Epidemiology

Multiple myeloma is the second most common hematologic malignancy. In the United States, myeloma caused an estimated 19,900 new cases and 10,700 deaths in 2008.¹ Myeloma is slightly more common in men than women, and the incidence of myeloma in African Americans is almost twice that of Whites. The median age at diagnosis is between 65 and 70 years. Solitary plasmacytomas tend to occur in younger, male patients.

Etiology

The cause of multiple myeloma is unknown. Exposure to radiation, petroleum products, organic solvents, pesticides, and herbicides may have a role, and tobacco use, obesity, diet, and exercise may also affect risk.² Chronic immune stimulation by autoimmune or infectious disorders is associated with an increased likelihood of developing myeloma.³ The role of inherited factors is uncertain, although myeloma has been reported in multiple family members.⁴

Genetics

Chromosomal abnormalities are critical predictors of survival in myeloma.⁵ Conventional metaphase cytogenetics often fails to identify chromosomal changes, likely because of the low proliferative rate of plasma cells, but more sensitive techniques have identified chromosomal abnormalities in nearly all patients.⁶ Clinically, fluorescence in situ hybridization (FISH) is utilized in conjunction with conventional cytogenetics to identify abnormalities.

Deletions of chromosomes 13 and 17p have been associated with poor prognosis. Del(13), particularly monosomy 13 or del(13q14), occurs in nearly half of patients with myeloma, but the target gene or genes have not been identified. Detection of del(13) by conventional cytogenetics may have a worse prognosis than identification by FISH.⁷ Deletion of 17p occurs in 10% of patients with myeloma, and the putative target is the p53 tumor suppressor gene at the 17p13 locus. Del(17p) is associated with an aggressive clinical presentation and very poor outcome. Abnormalities of chromosome 1 are less common but also portend a worse prognosis.⁸ In contrast, hyperdiploidy is associated with a better prognosis but may not be an independent prognostic factor.⁵

Translocations involving the immunoglobulin heavy chain locus at 14q32 are frequently detected in myeloma. The t(4;14)(p16;q32) translocation, found in 15% of patients, disrupts the fibroblast growth factor receptor 3 (FGFR3) and MMSET genes and is associated with a poor prognosis. The t(14;16)(q32;q23) translocation in 5% of patients results in overexpression of the transcription factor MAF and also portends a worse outcome. However, the t(11;14)(q13;q32) rearrangement, which alters cyclin D1 expression, is found in 20% of cases and is associated with a better prognosis.

Clinical Presentation

Patients with myeloma typically come to medical attention because of end organ damage caused by the neoplastic plasma cells and M protein. The most common symptom in over half of patients is bone pain, often in the back or chest. At diagnosis, three quarters of patients will have bone lesions on imaging, such as lytic lesions, diffuse osteopenia, or fractures. Other common presenting features are hypercalcemia, renal insufficiency, anemia, recurrent infections, fatigue, and neuropathy. Patients with neurologic symptoms suggestive of spinal cord compression require immediate evaluation, and radiculopathy is often due to nerve compression from an epidural tumor or a compression fracture. Hypercalcemia, present in 20% of patients, is caused by bone turnover and destruction. Renal insufficiency occurs in 20% of cases at diagnosis and is typically due to hypercalcemia or M protein–induced nephropathy. Marrow replacement by plasma cells and secondary suppression of erythropoietin production from renal insufficiency lead to anemia in 60% of patients. Patients with myeloma are prone to infections because of treatment related side effects and suppression of normal antibody production. Some patients are asymptomatic at presentation and come to attention when an elevated serum globulin fraction is noted on routine blood tests.

Evaluation

The initial diagnostic workup in patients with a suspected plasma cell malignancy should include a detailed medical history and comprehensive physical examination plus the following laboratory studies: complete blood count with differential; serum chemistries with creatinine and calcium; albumin; beta₂-microglobulin; serum protein electrophoresis with immunofixation; serum free light chains; quantitative immunoglobulins; and 24-hour urine total protein, protein electrophoresis, and immunofixation. C-reactive protein and lactate dehydrogenase can be helpful as markers of tumor mass, and serum viscosity is useful in the rare cases of symptomatic hyperviscosity.

A bone marrow aspirate and biopsy with cytogenetics and FISH is necessary. Plasma cells are increased in the bone marrow of nearly all patients with myeloma. These plasma cells typically express CD38, CD138, and cytoplasmic immunoglobulin but are usually negative for CD5, CD19, CD20, and surface immunoglobulin. Intracellular staining for κ and λ light chains can demonstrate clonality. Because the distribution of plasma cells in the marrow may not be uniform, CD138 immunohistochemistry is often utilized to characterize the extent of involvement in a core biopsy. Plasma cell labeling index is a marker of proliferation which is predictive of outcome but not routinely available.

A conventional skeletal survey should be performed in all patients. Magnetic resonance imaging (MRI) is useful in patients with suspected cord compression, osseous plasmacytomas, and bone pain in the absence of radiographic abnormalities. Computed tomography (CT) and positron-emission tomography (PET) may be helpful in patients with plasmacytomas to evaluate extramedullary disease. Bone densitometry can quantify the degree of osteopenia. Bone scans are generally not utilized, since this technique is not sensitive for myeloma.

Diagnosis

The International Myeloma Working Group definition of symptomatic myeloma requires three findings: clonal plasma cells in the bone marrow or a plasmacytoma; detectable monoclonal protein in the serum or urine; and evidence of related end organ impairment.⁹ This simplified triad for diagnosis has replaced the more complicated Durie–Salmon system. An acronym for the common findings of end organ damage is CRAB (hyperCalcemia, Renal impairment, Anemia, Bone lesions), although recurrent infections, other cytopenias, amyloidosis, and neurologic findings would also be evidence of impairment. As long as end organ damage is present, any detectable level of clonal plasma cells and monoclonal protein are acceptable. The types of M protein produced are IgG (60%), IgA (15%), IgD (2%), IgE (<1%), and light chain only (18%). True nonsecretory myeloma is now extremely rare, as the free light chain assay is abnormal in the majority of cases previously considered “nonsecretory.” Plasma cell leukemia is a variant of multiple myeloma with circulating neoplastic cells and is associated with a particularly poor prognosis.

Monoclonal gammopathy of undetermined significance (MGUS), asymptomatic (smoldering) myeloma, and primary light chain amyloidosis are disorders related to multiple myeloma. MGUS and smoldering myeloma do not have end organ impairment, and this is the key feature that distinguishes them from multiple myeloma. Asymptomatic myeloma has a higher M protein (≥3 g/dL) or bone marrow plasma cell content (≥10%) than MGUS. Both MGUS and asymptomatic myeloma can progress to multiple myeloma, and asymptomatic myeloma has a worse prognosis than MGUS. Overall, there is a 1% risk per year of progression from MGUS to multiple myeloma, and risk factors for progression include a M protein ≥1.5 g/dL, an abnormal free light chain ratio, and a non-IgG isotype.¹⁰ Half of patients with asymptomatic myeloma will develop active multiple myeloma within 5 years. An increased percentage of bone marrow plasma cells, a higher serum M protein, and an abnormal free light chain ratio are risk factors for progression in smoldering myeloma.^11,12 Primary light chain amyloidosis can be a manifestation of end organ damage in multiple myeloma. However, many patients with primary light chain amyloidosis do not meet the criteria for myeloma, because of the absence of an identifiable clonal plasma cell population or an undetectable M protein.

Solitary plasmacytoma of bone is defined as a single area of bone destruction from clonal plasma cells in the absence of any other sites. The most common site of disease is the axial skeleton, and patients usually present with bone pain or a pathologic fracture. Monoclonal plasma cells, identical to those seen in myeloma, are present on biopsy. A complete evaluation to rule out systemic myeloma should be performed, and MRI of the spine and pelvis can identify occult disease missed on plain radiographs. Solitary plasmacytoma of bone typically does not secrete large amounts of M protein, and there should not be other signs of end organ impairment. If these factors are present, then the patient likely has systemic multiple myeloma.

Solitary extramedullary plasmacytoma is a rare plasma cell tumor that arises outside the bone marrow. It typically involves the upper respiratory tract but can occur in virtually any organ. This tumor is often associated with an IgA M protein. The diagnosis is made by biopsy, and a complete evaluation for systemic disease should be performed. Multiple plasmacytomas, which can be extramedullary or osseous, occur in 5% of patients with a plasmacytoma.

Staging System and Response Criteria

A simplified international staging system has also replaced the more complicated Durie–Salmon staging system. The older Durie–Salmon staging system correlated with total tumor mass but did not predict prognosis or survival well. In contrast, the international staging system at diagnosis is predictive of survival, not tumor mass, and is based only on the serum albumin and beta₂-microglobulin.¹³ Patients with stage 1 disease have a normal beta₂-microglobulin (<3.5 mg/dL) and normal serum albumin (≥3.5 g/dL), and those with stage 3 disease have a beta₂-microglobulin ≥5.5 mg/L. All other patients have stage 2 disease. Beta₂-microglobulin is cleared by the kidneys, so patients with renal insufficiency typically have a higher stage at diagnosis.

International uniform response criteria for multiple myeloma have been developed to reflect the better outcomes attainable with newer therapies.¹⁴ A complete response (CR) is defined as negative immunofixation in the serum and urine, disappearance of any plasmacytomas, and ≤5% plasma cells in the bone marrow. A strict CR (sCR) also requires a normal free light chain ratio and absence of clonal cells by immunohistochemistry or flow cytometry. A very good partial response (VGPR) is defined as a ≥90% reduction in measurable serum M protein plus urine M protein <100 mg/24 hr. A partial response (PR) is defined as ≥50% reduction in serum M protein and ≥90% reduction in urine M protein. Patients who achieve a VGPR or better in response to therapy have a significantly improved survival compared to those who reach only a PR.

Systemic Therapies

The treatment of multiple myeloma is rapidly evolving, and the survival of patients has improved significantly. Patients without end organ damage do not require immediate therapy, and there is no evidence that early treatment of MGUS or smoldering myeloma improves survival. Patients with organ impairment or symptoms require treatment, and the choice of initial therapy depends upon risk stratification and whether a patient is a transplant candidate. Patients with high risk cytogenetic abnormalities, such as del(13), del(17p), t(14;16), and t(4;14), have a poor outcome with conventional chemotherapy and stem cell transplant and should be treated with the newer agents.

The major classes of drugs active in myeloma are glucocorticoids, alkylators, immunomodulatory agents, and proteasome inhibitors. The newer immunomodulatory agents and proteasome inhibitors have markedly changed the therapy and survival of patients with myeloma. Thalidomide, an immunomodulatory agent, and lenalidomide, a more potent derivative, both target the microenvironment of the plasma cell by inhibiting stromal interactions, suppressing angiogenesis, and stimulating immune function. They may also have direct antiproliferative effects on the plasma cell. Bortezomib, a proteasome inhibitor, induces apoptosis in neoplastic plasma cells and also affects the microenvironment. The immunomodulatory agents are renally cleared, so bortezomib is often preferentially used in patients with significant renal insufficiency. Anthracyclines, topoisomerase inhibitors, vinca alkaloids, and platinum compounds are also utilized in combination therapy. Several other classes of drugs are in development, particularly chaperone (Hsp90) inhibitors, histone deacetylase inhibitors, and kinase inhibitors.¹⁵ Agents from different classes are typically combined for optimum effect. Frequently utilized combinations include: melphalan, prednisone, thalidomide (MPT); melphalan, prednisone, bortezomib (MPV); lenalidomide and dexamethasone; thalidomide and dexamethasone; bortezomib and dexamethasone; bortezomib and liposomal doxorubicin; and bortezomib, dexamethasone, thalidomide (VDT). Before the newer agents, vincristine, doxorubicin, dexamethasone (VAD) and melphalan and prednisone (MP) were common regimens. Many other combinations are also under investigation.

Combination induction regimens incorporating novel agents in newly diagnosed patients have reported overall response rates of 70% to 90% with quality responses (VGPR or better) in the 20% to 40% range.^16–21 This compares favorably to the 40% overall response rate with few quality responses seen with melphalan and prednisone, which was the standard of care until recently for patients who were not transplant eligible. Although more aggressive combinations of conventional chemotherapy are not more effective than melphalan and prednisone,²² the addition of thalidomide to MP markedly improved response rates, response quality, and survival in phase 3 trials.^16,19 The optimal induction therapy for newly diagnosed patients who are transplant candidates is under investigation, although agents that damage marrow reserve, such as melphalan, should be avoided before stem cell collection. Typically, transplant eligible patients now receive a bortezomib- or lenalidomide-based induction regimen.

The role of transplant in myeloma is changing due to the improvement in outcomes seen with the newer agents. Compared to conventional chemotherapy, high dose melphalan with autologous stem cell support improves survival by 1 to 2 years but is not curative.^23,24 Patients who do not achieve at least a VGPR may benefit from a second autologous transplant.^25,26 The value of allogeneic grafts is controversial, as studies have produced conflicting results.^27,28 Although glucocorticoids and interferon are not helpful, immunomodulatory agents and proteasome inhibitors are under investigation as maintenance therapy post-transplant.²⁹ Novel induction regimens before transplant improve outcome when compared to conventional induction chemotherapy, but no trial to date has directly addressed whether transplant is still necessary after an optimal induction using novel agents. ³⁰

A variety of regimens are active in patients with relapsed or refractory disease.^31–34 Patients with a long progression-free interval can be retreated with a previous regimen. Typically, patients are treated successively with different active combinations, although the duration and quality of responses decrease over time. Toxicity often limits therapeutic options, as both thalidomide and bortezomib are associated with peripheral neuropathy. Lenalidomide is generally better tolerated and more effective than thalidomide, but it frequently causes cytopenias. Unfortunately, none of the available therapies are curative.

Supportive care is an integral part of the management of myeloma. Bisphosphonate therapy improves quality of life, reduces fractures, and improves pain in patients with bone lesions.³⁵ However, bisphosphonate use is associated with osteonecrosis of the jaw and renal dysfunction, and patients should undergo dental evaluation before bisphosphonate therapy.³⁶ Erythropoiesis stimulating agents improve the anemia associated with myeloma.³⁷ Intravenous immunoglobulin may be helpful in selected patients with recurrent, severe bacterial infections. Fungal, viral, and Pneumocystis jirovecii prophylaxis should also be considered, particularly with immunosuppressive therapy. Regimens containing immunomodulatory agents and steroids are associated with a significant risk of deep venous thrombosis, so prophylaxis for thrombosis is necessary.³⁸

Radiation Therapy of Myeloma

Radiation is an effective palliative therapy for local bone pain in myeloma. Other indications for radiotherapy include: impending pathologic fracture, associated symptomatic soft-tissue mass, spinal cord compression, and pressure on cranial and peripheral nerves. The efficacy of radiotherapy in preventing impending pathologic fracture is unclear. It is important that lesions at risk of pathologic fracture, particularly in weight-bearing sites, be referred for surgical stabilization first, and that radiation for residual disease should be considered at a later stage. Adequate treatment of long bone lesions does not require irradiation of the entire bone, and involved-field treatment (radiographic lesion with margin) is sufficient.³⁹ Restriction of the radiation field size and dose is preferable to preserve future options for therapy, such as stem cell mobilization, local reirradiation, and pretransplant total body irradiation. However, the use of local radiation alone does not appear to affect the quality of stem cell harvest for patients undergoing leukapheresis before high dose therapy and autologous transplant.⁴⁰

The radiosensitivity of multiple myeloma allows for the use of a relatively low radiation dose (10 to 30 Gy) for palliation of bone pain. Although still effective in controlling pain, low-dose irradiation does not compromise bone marrow function and potential bone healing. There are few modern dose-response studies of radiation therapy for palliation of local lesions. An early study by Farhangi and Ossterman suggested that the optimal total dose of radiation for local palliation of bone pain is 10 to 20 Gy, delivered within 1 to 2 weeks.⁴¹ Mill et al. confirmed this low dose range for effective palliation of bone pain.⁴² Their study involved 278 radiation fields in 128 patients with multiple myeloma who were evaluated for responses to irradiation administered over a large dose range (from a few Gy up to 44 Gy in 2- to 3-Gy fractions). The primary indications for treatment included bone pain in 80% of the patients, cord compression in 9%, pathologic fracture in 9%, and soft-tissue mass in 2%. Of 116 patients available for pain relief assessment at the end of radiotherapy, 21% achieved a complete response and 70% had a partial response. Only 6% of the sites required retreatment for recurrence of pain. The median dose at which subjective pain relief was first noted was between 10 and 15 Gy, with responses noted after irradiation with only 5 Gy. No correlation between dose and need for retreatment could be demonstrated. The authors recommended a dose of 10 to 20 Gy in 2- to 2.5-Gy fractions for palliation of pain in patients receiving chemotherapy. Higher radiation doses were suggested for patients with slower disease progression in order to potentially increase response duration.

Leigh et al. analyzed the University of Arizona experience with palliative local radiation for multiple myeloma.⁴³ The analysis included 306 symptomatic sites in 101 patients. The main indication for irradiation was bone pain (94% of patients). Other indications included neurologic impairment (6%), pathologic fracture (1%), and large plasma cell mass (2%). Overall, 97% of the patients experienced pain relief when treated with a mean tumor dose of 25 Gy (range: 3.0 to 60 Gy). A complete response was noted in 26% of patients and a partial response in 71%. No distinction in efficacy for relieving symptoms was noted between doses lower than 10 Gy (92% of 13 patients) and doses above 10 Gy (98% of 293 patients). No relationship was noted between the use of concurrent chemotherapy and the rate of complete response. A time-dose scattergram showed no correlation between radiation dose and time to relapse. Furthermore, the efficacy of palliation was not influenced by site or presenting symptom. Only 6% of patients had a local recurrence.

Yaneva et al. followed 87 patients who were treated with palliative irradiation according to two different schedules: 8 Gy × 2 and 4 Gy × 5.⁴⁴ Ninety percent of patients experienced complete or partial pain relief and 59% of patients had resolution of their neurologic symptoms.

Although fractionated doses as low as 10 Gy may provide pain relief, the dose required to attain healing of lytic lesions may be larger. Norin’s study of 53 irradiated lesions demonstrated no objective radiographic improvement with a cumulative dose below 10 Gy, and suggested that the optimal cumulative dose was at least 15 Gy.⁴⁵ These results were supported by other studies^42,46 and are inconsistent with the study by Leigh et al.⁴³ The conflicting data may arise from differences in response parameters, follow-up quality, and patient selection.

The dose required to relieve the symptoms of spinal cord compression may also be greater. Rades et al. reported 172 patients treated for spinal cord compression.⁴⁷ Some of the patients were treated with a “short course” (8 Gy × 1 or 4 Gy × 5) and others received a “long course” (3 Gy × 10, 2.5 Gy × 15, or 2 Gy × 20). Overall, improvement in motor function improved in 52% of patients, and was significantly related to how promptly radiation therapy was initiated after the onset of motor deficits. Functional outcome was better for the patients treated with the longer course, but not different for the three different fractionation schedules defined as “long course.”

It is conceivable that several processes underlie the response of multiple myeloma to radiation. It has been postulated that the lytic lesions created in multiple myeloma are due to paracrine-type pathways in which myeloma cells secrete cytokines that activate osteoclasts to generate bony destruction and pain.⁴⁸ Corticosteroids are important in inhibiting these pathways. It is possible that lower doses of radiation may also abrogate these pathways to alleviate pain. Yet higher doses may be required to kill myeloma cells, debulk the tumor, allow for bone healing, and provide longer duration of relief.

The multiple retrospective series support the notion that the palliative radiation dose to skeletal multiple myeloma lesions should be markedly lower than the standard radiation therapy dose commonly practiced in the treatment of bony metastases from solid tumors (30 Gy in 10 fractions).

In general, most patients will obtain pain relief and disease control with doses of 20 to 30 Gy using fractions of 1.5 to 2 Gy. Higher doses (30 to 36 Gy) may be required for treatment of cord compression or disease with a bulky soft tissue component. The choice of dose and field is also influenced by the extent of critical lesions, potential normal tissue toxicity, bone marrow reserve, history of previous treatment, future treatment options, and overall disease and patient status and prognosis.⁴⁹

In view of the general radiosensitivity of myeloma lesions and their frequent disseminated distribution, programs of hemibody or sequential hemibody irradiation have been used for palliation, although its use has declined as more effective systemic agents have become available. Patients were treated with single dose or fractionated doses to totals of ∼10 Gy to the lower body and ∼8 Gy to the upper body.⁵⁰ Response rates were as high as 80%, but the procedure was associated with significant hematologic toxicity.

Several high-dose therapy programs with autologous stem cell transplantation (ASCT) for MM incorporated total body irradiation (TBI) into the conditioning regimen, exploiting the high sensitivity of MM to radiation. A variety of fractionation schedules have been employed and these are discussed in Chapter 15. Of interest in the use of image-guided total marrow irradiation using helical tomotherapy.⁵¹ This approach has the potential for limiting the radiation dose to sensitive organs such as the lungs and gastrointestinal tract while maximizing the dose to the active bone marrow and bones.

Radiation Therapy of Plasmacytomas

Radiation therapy is the treatment of choice for solitary plasmacytoma, whether originating in bone or soft tissue. Issues often debated include the extent of the radiation field and dose and occasionally the role of surgery or chemotherapy.

Radiation therapy achieves local control in 83% to 96% of patients with solitary plasmacytoma of bone.⁴⁹ In the past, it was common to treat the entire bone. However, contemporary imaging with MRI ⁵² (and perhaps PET⁵³) is an accurate means for identifying the extent of bony involvement, enabling one to limit the size of the radiation field. Generally, the GTV may correspond to the area of imaging abnormality, with the CTV including a margin of 2 to 5 cm. This is especially useful for plasmacytomas that arise in the pelvis or long bones, enabling one to spare significant volumes of marrow.

There is some disagreement in the literature regarding the appropriate radiation dose. Traditionally, a dose of ∼40 Gy (2 Gy fractions) has been recommended, sometimes boosting to as high as 50 Gy total for larger (>5 cm) disease, in order to achieve a high likelihood of long term local control.^54–56 This recommendation is based on relatively small, single-institution retrospective studies, with variable endpoints. In contrast, in a series of patients treated at the Princess Margaret Hospital, no dose-control relationship could be demonstrated for patients treated to at least 35 Gy.⁵⁷ Recently, a Rare Cancer Network retrospective study of solitary plasmacytoma was completed that included 258 patients, 206 of whom had plasmacytoma of bone.⁵⁸ They analyzed the risk of local relapse versus the biologic effective radiation dose (2 Gy equivalents). The risk of local relapse was 14% (median 20 months). No increase in the likelihood of local control could be identified when doses exceeding 30 Gy were utilized. Local control was slightly worse (but not significantly) for plasmacytomas >4 cm. Nevertheless, published guidelines still recommend doses of 40 Gy⁵⁹ or greater⁶⁰ with doses as high as 50 Gy recommended for larger tumors (>5 cm).⁵⁹

Extramedullary plasmacytomas are also usually treated with radiation therapy, with local control rates reported to be 80% to 100%.⁴⁹ Some series in the literature recommend including regional lymphatics in the treatment volume. This is based on lymph node failure rates reported in some series to be as high as 20%.⁶¹ Other series report lower risks and question the need for nodal treatment. In a series of 68 patients from the Princess Margaret Hospital, 39 of whom were treated with local radiation therapy alone, the regional (nodal) recurrence rate was 5%.⁶² The Rare Cancer Network study included 52 patients with extramedullary plasmacytoma.⁶³ Regional lymph nodes were not treated and there were no lymph node failures. With respect to dose, some authors recommend higher doses for extramedullary plasmacytoma than for plasmacytoma of bone. Again, this is based on retrospective single-institution data. The Rare Cancer Network study showed no difference in local control for extramedullary versus bone, and no indication that doses exceeding 30 Gy in 2 Gy fractions improve local control.⁶³ Both US and UK guideline groups recommend the same dose for extramedullary and bone plasmacytomas; however, in both cases the recommendation is for a dose of 40 to 50 Gy, depending on the size of the tumor.^59,60 The UK group recommends consideration of nodal treatment only for plasmacytomas that originate in the Waldeyer lymphoid tissue.

Surgery is employed occasionally for plasmacytomas in any site. Some series suggest improved local control rates when combined surgery and postoperative radiation is employed, compared to radiation alone.⁵⁵ The data on this issue are conflicting. However, one thing that is clear regarding surgery is that it is likely insufficient as a single modality. The Rare Cancer Network study included eight patients treated by surgical excision only who had negative margins, and seven of the eight relapsed.⁶³ The role of surgery is primarily to provide stabilization of a long bone that is at risk for fracture, to be followed by irradiation.

More than 70% of bone plasmacytomas and about one third of extramedullary plasmacytomas will evolve into multiple myeloma. In addition to site of origin, the other major factor associated with a risk of progression to multiple myeloma is older age. Given this risk, it is tempting to consider the use of chemotherapy as a means to decrease that likelihood. Data in the literature are spotty. The Rare Cancer Network study included 34 patients who received chemotherapy following irradiation, but the risk of developing multiple myeloma was not reduced.⁶³ However, one randomized trial compared treatment with irradiation alone to irradiation followed by melphalan-prednisone every six weeks for three years.⁶⁴ Fifty-three patients were included in the trial. The risk for developing multiple myeloma was significantly decreased in the combined modality group (12% versus 54%, P < .01). Despite this study, expert guideline groups do not recommend routine chemotherapy for patients with solitary plasmacytoma. It remains a question for clinical trials.

Prognosis

The median survival of patients with stage 1, 2, and 3 myeloma is 62, 44, and 29 months, respectively.¹³ Del(13), del(17p), t(4;14) and t(14;16) are chromosomal abnormalities associated with a poor outcome, and plasma cell leukemia, elevated lactate dehydrogenase, poor performance status, and older age are also features that portend a worse survival. However, the newer agents have markedly improved the survival of patients with myeloma,⁶⁵ and currently survival data are still evolving to reflect these changes. Novel agents may also negate some traditional poor prognostic factors. For example, bortezomib appears to overcome the poor prognosis associated with del(13).⁶⁶

Systemic myeloma ultimately becomes evident in most patients with solitary plasmacytoma of bone. The median onset of progression to myeloma is 1.5 to 2 years, but late conversion also occurs.^54,58,67 Persistence of an M protein after local therapy strongly correlates with eventual progression to myeloma.^67,68 Other factors that predict for conversion include larger lesions, older age, and axial location.^57,58,69 A risk model for progression incorporating an abnormal free light chain at diagnosis and a persistent M protein one year after diagnosis has been proposed.⁷⁰

Solitary extramedullary plasmacytoma is less likely to progress than solitary plasmacytoma of bone.^63,71 Progression to systemic myeloma occurs in less than one third of patients, and the 10 year disease specific survival is 50% or better, depending upon the series.^57,71–73 Bulky and high grade tumors are more likely to recur.^57,74 Many patients with solitary extramedullary plasmacytoma do not have a detectable M protein at diagnosis, and the prognostic impact of a persistent M protein posttherapy has not been determined.