of angiogenesis (67) are associated with a poor outcome. Anaplastic plasmacytomas share some common pathologic and clinical features with aggressive B-cell lymphomas (plasmablastic type) and can arise in the context of immunosuppression and Epstein-Barr virus infection (28,42).

With respect to local control, tumor bulk appears to be an important unfavorable factor. Tumors <5 cm achieved a high level of local control with 35 Gy, whereas those >5 cm had a local failure rate of 58% (7/12 patients, total dose range 25 to 50 Gy) (117). The importance of tumor bulk is also supported by other studies (56,77,90).

Multiple Myeloma

Univariate analysis of over 1,000 patients evaluated at the Mayo Clinic revealed the following adverse prognostic risk factors: Eastern Cooperative Oncology Group performance status 3 or 4, serum albumin <3 g/dL, serum creatinine ≥2 mg/dL, platelet count <150,000/µL, age ≥70 years, β2 microglobulin >4 mg/L,

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plasma cell labeling index ≥1%, serum calcium ≥11 mg/dL, hemoglobin <10 g/dL, and bone marrow plasma cell ≥50% (68).

A new International Staging System has been validated to assist in prognostication (50). Over 10,000 patients were evaluated, and the three-stage system was developed based on two variables: serum albumin and β2 microglobulin (see Table 79.3). In addition to stage, the other area emerging as important to prognosis is cytogenetics. Much like acute leukemia, cytogenetic and molecular features are influencing treatment options. Some abnormalities demonstrated to carry a poorer prognosis include: deletion of chromosome 13 (39), presence of the t(4;14) translocation (25), and p53 deletion (92). It is expected that additional cytogenetic and molecular features of prognostic significance will be identified, especially with enhanced techniques such as fluorescence in situ hybridization and gene microarray analysis.

Management of Solitary Plasmacytoma

RT is the standard treatment for solitary plasmacytoma. Surgery should be considered for structural instability of bone or rapidly progressive neurologic compromise such as spinal cord compression (37,109,111). For patients treated with gross tumor excision, RT is still indicated due to a high likelihood of microscopic residual disease. Surgery alone without RT leads to an unacceptably high local recurrence rate (90). A review of the literature for solitary bone plasmacytoma in Table 79.4 indicates a high local control rate with RT (79% to 95%), yet a modest overall survival of approximately 50% at 10 years. This is due to a high rate of progression to multiple myeloma in the bone plasmacytomas, a finding consistently reported from all series (see Fig. 79.1) (14,24,44,45,56,59,63,90,117,121). As shown in Table 79.4, over 60% of patients with solitary bone tumor progressed to myeloma, at a median of 2 to 3 years after treatment. When actuarial methods were not used, the progression rate is slightly lower (crude rates ranges 53% to 54%) (44,56). Therefore, solitary plasmacytoma of the bone appears to be an early form of multiple myeloma. Studies have documented about 29% to 50% of patients with apparent solitary plasmacytoma will have multiple asymptomatic lesions detected in the spine on MRI (76,87,118). Provided that all the other diagnostic criteria for solitary plasmacytoma are satisfied, it is still appropriate to treat with local RT to the presenting site (109). For these patients the risk of developing symptomatic myeloma in a short time is high (76,86,118). Chemotherapy can be started at the time of symptomatic progression. The presence of low level M-protein preradiation is extremely common and is not associated with a higher risk of progression to multiple myeloma. However, its persistence following radiation is highly predictive of subsequent systemic failure (31,45,74,121), attesting to the importance of monitoring this as part of posttreatment follow-up.

The addition of adjuvant chemotherapy is theoretically attractive, both in enhancing local control and eradicating subclinical disease to prevent the development of myeloma. One randomized trial suggested a benefit with adjuvant melphalan and prednisone given for 3 years after RT (10). With a median follow up of 8.9 years, those treated with chemotherapy had a myeloma progression rate of 12%, whereas with RT alone it was 54% (10). However, this was a small study and the concerns regarding prolonged use of alkylating agents on the bone marrow (negative effect on stem cell reserve and risk of leukemia) do not justify its routine use.

It has been observed that some patients recur with plasmacytoma(s) of bone or soft tissues, without bone marrow involvement (14,56,64). This is infrequent and the subsequent development of multiple myeloma is high, 75% in one series (14).

In the management of EMP, while complete surgical excision may be curative for small lesions, most patients with larger lesions or those with tumor location not amenable to complete excision should receive local RT. Postoperative RT is indicated for incompletely excised lesions. In contrast to bone plasmacytoma, EMPs are frequently controlled with local radiation (Table 79.5), with a lower rate of progression to myeloma, ranging from 8% to 44% (22,27,46,61,64,75,90,108,110,112,116,122), indicating a significant proportion of patients are cured of their disease. Although the 10-year survival varies widely in the reported literature (range 31% to 90%), the two largest series report 10-year survival rates of 72% (90) and 78% (46). The issue of dose will be discussed later.

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Management of Multiple Myeloma

A description of therapy of myeloma would not be complete without addressing the need to treat not only the disease itself, but the complications of this disease. Patients often present with both bony disease and anemia—both of these complications are treatable, allowing an improved quality of life. Erythropoietic agents have become the mainstay of anemia management, as have bisphosphonates (15,16,17,35) and local RT for bony disease. Newer surgical techniques such as vertebroplasty and kyphoplasty are also being used to improve back pain and spinal symptoms. Other supportive care interventions being addressed include diet, exercise, and patient support groups.

Initial Treatment of Symptomatic Multiple Myeloma

Patients who have symptomatic multiple myeloma require treatment of the malignant plasma cell clone. Once the decision is made to treat, however, the first step is to determine candidacy for autologous stem cell transplantation (ASCT) (Fig. 79.2). As this modality has become the standard of care for eligible patients, it is necessary to stratify patients initially so that the ability to collect stem cells is not compromised by induction therapy (49).

Patients Eligible for Autologous Stem Cell Transplantation

In patients who are candidates for ASCT, various regimens can be used to induce response prior to stem cell collection. Historically most regimens are high dose and steroid based, either with high-dose dexamethasone alone (3) or with vincristine, adriamycin, and dexamethasone (VAD) (104). An alternative induction is the combination of thalidomide and dexamethasone. Rajkumar et al. (95) demonstrated in 50 patients that this combination yields a response rate of 64% (similar to VAD), without compromising the ability to collect stem cells, but with a rate of deep vein thrombosis of 12% (95). Newer agents that have been validated in the relapse setting, such as bortezomib and lenalidomide, are now being tested as initial therapy with impressive results. Early studies with bortezomib, a first-in-class proteosome inhibitor, have produced response rates of 75% to 100%, with complete remission rates of 20% to 30% (97). Lenalidomide, a derivative of thalidomide, has also been tested in newly diagnosed patients. Rajkumar et al. (96) evaluated the combination of lenalidomide with dexamethasone in 34 patients, with a response rate of 91%.

Patients Not Eligible for Autologous Stem Cell Transplantation

In patients who will not be undergoing a transplant, there are various options available for initial therapy. Most will receive alkylator-based therapy, commonly melphalan and prednisone (MP) (94). This regimen yields partial remissions in approximately 55% of patients, with the occasional complete response. Recent trials have evaluated the addition of thalidomide to melphalan and prednisone (MPT). For patients aged 60 to 85, Palumbo et al. (91) demonstrated a 76% response rate with MPT, superior to the 48% in the MP arm; however, thromboses were more common with thalidomide with an incidence of 12% (vs. 2% in the MP group). Newer agents are now being incorporated into trials in this population as well, including bortezomib and lenalidomide. The precise role of these agents in older patients has yet to be determined.

Autologous Stem Cell Transplantation

ASCT has become the standard of care for eligible patients, as it has been demonstrated in multiple trials to improve the likelihood of complete response, prolong disease-free survival, and

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extend overall survival (9,19,66). Treatment-related mortality rates are now <2%, and often the transplant can be performed entirely as an outpatient. Melphalan 200 mg/m2 is the most commonly used conditioning regimen, although it may be reduced in elderly patients or patients with renal insufficiency.

Tandem Transplantation

Tandem or double transplantation refers to a planned second ASCT after the patient has recovered from the first. A phase III trial in France evaluated tandem transplant versus single ASCT and demonstrated superior overall survival in the tandem group (8); however, when further analyzed, the patients who benefited most from the second transplant were those who did not achieve a 90% reduction in their disease after the first ASCT. Therefore, it may be more prudent to consider tandem transplantation only in patients whose response to the first ASCT is suboptimal.

Allogeneic Stem Cell Transplantation

Myeloablative stem cell transplant is perhaps the only current potential cure for patients with myeloma, as the graft is not contaminated with tumor cells and may produce a profound graft versus myeloma effect (79). However, its use is very limited due to the lack of donors, age restriction, high treatment-related mortality, and graft versus host disease.

The general approach to myeloma is to provide sequential therapies to patients, knowing each will not be curative but will prolong the period of disease control. The goal is to convert the disease into a chronic illness. Whereas there used to be very limited treatment options, the armamentarium available has grown considerably over the past few years. This has contributed to a prolongation of the median survival of patients with myeloma. Patients will relapse after a median of 2 years after first ASCT (81), and several options may be pursued for treatment (Table 79.6). The most exciting is the development and availability of novel, biological agents. Bortezomib is the first proteosome inhibitor to be used in clinical trials. Various phase I and II studies have been completed, and a large multicenter phase III trial compared bortezomib to high-dose dexamethasone (99). The updated results of 669 patients revealed time to progression of 6.2 months in the bortezomib arm and 3.5 months in the dexamethasone arm, along with a superior 1-year overall survival (80% vs. 67%) favoring bortezomib (98). Side effects included peripheral neuropathy, cyclical thrombocytopenia, and diarrhea.

Lenalidomide is an immunomodulatory drug derived from thalidomide and is currently undergoing extensive clinical investigation worldwide. Its role has been established for relapsed disease based on a large phase III trial comparing the combination of lenalidomide and dexamethasone with dexamethasone alone (32). The trial was stopped prematurely due to a large difference between the treatment groups favoring the lenalidomide combination arm. Time to progression was 4.7 months with dexamethasone alone and 11.3 months in the combination arm. Overall response rates were 24% (4% complete response [CR] and 20% partial response [PR]) with dexamethasone alone and 59% (17% CR and 42% PR) in the combination group. There was also an overall survival advantage, with median overall survival of 104 weeks in the dexamethasone alone arm, but this end point had not been reached yet in the lenalidomide arm (32). Side effects included neutropenia, thrombocytopenia, and constipation.

Radiation Therapy of Multiple Myeloma

Total Body Irradiation

Some high dose chemotherapy protocols for multiple myeloma incorporate total body irradiation (TBI) into the conditioning regimen. Because of toxicity concerns (mucosal and

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hematologic) with TBI, many programs use chemotherapy alone, most commonly melphalan. A phase III French study (Intergroupe Francophone du Myelome [IFM] trial 9502) examined melphalan, 200 mg/m2 alone (M200) versus melphalan 140 mg/m2 with TBI, 8 Gy in four fractions (M140/TBI) (84) and found that patients in the TBI-containing arm suffered more grade 3 or 4 mucosal toxicity, heavier transfusion requirement, and longer hospitalization stay. There was a higher toxic death rate in the M140/TBI arm (3.6% vs. 0% for the M200 arm). The event-free survival was no different between the two treatments, but the 45-month overall survival favored the M200 arm (M200: 65.8%, M140/TBI: 45.5%; p = .05) (84).

Similarly, another IFM protocol tested TBI in the tandem transplant setting by intensifying the conditioning regimen for the second transplant to melphalan 200 mg/m2 without TBI and comparing with the standard tandem regimen (M140 for the first, M140/TBI for the second). There was no benefit with TBI, and increased toxicity was again observed. Therefore, all subsequent IFM trials abandoned the use of TBI (52). Another study from the Spanish bone marrow transplant registry compared M140/TBI with three other chemotherapy conditioning regimens (71). There were no significant differences in the hospitalization duration, hematologic recovery, event-free survival, and overall survival among the four regimens. The authors concluded that no one regimen was clearly superior to another.

The Toronto protocol with intensification of the conditioning regimen to melphalan 140 mg/m2, etoposide 60 mg/kg, and fractionated TBI (12 Gy in six fractions over 3 days, with a high dose rate) was used in 100 patients. The main toxicity was interstitial pneumonitis (28% of patients) of whom seven died (1), leading to discontinuation of the TBI in the subsequent protocol. Presently, the use of TBI is based on institutional experience and the specific drug regimen used for conditioning. The tandem transplant program at the University of Arkansas (11,12,30) and the Memorial Sloan-Kettering Cancer Center (57) continue to use TBI in their ASCT programs for specific indica-tions.

Hemibody Radiation

Diffuse bone pain involving wide areas of the skeleton can be effectively palliated by half body radiation with single doses of 5 to 8 Gy (21,78,115), although this is rarely used now. The bone marrow in the unirradiated half body serves as a stem cell reserve and will slowly repopulate the irradiated marrow after treatment. The dose for upper half body should not exceed 8 Gy due to lung tolerance (119). The main toxicity is myelosuppression. The use of hemibody radiation must be carefully considered in patients heavily pretreated with chemotherapy. Growth factor support may be helpful, while transfusions of blood products should be given as needed. The sequential hemibody radiation technique has been used in phase II (102,107) and phase III trials as “systemic” treatment to control myeloma, in patients with or without skeletal pain. A phase III trial by the Southwest Oncology Group (SWOG) included newly diagnosed patients treated initially with chemotherapy, with complete responders randomized to sequential hemibody radiation (7.5 Gy in five fractions, upper hemibody, followed 6 weeks later by lower hemibody) or further chemotherapy. Survival was significantly poorer with radiation compared with chemotherapy (103). At present, there is no standard role for sequential hemibody radiation as systemic treatment for myeloma outside of a clinical trial, although it may remain useful for palliation of advanced disease in chemotherapy-refractory patients.

Local External Beam for Palliation

The most common use of RT in the management of plasma cell tumors is for palliative treatment of bony disease (2,21,73), relief of compression of spinal cord (6,93,120), cranial nerves, or peripheral nerves. It has been estimated that approximately 40% of patients with multiple myeloma will require palliative RT for bone pain at some time during the course of their disease (40). In practice the actual proportion is lower than estimated varying from 24% to 34%, leading investigators in Australia to suggest that this potentially useful modality of treatment has been underutilized, even taking into account the beneficial effect of bisphosphonates, particularly for the elderly (40). Palliative RT to the spine reduces the incidence of future vertebral fractures or appearance of new lesions (72). However, the role of RT in preventing impending pathologic fracture is unclear. In general, lesions at high risk for pathologic fracture should be referred for surgical stabilization, and RT can be administered after surgery for control of residual disease at the local site.

When RT is given for pain due to disease involving a long bone, a local field suffices. It is unnecessary to treat the entire bone (23). Doses of 10 to 20 Gy (in five to 10 fractions) are effective, although the pain relief is often partial (82). With an average dose of 25 Gy given to 306 sites in 101 patients, Leigh et al. (73) found a symptomatic response rate of 97% (complete pain relief in 26%, and partial relief in 71%). There was no dose-response relationship above 10 Gy. Recurrence of symptoms requiring further treatment was seen in 6% of sites after a median of 16 months.

It is not clear if pain relief is better if RT is given concurrently with chemotherapy. A study by Adamietz et al. (2) reported complete pain relief in 80% of patients receiving RT with chemotherapy, compared with 40% among those receiving RT alone. In contrast, Leigh et al. (73) found no significant difference in pain relief when RT was given with or without concurrent chemotherapy. For spinal cord compression, motor improvement is expected in approximately 50% of irradiated patients. A multicenter study suggested that a longer fractionated regimen (30 Gy in 10 fractions or higher) was associated with better neurologic recovery than 20 Gy in five fractions or a single 8 Gy fraction (93). With the availability of newer drugs, the advantage of radiation sensitizing efforts with drug-radiation combinations requires continued investigation, both in terms of enhancing local control (48) and possible toxicity. Bortezomib and spinal radiation given concurrently was reported to result in severe enteritis (83). The use of bisphosphonates (e.g., pamidronate) has been shown to reduce skeletal complications and pain (15,16,17,35) with a reduction of the use of RT from 50% to 34% in one study (16).

Radioimmunotherapy Approaches

Bone seeking radiopharmaceuticals targeting the bone marrow have been studied as an alternative to TBI. Typically a β-emitting isotope is conjugated to a phosphonate complex, such as 153Samarium-ethylene diamine tetramethylene phosphonate (153Sm-EDTMP). The isotope also emits a γ-ray permitting scanning to locate areas of uptake. This agent has been used for palliation of bone metastasis (7,13). The feasibility of this approach in a small number of myeloma patients has been reported for stem cell transplantation both in the autologous (34,55) and allogeneic settings (62). Another bone-seeking pharmaceutical is 166Holmium-DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid), with a higher energy β-emission (maximum energy 1.85 MeV) than 153Sm, and a shorter T1/2 of 26.8 hours. It also has a γ-emission (81 KeV) suitable for imaging. A phase I/II study incorporating 166Holmium-DOTMP into a transplant regimen has been performed at the M.D. Anderson Cancer Center with encouraging results (47). With the ability to deliver much higher doses to the bone marrow than TBI, in the range of 30 to 60 Gy, yet sparing the dose-limiting normal tissues such as lung, mucosa, and kidneys, the concept of targeted radiation therapy is tantalizing.

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However, there remains a problem of heterogeneity of uptake in the skeleton, and the dosimetric variation may be even larger at a microscopic level due to the limited range of the β particle. Whether this approach will have a more favorable therapeutic ratio than standard conditioning regimens in the transplant setting awaits larger scale phase II and phase III trials.

Radiation Therapy Techniques

Radical Radiation Therapy for Local Control of Solitary Plasmacytoma

Accurate evaluation of tumor extent is an important feature of radical RT for solitary plasmacytoma. MRI is useful to evaluate the extent of disease both within and beyond bone. This is particularly true for the paranasal sinuses, where inflammatory changes may be difficult to distinguish from tumor on CT imaging. Currently, the accuracy of FDG-PET in the evaluation of tumor extent is uncertain.

There are few data to support specific guidelines regarding RT treatment volumes. CT and MRI imaging should be used to determine gross tumor volumes (GTV). Clinical target volumes (CTV) should encompass probable routes of microscopic spread, recognizing that barriers to the extension of local disease will vary according to anatomic location, as will the morbidity of treating adjacent normal tissues (Fig. 79.3). For the spine, inclusion of two vertebral bodies above and below the grossly involved vertebra(e) is a common practice. As this is based on relapse patterns seen following RT for spinal metastases for solid tumors rather than plasmacytomas, it may not be directly applicable to solitary plasmacytoma.

For RT of long bone lesions, while coverage of the entire involved bone has been recommended by some authors, a study of palliative RT to only the symptomatic area for multiple myeloma found that recurrence in the untreated portion of the involved bone was rare (23), and similarly, no marginal recurrences were seen among 30 patients with solitary plasmacytoma treated with RT that encompassed only the tumor with a margin (60). Prophylactic regional nodal coverage is not necessary in solitary plasmacytoma of bone as multiple studies have found a very low risk of regional nodal failure after involved-field radiation without intentional coverage of adjacent nodes (i.e., 0% to 4%) (60,75,112,117). For extramedullary plasmacytoma, nodal involvement at presentation is observed in 10% to 20%, and occasional nodal failure in the literature led to a common practice of extending the RT coverage to the draining lymph node region (20,57,110). Some authors specifically recommend this practice if the primary disease involves a lymphatic structure (e.g., lymph nodes, or Waldeyer's ring) (53,64,117). However, this is controversial as some series reported a low incidence of regional nodal failure without routine prophylactic nodal irradiation (53,64,77), leading to variation in practice between centers (110). After reviewing their own series of 26 patients with EMP and contrasting the results with the literature, Strojan et al. (110) concluded that prophylactic nodal radiation is probably unnecessary.

Planning target volumes (PTV) should account for day-to-day setup variation and will typically add 5 to 10 mm around CTV volumes depending on the immobilization technique employed (see Fig. 79.3). Overall, RT field edges are typically 2 to 3 cm from gross tumor seen on imaging. Although parallel-opposed fields are commonly adequate to encompass disease without significant irradiation of normal tissues, CT-based planning, and the use of conformal techniques, including intensity modulated radiation therapy, should be employed when needed to treat the PTV adjacent to critical structures. This can be particularly important in extramedullary disease involving the paranasal sinuses, where avoidance of the optic structures and salivary glands is desirable.

Radiation Therapy Dose

Studies evaluating RT dose response in plasmacytoma have produced differing results. Most studies have found response rates >85%

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among patients treated with ≥35 Gy; some investigators have found better local control following doses ≥45 Gy (44,116), while others have found no indication of improved outcome with higher doses (60,90). Based on a dose–response analysis of 81 patients by Mendenhall et al. (80) reported in 1980, a minimum dose of 40 Gy was recommended, including osseous and extramedullary lesions. A total dose of 40 Gy and above resulted in a local failure rate of 6% versus 31% for lower doses. Therefore, the usual practice is to administer a dose of 40 to 45 Gy or even higher for bulky tumors. However, in the largest of these studies (n = 258), there was no evidence of improved local control with RT doses ranging from 30 to 50 Gy, including a subset of patients with tumors >4 cm (90). In fact there was a worse local control rate for the group receiving total dose ≥50 Gy, although not statistically significant (90). It should be noted, however, that retrospective studies of dose response are typically confounded by selection bias, as higher doses are prescribed to larger tumors with worse prognosis. Several studies have demonstrated durable local control in >85% of tumors <5 cm with 35 to 40 Gy, and there is little evidence that higher doses are necessary for small tumors, regardless of bone or EMP locations. In contrast, plasmacytomas >5 cm have worse local control (90,117), and doses of 45 to 50 Gy are recommended in these bulkier tumors, which also tend to be EMPs. However, one should be aware that the quality of evidence supporting the use of higher RT doses is limited, and local failures are occasionally observed even after doses exceeding 50 Gy (80,90,117).

Assessment of Response and Follow-Up

Reimaging is of greatest value in the response assessment of extramedullary plasmacytoma. Repeat imaging, preferably MRI, should be done approximately 6 to 8 weeks following completion of treatment. It is rare to have symptoms suggestive of local progression that necessitate reimaging prior to this. It is common for a residual soft-tissue abnormality to persist on follow-up imaging, and periodic reimaging may be required every 4 to 6 months until any residual mass disappears or remains stable on consecutive scans. It is generally not beneficial to continue to reimage a stable abnormality.

Bone destruction caused by tumor can produce persistent abnormalities on imaging following RT for painful bone metastases or isolated plasmacytoma of bone. Consequently, repeat imaging is of less value in establishing response in such cases.

With a high risk of recurrence of disease as multiple myel-oma, the occurrence of new bone pain requires further investigations, including imaging as appropriate. Repeat measurement of the M-protein often detects the onset of systemic disease prior to the development of symptoms and can be used as an indicator of disease burden (26,121). Complete blood counts should be taken periodically to evaluate bone marrow function. A team of international investigators have recently developed recommendations for uniform response criteria for assessing the treatment of multiple myeloma (36).

RT doses used for myeloma are rarely associated with significant delayed side effects. Treatment of significant volumes of the parotid or submandibular glands may result in prolonged xerostomia and should be avoided. As noted previously, TBI has been associated with significant toxicity and is not widely used. Evaluation of renal function should be undertaken prior to initiating RT that may include the kidneys, and blood counts should be evaluated prior to treating a large volume of bone marrow in the spine or pelvis. Reirradiation of vertebral metastases is possible, but careful evaluation of all prior RT records is required to ensure that the tolerance of the spinal cord is not excee-ded.