Radiation Oncology: A Question-Based Review

73
Plasmacytoma/Multiple Myeloma

Russell K. Hales and Robert Prosnitz

image Background


What is the cell of origin in multiple myeloma (MM), and what does this cell usually secrete?

Mature B cells are the cell of origin in MM, and they usually secrete immunoglobulins that are also known as M proteins.

Approximately how many cases of MM are diagnosed annually in the U.S.?

~15,000 cases/yr of MM are diagnosed in the U.S.

What % of plasma cell tumors are MM? Solitary plasmacytoma (SP)?

MM constitutes 90% of plasma cell tumors, while SP constitutes 10% of plasma cell tumors.

Is there a racial or gender predilection for MM?

Yes, with regard to race. The incidence of MM is greater in blacks than whites (2:1). However, the incidence is similar among men and women.

What is the avg decade of life in which pts present with MM?

On avg, pts present with MM in the 5th–6th decades of life.

What environmental exposure is most strongly associated with MM?

Ionizing RT is strongly linked to MM, as seen in A-bomb survivors in Hiroshima.

What are the 2 forms of SP?

The 2 forms of SP are solitary bone plasmacytoma (SBP) and solitary extramedullary plasmacytoma (SEP).

What environmental or genetic alterations are consistently associated with MM?

There are no strong genetic or environmental patterns associated with MM. There may be a modest but increased risk of MM with exposure to RT (latency 20+ yrs) or the chemical alachlor, a commonly used pesticide.

What % of pts with SBP will progress to MM at 10 yrs?

SBP will progress to MM in 50%–80% of pts at 10 yrs. (Hu K et al., Oncology 2000)

What % of pts with SEP will progress to MM at 10 yrs?

SEP will progress to MM in 10%–40% of pts at 10 yrs. (Hu K et al., Oncology 2000)

What is the most common site of SEP?

The most common site of SEP is the H&N region (80% of SEP); the nasal cavity and paranasal sinuses are the most common subsites for SEP.

What is the relationship between secretory patterns in SBP vs. SEP?

Most pts with SBP have a secretory tumor, whereas most pts with SEP have a nonsecretory tumor.

What is the relationship between LN involvement in SBP vs. SEP?

SBP rarely involves LNs, but SEP will have LN involvement 30%–40% of the time.

What 3 lab abnormalities may prompt a clinician to evaluate for a plasma cell neoplasm?

Laboratory abnormalities that may prompt evaluation for a plasma cell neoplasm:

1.     Unexplained normochromic/normocytic anemia

2.     Unexplained renal insuffiency

3.     Hypercalcemia

What lab tests are used for screening of a plasma cell abnormality?

Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) are lab tests used to screen for a plasma cell abnormality. A positive screen on these tests results when a monoclonal population (or spike) is detected.

What is the common pattern of bone Dz in MM?

Lytic bone lesions are the most common bone abnormality seen on imaging of pts with MM.

What is monocloncal gammopathy of undetermined significance (MGUS), and how often will it transform to MM?

MGUS is a condition with clonal proliferation of an immunoglobulin in the absence of clinical, radiographic, or lab evidence of MM. The risk of transformation from MGUS to MM is 1%/yr.

What is 1 factor that predicts the risk of transformation from MGUS to MM?

The risk of transformation from MGUS to MM is predicted by the initial size of the M-protein peak.

What is the most common clinical Sx seen at Dx of MM or SP?

Bone pain is the most common clinical Sx seen at Dx of MM or SP. A subset of these pts will present with a pathologic fracture.

What is POEMS syndrome?

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) is a variant of MM with solitary or limited sclerotic bone lesions that often responds to radiotherapy with a spontaneous improvement in neuropathy.

What 3 diagnostic criteria are required for MM?

Criteria requisite for Dx of MM (all are required):

1.     Clonal plasma cells of ≥10% (on either BM Bx or a Bx from other tissue)

2.     Monoclonal protein in serum or urine

3.     Evidence of end organ damage

(No author, Br J Haematol 2003)

Name 7 factors that can be used as evidence of end organ damage in MM.

Factors that can be used as evidence of end organ damage in MM:

1.     Hypercalcemia

2.     Renal insufficiency

3.     Anemia

4.     Bone lesions

5.     Frequent severe infections

6.     Amyloidosis

7.     Hyperviscosity syndrome

(No author, Br J Haematol 2003)

What is the difference between symptomatic MM and asymptomatic (smoldering) MM?

Smoldering (or asymptomatic) MM requires the presence of serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10% but no evidence of end organ damage attributable to plasma cell dyscrasia. (No author, Br J Haematol 2003)

What 3 criteria are necessary for the Dx of MGUS?

Criteria necessary for the Dx of MGUS:

1.     Serum monoclonal protein <3 g/dL

2.     BM plasma cell <10%

3.     No end organ damage attributable to plasma cell dyscrasia

(No author, Br J Haematol 2003)

What 4 criteria are necessary for the Dx of SP?

Criteria necessary for the Dx of SP:

1.     Solitary bone lesion on skeletal survery

2.     Histologic evidence of plasmacytoma by Bx

3.     <5% plasma cells on marrow aspirate

4.     No other end organ damage attributable to plasma cell dyscrasia

(No author, Br J Haematol 2003)

image Workup/Staging


What is β2-microglobulin (β2M)?

β2M is a component of major histocompatibility complex class 1 molecules. Increasing levels of β2M are associated with a worse prognosis in MM.

What are the 2 most commonly used staging systems for MM?

The 2 most commonly used staging systems for MM are the Durie-Salmon Staging and the International Staging System (ISS).

What 2 factors are used to stage pts in the ISS system, and how are they grouped?

The 2 factors used in the ISS system are β2M and albumin. They are used to stage pts as follows:

1.     Stage I: β2M <3.5 mg/L, albumin ≥3.5 g/dL

2.     Stage II: β2M <3.5 mg/L, albumin <3.5 g/dL, or β2M ≥3.5 and <5.5

3.     Stage III: β2M ≥5.5

What is the MS of MM by ISS stage?

MS of MM by ISS stage:

1.     Stage I: 62 mos

2.     Stage II: 44 mos

3.     Stage III: 29 mos

(Greipp PR et al., JCO 2005)

What is the Durie-Salmon staging scheme for MM?

Durie-Salmon staging scheme for MM:

1.     Stage I: all of the following are required:

1.     Hgb >10 g/dL

2.     normal calcium

3.     skeletal survey with no lytic bone lesions

4.     serum paraprotein level <5 if IgG (<3 if IgA)

5.     urinary light chain excretion <4 g/24 hrs

2.     Stage II: not fitting stage I or III

3.     Stage III: 1 or more of the following:

1.     Hgb <8.5 g/dL

2.     calcium >12

3.     skeletal survey with ≥3 lytic lesions

4.     serum paraprotein level >7 if IgG (>5 if IgA)

5.     urinary light chain excretion >12 g/24 hrs

The Durie-Salmon staging system gives a subclassification of A or B based on what factor?

Durie-Salmon staging subclassification distinguishes pts based on serum Cr: A, Cr <2 mg/dL; B, Cr ≥2 mg/dL.

Besides a careful H&P, what lab and radiographic studies are necessary to evaluate a pt with newly diagnosed or suspected MM?

The lab and radiographic workup of MM includes CBC with differential, LDH, calcium and albumin levels, β2M, 24-hr total protein, SPEP/UPEP, skeletal survey, and unilat BM aspirate and Bx (with BM flow cytometry or immunohistochemistry). Other studies that may be helpful in select cases include MRI for suspected vertebral compression or tissue BM to Dx an SP.

What is the role of a bone scan in the workup and staging for plasma cell neoplasms?

There is no role for routine staging with a bone scan in pts with plasma cell neoplasms b/c the lesions are primarily lytic with little evidence of bone repair and consequent low isotope uptake.

image Treatment/Prognosis


What is the recommended management of smoldering (asymptomatic) MM?

The recommended management of smoldering MM is close observation (expectant management).

What is the recommended management of SBP?

The recommended management of SBP is involved-field RT to ≥45 Gy.

What is the recommended management of SEP?

The recommended management of SEP is either involved-field RT to ≥45 Gy, surgery, or surgery + RT.

In what subgroup of pts with SEP may combined modality therapy (surgery → RT) be preferred?

In 1 study of pts with SEP in the upper aerodigestive tract, surgery → RT yielded improved OS in retrospective comparison of surgery or RT alone. (Alexiou C et al., Cancer 1999)

What is the role of RT in the Tx of MM, and what dose should be given?

The role of RT in the management of MM is for the palliation of symptomatic bone mets, prevention of pathologic fractures, and the relief of cord compression. The dose of RT given in MM is generally 20–36 Gy in 1.5–2 Gy/fx.

Why is the dose of RT for the management of SP higher than the dose used in MM?

RT used in MM is for palliation of Sx, and doses of 20–30 Gy are generally sufficient to palliative this radioresponsive tumor. By definition, SP is a localized neoplasm, and a curative paradigm is employed. Dose escalation is used under the assumption that complete eradication of tumor can occur at higher doses.

What is the role of bisphosphonates in the management of MM?

Bisphosphonates are given with 1st-line antimyeloma therapy b/c they have been shown to decrease the risk of skeletal events (41% vs. 24%) and decrease bone pain. (Berenson JR et al., NEJM 1996)

What is the initial management of transplant candidate pts with MM?

The recommended management of potential transplant candidates with MM is induction bisphosphonate/bortezomib/dexamethasone + / − thalidomide.

What is the initial management of non-transplant candidate pts with MM?

The recommended management of nontransplant candidates with MM is induction bisphosphonate/melphalan/prednisone + either bortezomib or thalidomide.

What type of BMT is preferred in the management of MM?

In 1 study, an autologous transplant followed by a nonmyeloablative allograft was superior in terms of OS in comparison to tandem autologous graft in the management of MM. (Bruno B et al., NEJM 2007)

What is the preferred conditioning regimen for pts receiving a myeloablative BMT in MM?

High-dose melphalan is the preferred conditioning regimen in pts with MM undergoing BMT. A randomized study of high-dose melphalan vs. total body irradiation (8 Gy in 4 fx) + low-dose melphalan showed worse hematologic toxicity and worse OS in pts treated with RT. (Moreau P et al., Blood 2002)

What RT Tx portal should be used in the management of SBP?

If toxicity allows, treat the entire involved bone with a 2–3-cm margin in RT Tx of SBP. In the spine, include 2 vertebral bodies above and 2 vertebral bodies below the lesion.

What RT Tx portal should be used in the management of SEP?

The Tx portal recommended in the primary management of SEP is the extraosseous SP + primary draining LNs.

What is the recommended follow-up for pts with SP?

Recommended SP follow-up: clinical evaluation + quantitative immunoglobulins, M protein, CBC, CMP, LDH, and β2M q3mos for 1 yr. A bone survey should take place q6–12mos for the 1st 2 yrs. After 2 yrs, continued clinical evaluation and annual bone survey is appropriate.