Multiple Myeloma



Multiple Myeloma


David K. Gaffney, MD, PhD

















































Durie and Salmon PLUS Staging System



Classification

Bone Marrow

Laboratory Parameters

Imaging Parameters1


Monoclonal gammopathy of undetermined significance (MGUS): Not included in staging

< 10% plasma cells


No intra- or extramedullary disease


Smoldering multiple myeloma (SMM): Stage IA2

≥ 10% plasma cells

All of the following: Hemoglobin > 10 g/dL; sCa++ ≤ 12 mg/dL; low M-component production; IgG < 5.0 g/dL; IgA < 3.0 g/dL; urine M-protein < 4g/24h

Limited disease (definition evolving)


Multiple myeloma (MM): Stages IB-III

≥ 10% plasma cells &/or plasmacytoma + end organ damage3

Variable by stage

Variable by stage

Stage IB2


Same as stage IA

< 5 focal lesions4; mild diffuse disease5 on T1 MR

Stage IIA/B2


Neither stage I nor stage III

5-20 focal lesions4; moderate diffuse disease5 on T1 MR

Stage IIIA/B2


1 or more of the following: > Hemoglobin < 8.5 g/dL; sCa++ > 12 mg/dL; IgG > 7.0 g/dL; IgA > 5.0 g/dL; urine M-protein > 12g/24h

> 20 focal lesions4; severe diffuse disease5 on T1 MR


1 The imaging appearance of bone marrow is variable. Patients with stage III myeloma by clinical criteria can have a normal MR appearance of bone marrow, which is associated with a more favorable prognosis.
2 A: Serum creatinine < 2.0 mg/dL & no extramedullary disease; B: Serum creatinine > 2.0 mg/dL &/or extramedullary disease.3 End organ damage includes calcium elevation, renal insufficiency, anemia, or bone abnormalities.
4 Focal lesions ≥ 5 mm.
5 Degree of diffuse disease is evaluated on T1 images. Mild = micronodular or “salt and pepper” pattern of infiltration; moderate = diffuse lower T1 signal than normal marrow but with contrast between vertebral bone marrow and disc; severe = low T 1 signal throughout the vertebral bone marrow with signal less than that of the adjacent disc.























International Staging System


Stage

Criteria


I

Serum β2-microglobulin < 3.5 mg/L

Serum albumin ≥ 3.5 g/dL


II

Not stage I or III


III

Serum β2-microglobulin ≥ 5.5 mg/L


The International Staging System is useful in imaging facilities without advanced imaging with MR or PET and as a measure of survival. Median survival for stage I: 62 months; stage II: 44 months; stage III: 29 months.








This sagittal graphic depicts micronodular foci image of plasma cells within the axial bone marrow of the lumbar spine. Normal bone marrow by imaging is also associated with stage I disease.






This sagittal graphic demonstrates multifocal disease image within the lumbar spine, which is associated with more advanced (stage II/III) disease. Moderate diffuse infiltration or 5-20 focal lesions is stage II disease whereas > 20 focal lesions or severe diffuse disease is stage III disease.



OVERVIEW


General Comments



  • Heterogeneous plasma cell (PC) disorder


  • Characterized by bone marrow (BM) infiltration


  • Diagnosed by combination of blood tests, BM biopsy and aspirate, urine protein studies, and x-rays


  • Chemotherapy improves survival but is not curative unless an allogeneic transplant is performed


Classification



  • Based on increasing malignant potential



    • Monoclonal gammopathy (MG) of undetermined significance (MGUS)



      • Progression risk → multiple myeloma (MM) = 1% per year


      • < 3 g/dL serum M-protein & < 10% BM PCs


      • When progression occurs, it usually leads to MM or Waldenström macroglobulinemia


      • Potentially can also progress to



        • Primary amyloidosis


        • Chronic lymphocytic leukemia


        • Lymphoma


      • MG of borderline significance (MGBS)



        • Subclassification (not universally used)


        • Higher risk of progression to MM than MGUS


        • Difference = ↑ PC number in BM (10-30% for MGBS vs. < 10% for MGUS)


    • Smoldering multiple myeloma (SMM)



      • ≥ 3g/dL serum M-protein & ≥10% BM PCs


      • No end organ damage (EOD) (asymptomatic)


      • Higher risk of progression to MM


    • Multiple myeloma



      • Symptomatic: EOD present


      • EOD includes any of the following (CRAB)



        • Calcium elevation


        • Renal insufficiency


        • Anemia


        • Bone abnormalities (lytic or osteopenic)


      • Nonsecretory



        • No elevated M-protein in urine or blood


        • Disease best followed by PET/CT


      • POEMS syndrome



        • Polyneuropathy, organomegaly, endocrinopathy, m-protein, skin changes


        • Sclerotic bone lesions


      • PC leukemia is characterized by > 20% circulating PCs at any time


NATURAL HISTORY


General Features



  • Comments



    • Disorder with abnormal proliferation of BM PCs


    • Aggressiveness varies 2° to genetic alterations in PCs


    • Plasmacytoma generally refers to solitary lesion


    • Receptor activator of nuclear factor-κB ligand (RANKL) activates osteoclasts → bone resorption → hypercalcemia


  • Location



    • Bone marrow


    • Extramedullary plasmacytomas most commonly occur in upper respiratory tract


Etiology



  • Unknown


  • Exposure to herbicides, insecticides, benzene, and ionizing radiation may contribute


Epidemiology & Cancer Incidence



  • Number of cases in USA per year



    • 21,700 estimated new cases in 2012 with 10,710 deaths


  • Sex predilection



    • M>F


  • Most common primary bone malignancy


  • 10% of all hematologic malignancies


  • 2x ↑ incidence for African-Americans


Genetics



  • Common translocations



    • Chromosomal abnormalities of 14 and 13 seen (˜ 50% of cases each)


  • Rarely hereditary


  • Multiple PC genetic subclassifications



    • Poor prognostic factors



      • Del chromosome (chr) 13 → retinoblastoma-1 (RB1) mutation


      • ↑ PC proliferation index


      • Del chr 17p13 → inactivation of p53 tumor suppressor gene


      • t(4;14) → upregulation of fibroblast growth factor (FGF) receptor 3


      • t(14;16) → upregulation of MAF transcription factor


    • Neutral/favorable prognostic factors



      • Absence of poor prognostic factors, plus 1 of the following



        • t(11;14) → upregulation of cyclin D1


        • t(6;14) → upregulation of cyclin D3


        • Hyperdiploidy


Associated Diseases, Abnormalities



  • Myelofibrosis


  • Fanconi syndrome type II (renal tubular acidosis)


Gross Pathology & Surgical Features



  • Focal or widespread BM infiltration by genetically altered PCs


  • Focal extramedullary disease is termed plasmacytoma


Microscopic Pathology



  • H&E



    • % of BM PCs important for classification of MM


    • BM analysis: May be subject to sampling error



      • Aspirate can underestimate or overestimate number of PCs


      • BM biopsy more accurate


  • Special stains



    • Wright-Giemsa considered superior


    • CD138 immunohistochemistry most accurate


    • Typically positive for CD56, CD38, and CD138 and negative for CD19 and CD45


Routes of Spread



  • Primarily intramedullary spread


  • Extramedullary spread, especially in advanced disease


  • Plasmacytoma of bone progresses to MM in 50-60% of cases



  • Extramedullary plasmacytomas progress to MM in ˜ 15% of cases


IMAGING


Detection

Tags:
Jun 1, 2016 | Posted by in ONCOLOGY | Comments Off on Multiple Myeloma

Full access? Get Clinical Tree
Get Clinical Tree app for offline access