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Part 2 book “Handbook of hematologic malignancies” has contents: Multiple myeloma, hodgkin lymphoma, immunoglobulin light chain amyloidosis, burkitt lymphoma, double hit lymphoma, mantle cell lymphoma, primary central nervous system lymphoma, follicular lymphoma, marginal zone lymphoma,… and other contents.
Plasma Cell Disorders 25 Monoclonal Gammopathy of Unknown Significance, Smoldering Myeloma, and Plasmacytomas Srinath Sundararajan, Abhijeet Kumar, Amit Agarwal, and Neha Korde INTRODUCTION Plasma cell (PC) dyscrasias are disorders characterized by clonal proliferation of PCs with or without elevated levels of monoclonal protein (M protein) and immunoglobulin fragments It encompasses a number of disorders including monoclonal gammopathy of unknown significance (MGUS), smoldering myeloma (SMM), solitary plasmacytoma (SP), multiple myeloma (MM), PC leukemia, Waldenstrom’s macroglobulinemia (WM), and amyloidosis (AL) In this chapter, we focus on MGUS, SMM, and plasmacytoma (see Chapters 26–28) MONOCLONAL GAMMOPATHY OF UNKNOWN SIGNIFICANCE MGUS is an asymptomatic clonal PC disorder and is a precursor for MM The incidence and prevalence of MGUS increases with age, with a prevalence in the United States estimated to be slightly greater than 3% in Whites who are 50 or older In a population-based study from Olmstead County, Minnesota, the annual incidence of MGUS was noted to be 120 per 100,000 and 60 per 100,000 in men and women greater than 50 years, respectively (Mayo Clin Proc 2010;85(10):933-942) In men and women greater than 90 years, the incidence of MGUS increased to 530 per 100,000 and 370 per 100,000, respectively DIAGNOSIS The 2014 International Myeloma Working Group (IMWG) definition for MGUS is summarized in Table 25.1.1 By definition, patients with MGUS are asymptomatic Commonly, patients are diagnosed incidentally while being worked up for other disorders Considering the lack of proven benefit, health care burden, and psychological implications, universal screening for MGUS is not advocated The workup for MGUS needs to incorporate the tests to rule out more serious conditions, such as SMM or MM (Figure 25.1) Bone marrow (BM) biopsy can be considered in patients who are less than 65 years and/or have high-risk MGUS (Figure 25.1) 147 148 PLASMA CELL DISORDERS Table 25.1 IMWG Definitions MGUS (non-IgM) • Serum non-IgM M protein 8 but 1 uninvolved Immunoglobulin • BM PC >20%, >95% of PC in BM are aberrant • t(4;14), del(17p), add(1q) • Gene expression profiling: 70 score ≥0.26, score >9.28 • MRI showing diffuse bone marrow abnormalities or > focal lesion • Increased circulating PCs BM, bone marrow; FLCR, Free light chain ratio; IgA, immunoglobulin A; M protein, monoclonal protein; PC, plasma cell 152 PLASMA CELL DISORDERS epidemiology, and end results (SEER) database review, the incidence rate of SP is about 0.34 per 100,000 person-years and SP is estimated to represent 6% of all PC disorders SBP is more common than EMP and a vast majority of EMP involves upper aerodigestive tract Bone pains, pathological fracture, symptoms of nerve compression, are some of the common presenting symptoms from SBP Based on the location of the EMP, a variety of presenting symptoms can occur including nasal congestion, obstruction, cough, epistaxis, hemoptysis, and other gastrointestinal symptoms DIAGNOSIS The 2014 IMWG definition for SP is summarized in Table 25.1 Preliminary work up for SP is similar to MGUS or SMM CBC, calcium, creatinine, SPEP, UPEP, immunefixation, FLCR should be obtained Biopsy of the suspected lesions is critical in diagnosis Furthermore, a skeletal survey with MRI or CT scan of spine and pelvis is recommended PROGNOSIS The risk for progression of SP to MM is about 10% within years However, the rate of progression to MM is higher and the survival is worse in patients with SBP compared to EMP In general, patients with SP were noted to have a median overall survival ranging from 86.4 months to 156 months in different studies Patients who have clonal PCs in marrow less than 10% or persistent monoclonal spike (M spike) more than year after radiation therapy (RT) have a higher risk for progression to MM (Cancer 2002; 94(5):1532-1537) TREATMENT Plasmacytomas are radiosensitive tumors and RT is the treatment of choice for both SBP and EMP A minimum cumulative radiation dose of 40 to 50 Gy (45 Gy for EMP) administered over weeks is recommended RT results in excellent local disease control rates of 90% to 100% (Int J Radiat Oncol Biol Phys 2006;64(4):1013-1017; Radiother Oncol 1990;17(4):293-303) Primary surgical resection is not a recommended treatment modality The role of further RT is unclear if a complete resection of the lesion is achieved during initial diagnostic workup Adjuvant radiation is recommended for partially or incomplete resected lesions Role of adjuvant chemotherapy is not well established and the data available so far are inconclusive in showing benefits with chemotherapy POTENTIAL PRACTICE-CHANGING CLINICAL TRIALS An ongoing study (NCT02415413) in patients with high-risk SMM and age less than 65 is investing carfilzomib, lenalidomide, dexamethasone induction (KRd) followed by high dose melphalan 25 MGUS, SMM, and Plasmacytomas 153 and autologous stem cell transplant Subsequently, patients get consolidation KRd followed by maintenance Rd This is the first study underway that is investigating the role of transplant in high-risk SMM and its results will guide the future direction of SMM treatment A randomized phase study (NCT02544308) is evaluating the role of adjuvant immunomodulatory therapy with lenalidomide and dexamethasone in high-risk SBP compared with RT only The emergence of monoclonal antibodies in the relapsed MM setting (see Chapter 26) has raised the possibility of using them as monotherapy or in combination in SMM given their excellent side effect profile; clinical trials using these agents are underway References for Supplemental Reading Rajkumar SV, Dimopoulos MA, Palumbo A, et al International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma Lancet Oncol 2014;15(12):e538-e548 Kyle RA, Durie BG, Rajkumar SV, et al Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management Leukemia 2010;24(6):1121-1127 Kyle RA, Remstein ED, Therneau TM, et al Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma N Engl J Med 2007;356(25):2582-2590 Perez-Persona E, Vidriales MB, Mateo G, et al, New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells Blood 2007;110(7):2586-2592 Dhodapkar MV, Sexton R, Waheed S, et al Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (swog s0120) Blood 2014;123(1):78-85 26 Multiple Myeloma Patrick Griffin and Rachid Baz INTRODUCTION Multiple myeloma (MM) is a neoplastic disorder of plasma cells Patients often present with symptoms of end-organ dysfunction including unexplained anemia, renal failure, and/or painful bone lesions MM accounts for about 1% of all malignancies, with a median age at diagnosis of 66 and a higher incidence among African Americans EVALUATION History and physical exam Labs: Complete blood count (CBC), complete metabolic panel (CMP), lactate dehydrogenase (LDH), beta 2-microglobulin (B2M), serum protein electrophoresis (SPEP) with immunofixation (IFE), quantitative immunoglobulins, serum free light chains (SFLC), 24-hour urine protein electrophoresis with IFE (Figure 26.1) Imaging: Skeletal survey; consider MRI for unexplained pain; consider PET-CT to rule-out occult bone lesions if no other evidence of end-organ dysfunction (Figure 26.2) Bone marrow (BM) biopsy: Including immunohistochemistry (IHC), flow cytometry, cytogenetic analysis, and fluorescence in situ hybridization (FISH) for recurrent cytogenetic abnormalities (e.g., t(4;14), t(14;16), t(14;20), del(17p), hypodiploidy); consider gene expression profiling DIAGNOSIS Morphology The peripheral blood can show rouleaux formation of red blood cells In the BM, ≥10% clonal plasma cells are present In contrast to normal BM plasma cells, which are located in perivascular regions, neoplastic plasma cells form clusters, large aggregates, or sheets Neoplastic plasma cells have a spectrum of morphologies but typically are oval with a round, eccentrically located nucleus and characteristic “clockface” chromatin, and abundant basophilic 154 26 Multiple Myeloma 155 Figure 26.1 SPEP with immunosubtraction shows a monoclonal spike (M-Spike) in the gamma region measuring 0.6 g/dL (Left Panel) IFE demonstrates an IgG (kappa) monoclonal gammopathy (Right Panel) Figure 26.2 Skeletal survey showing multiple lytic lesions in the skull cytoplasm with a perinuclear “hof,” or clearing zone containing the Golgi apparatus Occasionally, plasma cells with cytoplasmic (Russell bodies) or nuclear (Dutcher bodies) inclusions are identified (representing excess production of immunoglobulin) Malignant plasma cells are CD138+, CD38+, CD79a+, CD19−, with aberrant CD56+ in the majority of cases International Myeloma Working Group Diagnostic Criteria 20141 PLUS: End-organ dysfunction attributable to plasma cell dyscrasia: Anemia: Hemoglobin 2 g/dL below baseline Renal insufficiency: Glomerular filtration rate (GFR) 2.0 mg/dL 156 PLASMA CELL DISORDERS Lytic bone lesion >5 mm Hypercalcemia: Corrected calcium >11 mg/dL OR: High disease burden predicting inevitable progression to symptomatic disease: ≥60% clonal bone marrow plasma cells SFLC ratio ≥100 MRI/PET defined focal lesions KEY DIAGNOSTIC DILEMMA The differential diagnosis for a patient presenting with a newly identified monoclonal gammopathy includes monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SM), symptomatic MM, amyloid lightchain (AL) amyloidosis, and Waldentrom’s macroglobulinemia (WM) (see Chapters 25, 27, 28; see MM clinical case 39 available at www.demosmedical.com/ malignant-hematology) PROGNOSIS The Revised International Staging System (R-ISS) incorporates the original ISS criteria (based on serum albumin and B2M), high-risk FISH abnormalities, and serum LDH (Table 26.1).2 Other high-risk features include circulating plasma cells or a high-risk gene expression profile (e.g., GEP70).3 TREATMENT Outcomes for patients with MM have improved with the development of immunomodulatory drugs (IMiDs) and proteasome inhibitors, with median overall survival (OS) approaching years for patients with standard-risk disease Despite these gains, MM Table 26.1 R-ISS Staging for MM R-ISS Stage Criteria Overall Survival I ISS stage I and standard-risk FISH and normal LDH Median NR 5-y OS 82% II Not R-ISS stage I or III Median 83 mo 5-y OS 62% III ISS stage III and either high-risk FISH or LDH > ULN Median 43 mo 5-y OS 40% FISH, fluorescence in situ hybridization; LDH, lactate dehydrogenase; NR, not reached; OS,overall survival; R-ISS, Revised International Staging System ULN, upper limit of normal Definitions: ISS stage I: B2M