International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma

The updated criteria for the diagnosis of myeloma represent a paradigm shift in the approach to myeloma and have considerable impact on the management of the disease.

For decades the diagnosis of multiple myeloma required the presence of end-organ damage known as the CRAB criteria, including increased calcium level, renal dysfunction, anemia, and destructive bone lesions. The updated criteria allow for treatment of patients who are at such high risk of progression to symptomatic disease that it is clear they would benefit from therapy and also potentially live longer if they were treated before serious organ damage occurred.

The revised IMWG criteria allow, in addition to the classic CRAB features, three myeloma-defining events (MDEs). The presence of at least one of these markers is considered sufficient for a diagnosis of multiple myeloma, regardless of the presence or absence of symptoms or CRAB features. Each of these markers has been shown in two or more independent studies to be associated with an approximately 80% or higher risk of developing myeloma-related organ damage within two years.

The new definition of active multiple myeloma is:

Clonal bone marrow plasma cells: 10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following CRAB features and myeloma-defining events:

Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:

• Hypercalcemia: serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11mg/dL)
• Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177mol/L (>2mg/dL)
• Anemia: hemoglobin value of >20g/L below the lowest limit of normal, or a hemoglobin value <100g/L
• Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT. If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement

Any one or more of the following biomarkers of malignancy (MDEs):

• 60% or greater clonal plasma cells on bone marrow examination
• Serum involved / uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved light chain is at least 100mg/L (a patient’s involved free light chain either kappa or lambda is the one that is above the normal reference range; the uninvolved free light chain is the one that is typically in, or below, the normal range)
• More than one focal lesion on MRI that is at least 5mm or greater in size.

Definitions of related plasma cell proliferative disorders:

Plasma Cell Disorder	Definition
Smoldering multiple myeloma	Both criteria must be met: Serum monoclonal protein (IgG or IgA) ?30g/L or urinary monoclonal protein ?500mg per 24h and/or clonal bone marrow plasma cells 10-60% Absence of myeloma-defining events or amyloidosis
Non-IgM monoclonal gammopathy of undetermined significance (MGUS)	Serum monoclonal protein <30g/L Clonal bone marrow plasma cells <10% Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder
IgM MGUS	Serum IgM monoclonal protein <30g/L No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, hepatosplenomegaly, or other end-organ damage that can be attributed to the plasma cell proliferative disorder
Light chain MGUS	Abnormal FLC ratio (<0.26 or >1.65) Increased level of the appropriate free light chain (increased ? FLC in patients with ratio >1.65 and increased ? FLC in patients with ratio <0.26) No immunoglobulin heavy chain expression on immunofixation Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder Clonal bone marrow plasma cells <10% Urinary monoclonal protein <500mg/24h
Solitary plasmacytoma	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 hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder
Solitary plasmacytoma with minimal marrow involvement	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 hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder
POEMS syndrome	Polyneuropathy Monoclonal plasma cell proliferative disorder Any one of the 3 other major criteria: sclerotic bone lesions, Castleman’s disease, elevated levels of VEGFA Any one of the following 6 minor criteria: Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy) Extravascular volume overload (edema, pleurl effusion, or ascites) Endocrinopathy (adrenal, thyroid,pituitary, gonadal, parathyroid, pancreatic) Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails) Papilloedema Thrombocytosis/polycythemia
Systemic AL amyloidosis	Presence of an amyloid-related systemic syndrome (e.g., renal, liver, heart, gastrointestinal tract, or peripheral nerve involvement) Positive amyloid staining by Congo red in any tissue (e.g., fat aspirate, bone marrow, or organ biopsy) Evidence that amyloid is light-chain-related established by direct exmination of the amyloid using mass spectrometry-based proteomic analysis or immunoeletronmicroscopy Evidence of a monoclonal plasma cell proliferative disorder (serum monoclonal protein, abnormal free light chain ratio, or clonal plasma cells in the bone marrow)

Recommended exam, tests, and imaging studies for the diagnosis of myeloma

1. History and Physical Examination
2. Routine Testing

• Complete blood count with differential and peripheral blood smear review
• Chemistry panel including calcium and creatinine
• Serum protein electrophoresis, immunofixation
• Nephelometric quantitation of immunoglobulins
• Routine urinalysis, 24h urine collection for proteinuria,electrophoresis and immunofixation
• Quantification of both urine M-component level and albuminuria

1. Bone Marrow Testing: Obtain an aspirate plus trephine biopsy with testing for cytogenetics, fluorescent in situ hybridization (FISH) and immunophenotyping.
2. Imaging

• Bone survey including spine, pelvis, skull, humeri and femurs.
• The IMWG now recommends the use of low-dose whole-body CT (LDWBCT) or MRI in the work-up of smoldering multiple myeloma (SMM) and solitary plasmacytoma.
• The IMWG now recommends that one of PET-CT, LDWBCT, or MRI of the whole body or spine be done in all patients with suspected smoldering myeloma, with the exact imaging modality determined by availability and resources.
• Clear evidence of one or more sites of osteolytic bone destruction (?5mm in size) seen on CT (including LDWBCT) or PET-CT does fulfill the criteria for bone disease in multiple myeloma, and should be regarded as meeting the CRAB requirement irrespective of whether the lesions can be visualized on skeletal radiography or not.
• Increased uptake on PET-CT alone is not adequate for the diagnosis of multiple myeloma; evidence of underlying osteolytic bone destruction is needed on the CT portion of the examination.
• Bone densitometry studies are not sufficient to determine presence of multiple myeloma.
• The IMWG no longer recommends the presence of osteoporosis or vertebral compression fractures in the absence of lytic lesions as being sufficient evidence of bone disease for purposes of the diagnostic criteria.

Source: Lancet Oncol. 2016 Aug;17(8):e328-e346. doi: 10.1016/S1470-2045(16)30206-6.

International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.
Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, Munshi N, Lonial S, Bladé J, Mateos MV, Dimopoulos M, Kastritis E, Boccadoro M, Orlowski R, Goldschmidt H, Spencer A, Hou J, Chng WJ, Usmani SZ, Zamagni E, Shimizu K, Jagannath S, Johnsen HE, Terpos E, Reiman A, Kyle RA, Sonneveld P, Richardson PG, McCarthy P, Ludwig H, Chen W, Cavo M, Harousseau JL, Lentzsch S, Hillengass J, Palumbo A, Orfao A, Rajkumar SV, Miguel JS, Avet-Loiseau H.