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2016 International Myeloma Working Group uniform response criteria for multiple myeloma

2016 International Myeloma Working Group uniform response criteria for multiple myeloma
  Response criteria*
IMWG MRD criteria (requires a complete response as defined below)
Sustained MRD-negative MRD negativity in the marrow (NGF or NGS, or both) and by imaging as defined below, confirmed minimum of 1 year apart. Subsequent evaluations can be used to further specify the duration of negativity (eg, MRD-negative at 5 years).
Flow MRD-negative Absence of phenotypically aberrant clonal plasma cells by NGFΔ on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher.
Sequencing MRD-negative Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the LymphoSIGHT platform (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells◊ or higher.
Imaging plus MRD-negative MRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer uptake found at baseline or a preceding PET/CT or decrease to less than the mediastinal blood pool SUV or decrease to less than that of surrounding normal tissue.§
Standard IMWG response criteria¥
Stringent complete response Complete response as defined below plus normal FLC ratio‡ and absence of clonal cells in bone marrow biopsy by immunohistochemistry (κ/λ ratio ≤4:1 or ≥1:2 for κ and λ patients, respectively, after counting ≥100 plasma cells).†
Complete response Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates.
Very good partial response Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours.
Partial response ≥50% reduction of serum M-protein plus reduction in 24 hour urinary M-protein by ≥90% or to <200 mg per 24 hours. If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was ≥30%. In addition to these criteria, if present at baseline, a ≥50% reduction in the size (SPD)** of soft tissue plasmacytomas is also required.
Minimal response ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50 to 89%. In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size (SPD)** of soft tissue plasmacytomas is also required.
Stable disease Not recommended for use as an indicator of response; stability of disease is best described by providing the time-to-progression estimates. Not meeting criteria for complete response, very good partial response, partial response, minimal response, or progressive disease.
Progressive disease¶¶,ΔΔ Any one or more of the following criteria:
  • Increase of 25% from lowest confirmed response value in one or more of the following criteria:
    • Serum M-protein (absolute increase must be ≥0.5 g/dL);
    • Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL;
    • Urine M-protein (absolute increase must be ≥200 mg/24 hours);
    • In patients without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL);
    • In patients without measurable serum and urine M-protein levels and without measurable involved FLC levels, bone marrow plasma-cell percentage irrespective of baseline status (absolute increase must be ≥10%);
  • Appearance of a new lesion(s), ≥50% increase from nadir in SPD** of >1 lesion, or ≥50% increase in the longest diameter of a previous lesion >1 cm in short axis;
  • ≥50% increase in circulating plasma cells (minimum of 200 cells per microL) if this is the only measure of disease.
Clinical relapse Clinical relapse requires one or more of the following criteria:
  • Direct indicators of increasing disease and/or end organ dysfunction (CRAB features) related to the underlying clonal plasma-cell proliferative disorder. It is not used in calculation of time to progression or progression-free survival but is listed as something that can be reported optionally or for use in clinical practice;
  • Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression);
  • Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and ≥1 cm) increase as measured serially by the SPD** of the measurable lesion;
  • Hypercalcemia (>11 mg/dL);
  • Decrease in hemoglobin of ≥2 g/dL not related to therapy or other non-myeloma-related conditions;
  • Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and attributable to myeloma;
  • Hyperviscosity related to serum paraprotein.
Relapse from complete response (to be used only if the end point is disease-free survival) Any one or more of the following criteria:
  • Reappearance of serum or urine M-protein by immunofixation or electrophoresis;
  • Development of ≥5% plasma cells in the bone marrow;
  • Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia [refer to 'clinical relapse' above]).
Relapse from MRD negative (to be used only if the end point is disease-free survival) Any one or more of the following criteria:
  • Loss of MRD negative state (evidence of clonal plasma cells on NGF or NGS, or positive imaging study for recurrence of myeloma);
  • Reappearance of serum or urine M-protein by immunofixation or electrophoresis;
  • Development of ≥5% clonal plasma cells in the bone marrow;
  • Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia).
For MRD assessment, the first bone marrow aspirate should be sent to MRD (not for morphology) and this sample should be taken in one draw with a volume of minimally 2 mL (to obtain sufficient cells), but maximally 4 to 5 mL to avoid hemodilution. Special attention should be given to the emergence of a different monoclonal protein following treatment, especially in the setting of patients having achieved a conventional complete response, often related to oligoclonal reconstitution of the immune system. These bands typically disappear over time and in some studies have been associated with a better outcome. Also, appearance of monoclonal IgG κ in patients receiving monoclonal antibodies should be differentiated from the therapeutic antibody.
IMWG: International Myeloma Working Group; MRD: minimal residual disease; NGF: next-generation flow; NGS: next-generation sequencing; PET: positron emission tomography; CT: computed tomography; SUV: standardized uptake value; FLC: free light chain; M-protein: myeloma protein; SPD: sum of the products of the maximal perpendicular diameters of measured lesions; CRAB features: calcium elevation, renal failure, anemia, lytic bone lesions; FCM: flow cytometry; SUVmax: maximum standardized uptake value; MFC: multiparameter flow cytometry; 18F-FDG PET: 18F-fluorodeoxyglucose PET; ASCT: autologous stem cell transplantation.
* All response categories require two consecutive assessments made any time before starting any new therapy; for MRD there is no need for two consecutive assessments, but information on MRD after each treatment stage is recommended (eg, after induction, high-dose therapy/ASCT, consolidation, maintenance). MRD tests should be initiated only at the time of suspected complete response. All categories of response and MRD require no known evidence of progressive or new bone lesions if radiographic studies were performed. However, radiographic studies are not required to satisfy these response requirements except for the requirement of FDG PET if imaging MRD-negative status is reported.
¶ Sustained MRD negativity when reported should also annotate the method used (eg, sustained flow MRD-negative, sustained sequencing MRD-negative).
Δ Bone marrow MFC should follow NGF guidelines.[1] The reference NGF method is an eight-color two-tube approach, which has been extensively validated. The two-tube approach improves reliability, consistency, and sensitivity because of the acquisition of a greater number of cells. The eight-color technology is widely available globally and the NGF method has already been adopted in many flow laboratories worldwide. The complete eight-color method is most efficient using a lyophilized mixture of antibodies which reduces errors, time, and costs. 5 million cells should be assessed. The FCM method employed should have a sensitivity of detection of at least 1 in 105 plasma cells.
◊ DNA sequencing assay on bone marrow aspirate should use a validated assay such as LymphoSIGHT (Sequenta).
§ Criteria used by Zamagni and colleagues,[2] and expert panel (Italian Myeloma criteria for PET Use [IMPetUs]).[3,4] Baseline positive lesions were identified by presence of focal areas of increased uptake within bones, with or without any underlying lesion identified by CT and present on at least two consecutive slices. Alternatively, an SUVmax = 2.5 within osteolytic CT areas >1 cm in size, or SUVmax = 1.5 within osteolytic CT areas ≤1 cm in size were considered positive. Imaging should be performed once MRD negativity is determined by MFC or NGS.
¥ Derived from international uniform response criteria for multiple myeloma.[5] Minor response definition and clarifications derived from Rajkumar and colleagues.[6] When the only method to measure disease is by serum FLC levels: Complete response can be defined as a normal FLC ratio of 0.26 to 1.65 in addition to the complete response criteria listed previously. Very good partial response in such patients requires a ≥90% decrease in the difference between involved and uninvolved FLC levels. All response categories require two consecutive assessments made at any time before the institution of any new therapy; all categories also require no known evidence of progressive or new bone lesions or extramedullary plasmacytomas if radiographic studies were performed. Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments do not need to be confirmed. Each category, except for stable disease, will be considered unconfirmed until the confirmatory test is performed. The date of the initial test is considered as the date of response for evaluation of time dependent outcomes such as duration of response.
‡ All recommendations regarding clinical uses relating to serum FLC levels or FLC ratio are based on results obtained with the validated Freelite test (Binding Site, Birmingham, UK).
† Presence/absence of clonal cells on immunohistochemistry is based upon the κ/λ/L ratio. An abnormal κ/λ ratio by immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is κ/λ of >4:1 or <1:2.
** Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or dedicated CT scans where applicable. For patients with only skin involvement, skin lesions should be measured with a ruler. Measurement of tumor size will be determined by the SPD.
¶¶ Positive immunofixation alone in a patient previously classified as achieving a complete response will not be considered progression. For purposes of calculating time to progression and progression-free survival, patients who have achieved a complete response and are MRD-negative should be evaluated using criteria listed for progressive disease. Criteria for relapse from a complete response or relapse from MRD should be used only when calculating disease-free survival.
ΔΔ In the case where a value is felt to be a spurious result per physician discretion (eg, a possible laboratory error), that value will not be considered when determining the lowest value.
References:
  1. Paiva B, Gutierrez NC, Rosinol L, et al, for the GEM (Grupo Español de MM)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) Cooperative Study Groups. High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. Blood 2012; 119:687.
  2. Zamagni E, Nanni C, Mancuso K, et al. PET/CT improves the defi nition of complete response and allows to detect otherwise unidentifiable skeletal progression in multiple myeloma. Clin Cancer Res 2015; 21:4384.
  3. Usmani SZ, Mitchell A, Waheed S, et al. Prognostic implications of serial 18-fl uoro-deoxyglucose emission tomography in multiple myeloma treated with total therapy 3. Blood 2013; 121:1819.
  4. Nanni C, Zamagni E, Versari A, et al. Image interpretation criteria for FDG PET/CT in multiple myeloma: a new proposal from an Italian expert panel. IMPeTUs (Italian Myeloma criteria for PET USe). Eur J Nucl Med Mol Imaging 2015; 43:414.
  5. Durie BG, Harousseau JL, Miguel JS, et al, for the International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia 2006; 20:1467.
  6. Rajkumar SV, Harousseau JL, Durie B, et al, for the International Myeloma Workshop Consensus Panel 1. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 2011; 117:4691.
Reproduced from: Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 2016; 17:e328. Table used with the permission of Elsevier Inc. All rights reserved.
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