Multiple myeloma evolves from a clinically silent premalignant

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1 S. VINCENT RAJKUMAR Updated Diagnostic Criteria and Staging System for Multiple Myeloma S. Vincent Rajkumar, MD OVERVIEW There has been remarkable progress made in the diagnosis and treatment of multiple myeloma (MM). The median survival of the disease has doubled as a result of several new active drugs. These advances have necessitated a revision of the disease definition and staging of MM. Until recently, MM was defined by the presence of end-organ damage, specifically hypercalcemia, renal failure, anemia, and bone lesions (CRAB features) that can be attributed to the clonal process. In 2014, the International Myeloma Working Group (IMWG) updated the diagnostic criteria for MM to add three specific biomarkers that can be used to diagnose the disease in patients who did not have CRAB features: clonal bone marrow plasma cells greater than or equal to 60%, serum free light chain (FLC) ratio greater than or equal to 100 provided involved FLC level is 100 mg/l or higher, or more than one focal lesion on MRI. In addition, the definition was revised to allow CT and PET-CT to diagnose MM bone disease. These changes enable early diagnosis and allow the initiation of effective therapy to prevent the development of end-organ damage for patients who are at the highest risk. A new staging system has been developed that incorporates high-risk cytogenetic abnormalities in addition to standard laboratory markers of prognosis. Multiple myeloma evolves from a clinically silent premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS). 1,2 MGUS is a classic premalignant condition with a low risk of malignant conversion, but the risk of progression persists indefinitely. A small subset of patients has an intermediate clinical phenotype between MGUS and MM, and they are referred to as having smoldering multiple myeloma (SMM). 3 MGUS is associated with a risk of progression to MM or related malignancy at a rate of approximately 1% per year, whereas SMM has a much higher risk of progression of approximately 10% per year. 4,5 MGUS and SMM are typically asymptomatic and are typically diagnosed incidentally when a monoclonal (M) protein is detected during laboratory work-up of patients who have a wide spectrum of clinical conditions. Over the years the diagnosis of MM required evidence of end-organ damage attributable to the neoplastic clone of plasma cells: hypercalcemia, renal failure, anemia, and osteolytic bone lesions, commonly referred to as CRAB features. 6 This definition was conservative and intended to prevent patients with MGUS and SMM from receiving unnecessary and toxic chemotherapy. With major advances in therapy and identification of biomarkers that can distinguish MM from premalignant phases, it became necessary to revise the disease definition of MM. 7-9 REVISED DIAGNOSTIC CRITERIA FOR MULTIPLE MYELOMA In 2014, the IMWG revised the diagnostic criteria for MM. 10 The revised diagnostic criteria for MM allow the use of specific biomarkers to define the disease in addition to the established CRAB features. They also allow the use of modern imaging tools to diagnose MM bone disease and clarify several other diagnostic requirements. Table 1 provides the revised IMWG criteria for diagnosis of MM and related plasma cell disorders. 10 Myeloma-Defining Events The diagnosis of MM requires 10% or more clonal plasma cells on bone marrow examination or a biopsy-proven plasmacytoma plus the presence of one or more myeloma-defining events. 10 Myeloma-defining events include the presence of one or more CRAB features, or one or more biomarkers of malignancy. The three biomarkers included in the definition of MM are associated with an approximately 80% risk of progression to symptomatic endorgan damage in two or more independent studies. They are clonal bone marrow plasma cells greater than or equal to 60%, serum FLC ratio of 100 or higher, provided involved FLC level is 100 mg/l or higher, or more than one focal lesion on MRI. From the Division of Hematology, Mayo Clinic, Rochester, MN. Disclosures of potential conflicts of interest provided by the author are available with the online article at asco.org/edbook. Corresponding author: S. Vincent Rajkumar, MD, Division of Hematology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905; rajkumar.vincent@mayo.edu by American Society of Clinical Oncology. e ASCO EDUCATIONAL BOOK asco.org/edbook

2 NEW DIAGNOSTIC AND STAGING CRITERIA IN MYELOMA Extreme bone marrow clonal plasmacytosis. Clonal bone marrow plasma cell involvement of greater than or equal to 60% is extremely unusual in the absence of CRAB features. In a Mayo Clinic study of SMM, only six of 276 patients (2%) had clonal bone marrow plasma cells greater than or equal to 60%. In that study, patients with this level of marrow involvement progressed to symptomatic malignancy rapidly, with a median progression-free survival of 7.7 months. 7 In a separate cohort of 651 patients with SMM, only 21 (3.2%) had clonal bone marrow plasma cells greater than or equal to 60%, and 95% of these patients progressed to having MM within 2 years. 7 A study of 96 patients with SMM from the Greek Myeloma Group also found a markedly high risk of progression in this subgroup of patients, with a median time to progression (TTP) of 15 months. 11 Similar results were reported by the University of Pennsylvania; six of 121 patients (5%) with SMM had greater than or equal to 60% bone marrow involvement, and all progressed to having MM in less than 2 years. 12 Marked elevation of serum involved/uninvolved FLC ratio. In SMM, an abnormal FLC ratio is associated with a higher risk of progression to MM. 13 As the ratio increases, so does the risk of progression. In a Mayo Clinic study of 586 patients with SMM, a markedly abnormal involved/ uninvolved FLC ratio ($ 100) was seen in 90 (15%) patients. 8 The risk of progression to symptomatic end-organ damage within the first 2 years with an FLC ratio of 100 or higher was 72%; the risk of progression to MM or amyloid light-chain amyloidosis in 2 years was 79%. A similar finding was reported by Kastritis et al, who studied 96 patients with SMM. In their study, 7% of patients with SMM had an involved/uninvolved FLC ratio of 100 or higher, and almost all progressed to symptomatic disease within 18 months. 11 In a third study, at the University of Pennsylvania, patients KEY POINTS The diagnostic criteria for multiple myeloma and related disorders have been updated by the International Myeloma Working Group. Patients with 60% or more clonal plasma cell involvement of the marrow, serum free light chain ratio of 100 or higher (provided involved free light chain level 100 mg/l), and/or greater than one focal lesion on MRI are defined as MM even in the absence of endorgan damage. Low-dose whole-body CT, MRI, and FDG-PET and FDG- PET with PET-CT are more sensitive in detecting myeloma and must be considered in diagnosis and monitoring. In terms of renal involvement, only light chain cast nephropathy is considered a myeloma-defining event. The Revised International Staging System has been developed for myeloma that incorportates high-risk cytogenetic abnormalities. with SMM with an involved/uninvolved FLC ratio of 100 or higher had a 64% risk of progression within 2 years. 12 A markedly abnormal FLC ratio is thus an accurate predictor of patients who have a high risk of progression to end-organ damage within a short period of time. To reduce the possibility of error, in addition to the FLC ratio being 100 or higher, the IMWG also added a requirement for a minimal involved FLC level of at least 100 mg/l to be considered as a myeloma-defining event. 10 MRI with more than one focal lesion. MRI imaging study of the whole-body spine/pelvis can reveal focal or diffuse changes in SMM. In a study by Hillengass et al, 23 of 149 (15%) patients with SMM had more than one focal lesion seen on whole-body MRI. 14 The median TTP in these patients was 13 months, and the progression rate at 2 years was 70%. These results were confirmed by Kastritis et al, who found more than one focal lesion on spinal MRI in nine of 65 patients (14%) with SMM. 15 The median TTP was 15 months and 69% progressed to MM within 2 years. To increase predictive value, the IMWG added a requirement that focal lesions must be at least 5 mm or more in size and recommended follow-up examinations in 3 to 6 months for patients who had a solitary focal lesion, equivocal findings, or diffuse infiltration. 10 Assessment of myeloma bone disease. There have been many advances to imaging methods used to detect bone and extramedullary disease in MM. These include low-dose whole-body CT, MRI, and (18)Ffluorodeoxyglucose PET (FDG-PET) and FDG-PET with PET-CT The old IMWG criteria for the diagnosis of MM primarily relied on conventional radiographs to detect bone disease. 6 A systematic review compared MRI, FDG-PET, PET CT, and whole-body CT to conventional whole-body skeletal radiography in MM. 23 Newer imaging techniques had greater sensitivity compared with radiographic bone survey for detection of MM bone lesions, with as high as 80% more lesions detected by the newer imaging techniques. CT and MRI performed equally with respect to sensitivity. Based on these studies, the revised IMWG criteria for MM permit the use of CT, low-dose whole-body CT, PET-CT, and whole-body CT to diagnose lytic bone disease in MM. One or more sites of osteolytic bone destruction of at least 5 mm or more in size is required. Increased uptake on PET-CT alone is not adequate; there must be evidence of actual osteolytic bone destruction on the CT portion of the examination. A biopsy of one of the bone lesions should be considered if there is any doubt about the diagnosis. These changes will enable early and accurate diagnosis of MM. In addition to these changes, the IMWG clarified that the presence of osteoporosis, vertebral compression fractures, or bone densitometric changes in the absence of lytic lesions is not sufficient evidence of myeloma bone disease. Because the accurate diagnosis of MM is critical, at least one advanced imaging examination (PET-CT, low-dose whole-body CT, or MRI of the whole body or spine) is asco.org/edbook 2016 ASCO EDUCATIONAL BOOK e419

3 S. VINCENT RAJKUMAR TABLE 1. International Myeloma Working Group Diagnostic Criteria for Multiple Myeloma and Related Plasma Cell Disorders Disorder Non-IgM MGUS Smoldering MM MM IgM MGUS Light-Chain MGUS Solitary Plasmacytoma Solitary Plasmacytoma With Minimal Marrow Involvement** Disease Definition All three criteria must be met: Serum monoclonal protein (non-igm type), 3 g/dl Clonal bone marrow plasma cells, 10%* Absence of end-organ damage such as CRAB features that can be attributed to the plasma cell proliferative disorder Both criteria must be met: Serum monoclonal protein (IgG or IgA) $ 3 gm/dl, or urinary monoclonal protein $ 500 mg per 24 h and/or clonal bone marrow plasma cells 10% 60% Absence of myeloma-defining events or amyloidosis Both criteria must be met: Clonal bone marrow plasma cells $ 10% or biopsy-proven bony or extramedullary plasmacytoma Any one or more of the following myeloma defining events: Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: Hypercalcemia: serum calcium mmol/l (. 1 mg/dl) higher than the upper limit of normal or mmol/l (. 11 mg/dl) Renal insufficiency: creatinine clearance, 40 ml/min or serum creatinine. 177 mmol/l (. 2 mg/dl) Anemia: hemoglobin value of. 2 g/dl below the lower limit of normal, or a hemoglobin value, 10 g/dl Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT Clonal bone marrow plasma cell percentage $ 60% Involved: uninvolved serum FLC ratio $ 100 (involved FLC level must be $ 100 mg/l). 1 focal lesion on MRI studies (at least 5 mm in size) All three criteria must be met: Serum IgM monoclonal protein, 3 gm/dl Bone marrow lymphoplasmacytic infiltration, 10% No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder. All criteria must be met: Abnormal FLC ratio (, 0.26 or. 1.65) Increased level of the appropriate involved light chain (increased kappa FLC in patients with ratio and increased lambda FLC in patients with ratio, 0.26) No immunoglobulin heavy-chain expression on immunofixation Absence of end-organ damage that can be attributed to the plasma cell proliferative disorder Clonal bone marrow plasma cells, 10% Urinary monoclonal protein, 500 mg/24 h All four criteria must be met: Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells Normal bone marrow with no evidence of clonal plasma cells Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) Absence of end-organ damage such as CRAB features that can be attributed to a lympho-plasma cell proliferative disorder All four criteria must be met: Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells Clonal bone marrow plasma cells, 10% Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) Absence of end-organ damage such as CRAB features that can be attributed to a lympho-plasma cell proliferative disorder Abbreviations: MGUS, monoclonal gammopathy of undertermined significance; CRAB features, hypercalcemia, renal insufficiency, anemia, and bone lesions; MM, multiple myeloma; FLC, free light chain; SMM, smoldering multiple myeloma. *A bone marrow examination can be deferred for patients with low-risk MGUS (IgG type, M protein, 15 gm/l, normal FLC ratio) in whom there are no clinical features concerning for myeloma. ** Solitary plasmacytoma with 10% or more clonal plasma cells is considered as MM. Reproduced from Rajkumar et al. 10 e ASCO EDUCATIONAL BOOK asco.org/edbook

4 NEW DIAGNOSTIC AND STAGING CRITERIA IN MYELOMA recommended for patients before concluding that a patient has SMM or solitary plasmacytoma. 10,24 The choice between various imaging methods can vary depending on the clinical situation and availability. Other clarifications to MM diagnostic criteria. Several clarifications to the diagnostic criteria for MM were made. Importantly, the IMWG clarified that in terms of renal disease, only suspected or proven light-chain cast nephropathy is considered a myeloma-defining event. Other renal disorders associated with M proteins, such as light-chain deposition disease, membranoproliferative glomerulonephritis, and amyloid light-chain amyloidosis, are considered unique diseases and not MM. A renal biopsy to clarify the underlying cause of renal failure is recommended for patients with suspected cast nephropathy, especially if the serum involved FLC levels are less than 500 mg/l. 25 An estimated glomerular filtration rate less than 40 ml/min is preferred to the serum creatinine concentration for purposes of fulfilling the CRAB criteria. Solitary plasmacytoma. Solitary plasmacytoma is an earlystage plasma cell malignancy that is in between MGUS/SMM and MM along the spectrum of plasma cell disorders. It is defined by the presence of a single biopsy-proven plasmacytoma (bony or extramedullary) and a normal bone marrow examination (Table 1). Treatment consists of radiation therapy at 40 Gy to 50 Gy to the involved site. Patients with an apparent solitary plasmacytoma who have limited (, 10%) clonal marrow involvement are considered to have solitary plasmacytoma with minimal marrow involvement. These patients are also treated similar to patients with solitary plasmacytoma. The risk of recurrence or progression to myeloma within 3 years is approximately 10% for patients with solitary plasmacytoma versus 20% to 60% for patients with solitary plasmacytoma and minimal marrow involvement. REVISED INTERNATIONAL STAGING SYSTEM FOR MYELOMA There is major variation in survival of MM depending on host factors, tumor burden (stage), biology (cytogenetic abnormalities), and response to therapy. 26 Tumor burden in MM has traditionally been assessed using the Durie- Salmon Staging (DSS) 27 and the International Staging System (ISS). 28,29 Both these staging systems have some limitations. The DSS primarily classified patients based on tumor burden and had problems with reproducibility because some judgment is needed in interpretation of MM bone disease. The ISS is more reproducible but includes a host factor determinant, namely serum albumin. Thus, outcome using ISS can be disproportionately affected by TABLE 2. Cytogenetic Abnormalities on Clinical Course and Prognosis in Multiple Myeloma Clinical Setting in Which Abnormality Is Detected Cytogenetic Abnormality Smoldering Multiple Myeloma Multiple Myeloma Trisomies Intermediate-risk of progression, median TTP of 3 years Good prognosis, standard-risk MM, median OS 7-10 years Most have myeloma bone disease at diagnosis Excellent response to lenalidomide-based therapy t(11;14) (q13;q32) Standard-risk of progression, median TTP of 5 years Good prognosis, standard-risk MM, median OS 7-10 years t(6;14) (p21;q32) Standard-risk of progression, median TTP of 5 years Good prognosis, standard-risk MM, median OS 7-10 years t(4;14) (p16;q32) High-risk of progression, median TTP of 2 years Intermediate-risk MM, median OS 5 years Needs bortezomib-based initial therapy, early ASCT (if eligible), followed by bortezomibbased consolidation/maintenance t(14;16) (q32;q23) Standard-risk of progression, median TTP of 5 years High-risk MM, median OS 3 years Associated with high levels of FLC and 25% present with acute renal failure as initial MDE t(14;20) (q32;q11) Standard-risk of progression, median TTP of 5 years High-risk MM, median OS 3 years Gain(1q21) High-risk of progression, median TTP of 2 years Intermediate-risk MM, median OS 5 years Del(17p) High-risk of progression, median TTP of 2 years High-risk MM, median OS 3 years Trisomies Plus Any One of the IgH Translocations Isolated Monosomy 13, or Isolated Monosomy 14 Standard-risk of progression, median TTP of 5 years Standard-risk of progression, median TTP of 5 years May ameliorate adverse prognosis conferred by high risk IgH translocations, and del 17p Effect on prognosis is not clear Normal Low-risk of progression, median TTP of 7-10 years Good prognosis, probably reflecting low tumor burden, median OS years Abbreviations: TTP, time to progression; MM, multiple myeloma; OS, overall survival; ASCT, autologous stem cell transplantation; MDE, myeloma-defining event. Reproduced from Rajan and Rajkumar. 32 asco.org/edbook 2016 ASCO EDUCATIONAL BOOK e421

5 S. VINCENT RAJKUMAR TABLE 3. Revised International Staging System for Myeloma Stage Frequency (% of Patients) 5-Year Survival Rate (%) Stage I ISS stage I (serum albumin > 3.5, serum beta-2-microglobulin < 3.5) and No high-risk cytogenetics Normal LDH Stage II Neither stage I or III Stage III ISS stage III (serum beta-2-microglobulin > 5.5) and High-risk cytogenetics [t(4;14), t(14;16), or del(17p)] or elevated LDH Abbreviations: LDH, lactate dehydrogenase; ISS, International Staging System. Derived from Palumbo et al. 33 factors that are not disease-specific. Neither staging system considers disease biology a key determinant of overall survival in the disease. Disease biology in MM is best reflected based on the molecular subtype of the disease and the presence or absence of specific cytogenetic abnormalities. 30,31 For example, abnormalities such as t(4;14), t(14;16), t(14;20), gain (1q), del(1p), and del(17p) influence disease course, response to therapy, and prognosis in MM (Table 2). 32 The Revised International Staging System (RISS) combines elements of tumor burden (ISS) and disease biology (presence of high-risk cytogenetic abnormalities or elevated lactate dehydrogenase level) to create a unified prognostic index that helps in clinical care as well as in comparison of clinical trial data (Table 3). 33 The RISS was developed based on a study of 4,445 patients with newly diagnosed MM from 11 international trials. This study showed that the 5-year survival rate of patients with stage I, II, and III RISS was 82%, 62%, and 40%, respectively. The RISS will be of importance in the clinic in terms of counseling patients regarding prognosis, as well as in clinical trials to compare outcomes across clinical trials. FUTURE DIRECTIONS The updated diagnostic criteria for MM represent a paradigm shift in our approach to the disease. These changes will allow us to intervene before end-organ damage in selected patients who are at imminent risk of symptomatic progression. The revised staging system for MM allows us to better predict outcome and tailor treatments accordingly. Advances in imaging have not only enabled early and accurate diagnosis, but also provide ways of monitoring response to therapy. We must identify additional reliable biomarkers of malignancy. We must also develop a portfolio of clinical trials designed to determine whether early intervention can improve survival or provide a path to cure MM. References 1. Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009;113: Weiss BM, Abadie J, Verma P, et al. A monoclonal gammopathy precedes multiple myeloma in most patients. Blood. 2009;113: Rajkumar SV, Merlini G, San Miguel JF. Haematological cancer: Redefining myeloma. Nat Rev Clin Oncol. 2012;9: Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007; 356: Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346: International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121: Rajkumar SV, Larson D, Kyle RA. Diagnosis of smoldering multiple myeloma. N Engl J Med. 2011;365: Larsen JT, Kumar SK, Dispenzieri A, et al. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia. 2013; 27: Mateos M-V, Hernández M-T, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013;369: Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538-e Kastritis E, Terpos E, Moulopoulos L, et al. Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease. Leukemia. 2013;27: Waxman AJ, Mick R, Garfall AL, et al. Modeling the risk of progression in smoldering multiple myeloma. J Clin Oncol. 2014;32:A Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood. 2008;111: e ASCO EDUCATIONAL BOOK asco.org/edbook

6 NEW DIAGNOSTIC AND STAGING CRITERIA IN MYELOMA 14. Hillengass J, Fechtner K, Weber MA, et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol. 2010;28: Kastritis E, Moulopoulos LA, Terpos E, et al. The prognostic importance of the presence of more than one focal lesion in spine MRI of patients with asymptomatic (smoldering) multiple myeloma. Leukemia. 2014; 28: Dimopoulos M, Terpos E, Comenzo RL, et al; IMWG. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple Myeloma. Leukemia. 2009;23: Hillengass J, Landgren O. Challenges and opportunities of novel imaging techniques in monoclonal plasma cell disorders: imaging early myeloma. Leuk Lymphoma. 2013;54: Zamagni E, Cavo M. The role of imaging techniques in the management of multiple myeloma. Br J Haematol. 2012;159: Zamagni E, Nanni C, Patriarca F, et al. A prospective comparison of 18 F- fluorodeoxyglucose positron emission tomography-computed tomography, magnetic resonance imaging and whole-body planar radiographs in the assessment of bone disease in newly diagnosed multiple myeloma. Haematologica. 2007;92: Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol. 2007;25: Bartel TB, Haessler J, Brown TL, et al. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Blood. 2009;114: Waheed S, Mitchell A, Usmani S, et al. Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data. Haematologica. 2013;98: Regelink JC, Minnema MC, Terpos E, et al. Comparison of modern and conventional imaging techniques in establishing multiple myelomarelated bone disease: a systematic review. Br J Haematol. 2013;162: Dimopoulos MA, Hillengass J, Usmani S, et al. Role of magnetic resonance imaging in the management of patients with multiple myeloma: a consensus statement. J Clin Oncol. 2015;33: Hutchison CA, Batuman V, Behrens J, et al; International Kidney and Monoclonal Gammopathy Research Group. The pathogenesis and diagnosis of acute kidney injury in multiple myeloma. Nat Rev Nephrol. 2012;8: Russell SJ, Rajkumar SV. Multiple myeloma and the road to personalised medicine. Lancet Oncol. 2011;12: Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36: Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23: Hari PN, Zhang MJ, Roy V, et al. Is the International Staging System superior to the Durie-Salmon staging system? A comparison in multiple myeloma patients undergoing autologous transplant. Leukemia. 2009; 23: Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (msmart) consensus guidelines. Mayo Clin Proc. 2009;84: Kumar S, Fonseca R, Ketterling RP, et al. Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics. Blood. 2012; 119: Rajan AM, Rajkumar SV. Interpretation of cytogenetic results in multiple myeloma for clinical practice. Blood Cancer J. 2015;5:e Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015;33: asco.org/edbook 2016 ASCO EDUCATIONAL BOOK e423