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Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma

Leukemia volume 23, pages 39 (2009) | Download Citation


  • A Corrigendum to this article was published on 09 April 2014


New systems have emerged for diagnosis, staging and response assessment in multiple myeloma (MM). The diagnostic and response criteria recommended are primarily derived from the International Myeloma Working Group, with certain updates and clarifications. The International Staging System is the current standard for staging of myeloma. A new risk stratification model is provided to specifically define high-risk patients who may benefit from novel therapeutic strategies. This paper provides the current criteria for diagnosis, staging, risk stratification and response assessment of MM.


Multiple myeloma (MM) is a malignant disorder characterized by the proliferation of a single clone of plasma cells derived from B cells in the bone marrow. Frequently, there is invasion of the adjacent bone, which destroys skeletal structures and results in bone pain and fractures. Occasionally, plasma cells infiltrate multiple organs and produce a variety of symptoms. The plasma cell clone produces a monoclonal (M) protein that can lead to renal failure caused by light chains (Bence Jones protein) or hyperviscosity from excessive amounts of M protein in the blood. The diagnosis depends on the identification of abnormal monoclonal plasma cells in the bone marrow, M protein in the serum or urine, evidence of end-organ damage and a clinical picture consistent with MM. The key clinical and laboratory features are summarized in Table 1.1 This paper summarizes the current international consensus criteria for diagnosis, staging, risk stratification and response assessment of MM.

Table 1: Clinical and laboratory abnormalities in myeloma1

Diagnostic criteria

Standard diagnostic criteria

The International Myeloma Working Group (IMWG) and Mayo Clinic have established almost identical criteria for the diagnosis of the plasma cell proliferative disorders.6 Table 2 lists the current IMWG diagnostic criteria for MM with minor clarifications (as referenced); it also lists the diagnostic criteria for related plasma cell disorders that need to be differentiated from MM. MGUS is defined by an intact immunoglobulin <3 g/100 ml and <10% bone marrow plasma cells and absence of end-organ damage. End-organ damage includes hypercalcemia, renal failure, anemia and bone (CRAB) lesions that are felt related to a plasma cell proliferative disorder and not explained by another unrelated disease or disorder. Patients with only free serum κ and λ light chains (idiopathic Bence Jones proteinuria) should be excluded. Symptomatic MM is differentiated from MGUS and SMM (asymptomatic) based on the presence or absence of end-organ damage attributable to the underlying plasma cell proliferative process. Note that although a bone marrow biopsy is indicated at diagnosis in all patients with myeloma, in patients with clinical MGUS with a small monoclonal protein (less than 1.5 g/100 ml) and no end-organ damage it can be deferred. Conventional radiographs showing lytic lesions, osteoporosis or pathologic fractures are used to detect the presence of bone lesions.

Table 2: Diagnostic criteria for plasma cell disorders

Role of additional imaging procedures

Skeletal lesions may also be detected by MRI, fluoro-deoxyglucose positron emission tomography (PET) or CT. CT and MRI scans are more sensitive than conventional radiography in detecting bone and bone marrow involvement. Among asymptomatic MM patients with normal roentgenograms, up to 50% may have tumor-related abnormalities on MRI of the lower spine. One or more of these studies are indicated when symptomatic areas show no abnormality on routine radiographs. However, the routine use in assessing the extent of bone disease in addition to skeletal radiographs is unclear, and is not recommended on a routine basis in most patients except those with apparent solitary plasmacytoma. The specific role of new imaging modalities in management needs further investigation. The role of bone mineral density studies in myeloma and the use of these studies in identifying patients at risk for pathologic fractures and prophylactic bisphosphonate therapy also remain unresolved. We do not believe that asymptomatic skeletal lesions detected only by MRI, CT or PET scanning are routine indications for therapy, but should be evaluated in the clinical context and followed closely. Therapeutic decisions must be based on a case-by-case basis.


Durie–Salmon staging system

The Durie–Salmon clinical staging system was developed over 30 years ago to provide a practical way to measure MM tumor burden.17 Knowing the immunoglobulin production by each plasma cell and the half-life of the circulating immunoglobulin, it was possible to mathematically derive the total myeloma cell number and tumor burden. The tumor burden was then correlated with individual clinical, laboratory and X-ray features, including the levels of hemoglobin, serum calcium and creatinine, serum and urine M protein levels and the number and size of bone lesions to define the clinical staging system. This provided a simple and practical estimate of tumor burden. Patients were categorized as stage I, II or III, depending on the degree of anemia, hypercalcemia, levels of M protein in the serum and urine or bone lesions. In addition, patients with or without serum creatinine of 2 mg/100 ml or more were designated A or B.

International staging system

The Durie–Salmon staging was widely adopted as the standard staging system in MM. However, there are significant shortcomings with this system. The number of lytic lesions on routine radiographs, an important element of the Durie–Salmon system, is unfortunately observer dependent. In an effort to develop a more objective staging system, other features were proposed. Serum β2M (Sβ2M) is an easily reproducible readily available laboratory test. It has proven to be an important prognostic factor since its introduction more than 25 years ago.18 More recently, the IMWG has reported using only the albumin level and β2M (Table 3). Clinical and laboratory data were obtained on 10 750 previously untreated symptomatic MM patients from 17 worldwide institutions. The International Staging System (ISS) system consists of stage I: β2M <3.5 mg/l and serum albumin 3.5 g/100 ml (median survival 62 months); stage II, neither stage I nor stage III (median survival 44 months) and stage III (β2M 5.5 mg/l (median survival 29 months).19

Table 3: International staging system

Limitations of the ISS

The ISS has many advantages. It allows outcome in clinical trials to be compared with each other and is more reproducible than the Durie–Salmon system. However, the ISS also has many limitations. It is not useful unless the diagnosis of myeloma has already been made. The ISS has no role in MGUS, SMM or other related plasma cell disorders. It cannot be used to distinguish MGUS and SMM from myeloma. Stage III ISS is a composite group comprised of patients in whom the β2M is elevated because of tumor burden as well as patients in whom the elevation is due to renal failure. Thus, the ISS cannot be used for therapeutic risk stratification, and does not provide a good estimate of tumor burden. Finally, the prognostic role of the ISS in the era of new drugs is not established. It is possible that the ISS may not retain prognostic significance in the era of new drugs.

Recommendations regarding staging

We recommend that both the Durie–Salmon staging and the ISS be reported in clinical trials. Although the Durie–Salmon Staging System has several shortcomings, we believe that it remains useful in comparing patients in clinical trials and allows a better assessment of the disease burden of patients in a given study.

Risk stratification

Conventional cytogenetic studies show an abnormal karyotype in only one-third of patients with MM.20 However, the presence of hypodiploidy21 or the deletion of chromosome 13 predicts a significantly reduced survival.22 FISH reveals abnormalities in more than 90% of patients with MM (Table 4).20 In an Eastern Cooperative Oncology Group (ECOG) clinical trial of 351 patients, the presence of t4;14, t(14;16) or 17p− was associated with poor prognosis (median survival 25 months).25 The combination of monosomy and/or deletion of chromosome 13 by FISH and a Sβ2M level greater than 2.5 mg/l resulted in shorter survival.26 An elevated plasma cell labeling index also confers a significantly adverse prognosis.27 Gene expression profiling has been utilized to aid in the differentiation between normal plasma cells and those in MGUS, MM, amyloid light-chain amyloidosis, and extramedullary plasmacytomas. It has also been used to identify high risk patients with MM, and to further classify risk in poor prognosis MM patients such as those with t(4;14).

Table 4: Mayo risk stratification for myeloma: definition of high-risk disease7

Recommendations on risk stratification

As discussed earlier, the Durie–Salmon Staging System and the ISS are important for prognosis, but are not useful for therapeutic risk stratification. Independent prognostic markers discussed above provide a better estimate of differences in underlying myeloma biology. Either FISH or conventional cytogenetics, or preferably both, should be done at diagnosis in all patients. However, modifying therapy based on underlying risk factors remains controversial and needs further study. Gene expression profiling is also useful in risk stratification, but is limited by the lack of a uniform platform across many centers in the world and widespread availability.

Response criteria

The European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry/American Bone Marrow Transplant Registry (EBMT/IBMTR/ABMTR) published criteria for the response and progression of MM treated by stem cell transplantation, commonly referred to as the Blade criteria or the EBMT criteria.28 In addition, other commonly used response criteria were those developed by the Chronic Leukemia-Myeloma Task Force, Southwest Oncology Group (SWOG) and the ECOG. All these have been largely abandoned. In 2006, the IMWG recognized the need for uniformity and published uniform response criteria that are to be used in future clinical trials.29

The IMWG uniform response criteria were developed similarly to the EBMT criteria with several major exceptions: addition of FLC response and progression criteria for patients without measurable disease, modification of the definition for disease progression for patients in complete response (CR), addition of very good partial response (VGPR) and stringent response categories, elimination of the minor response category, elimination of the mandatory 6-week wait time to confirm response, and some additional clarifications and correction of errors. The IMWG criteria for response and progression are listed in Table 5.

Table 5: International Myeloma Working Group uniform response criteria for multiple myeloma29

Recommendations on response criteria

We believe that the IMWG supplements and clarifies some of the problems with the EBMT criteria, and is now the standard criteria that should be used in future clinical trials. It overcomes some significant limitations of the EBMT criteria that have become a significant issue recently such as the definition of progressive disease in patients achieving CR. However, we also recommend that for patients with relapsed refractory myeloma, the minor response category be reported (see below) in addition. Some of the main points pertaining to the assessment of response in myeloma are further discussed below.


The VGPR category is a useful measure of depth of response. It identifies patients with a better outcome who have achieved excellent response but are not yet in CR. VGPR has gained additional clinical significance by the finding that patients who obtained at least a VGPR with the first autologous stem cell transplant do not benefit from a second (tandem) transplant. It distinguishes patients who have had near disappearance in their M-spike but are still immunofixation positive from those patients who merely have a 50% reduction in their serum M-spike. The VGPR or better rate should be reported in clinical trials to enable comparison of regimens.

Response assessment using the serum FLC assay

The serum FLC assay criteria come into play only in patients who do not have evidence of measurable disease. As discussed earlier, measurable disease is defined as serum M protein 1 g/100 ml or urine M protein 200 mg per 24 h. The FLC assay is not to be used for response assessment in patients who have evidence of measurable disease in the serum or urine. In addition, the baseline level of the involved FLC should be at least 100 mg/l and the FLC assay should have an abnormal ratio (clonal).

The serum FLC assay consists of two separate assays, one to detect free-κ (normal range, 3.3–19.4 mg/l) and the other to detect free-λ (normal range, 5.7–26.3 mg/l) light chains. The test assesses clonality based on the ratio of κ/λ light chain levels (normal reference range, 0.26–1.65). Patients with κ/λ FLC ratio <0.26 are defined as having monoclonal λ FLC and those with ratios >1.65 are defined as having a monoclonal κ FLC. The monoclonal light chain isotype is referred to as the ‘involved’ FLC isotype, and the opposite light chain type is the ‘uninvolved’ FLC type.

FLC levels vary considerably with changes in renal function and do not solely represent monoclonal elevations. Thus, both the level of the involved and the uninvolved FLC isotypes (that is, the involved-uninvolved difference) are considered in assessing response.

Definition of disease progression in patients with CR

The IMWG uniform response criteria have clarified that patients in CR need to meet the same criteria for disease progression as other patients not in CR for purposes of calculating progression-free survival and time to progression.29 The relapse from CR definition should not be used to define progression in these patients as had been done earlier in the EBMT criteria. The immunofixation results used to define CR can vary significantly due to laboratory variation. Thus, using relapse from CR criteria would erroneously result in shorter time to progression and progression-free survival for CR patients as compared to those not in CR with regimens that produce high CR rates.

Definition of disease progression in SMM

The criteria used for MM cannot be used to determine disease progression in SMM. A recent American Society of Hematology/Food and Drug Administration (ASH-FDA) panel has defined specific criteria for disease progression in SMM (Table 5).

Minor response

The IMWG response criteria deleted the category of minor response, as it was not felt to be reliable. However, a recent ASH-FDA panel proposed that the category of minor response as defined in the EBMT criteria (Table 6) be used in patients with relapsed refractory myeloma to obtain a signal of activity in phase I/II trials of novel agents. Table 5 also defines relapsed myeloma and relapsed and refractory myeloma recommended by the ASH-FDA panel.

Table 6: Additional response criteria for specific disease stages30

Survival estimates

Several estimates of survival such as overall survival, disease-free survival, progression-free survival, time to progression and event-free survival are used to describe outcome in myeloma. The specific definitions of these terms and their respective role in myeloma are listed in Table 7.

Table 7: Definitions of time to event end points30


We provide a summary of current criteria and definitions that are used in diagnosis, prognosis, risk stratification and response assessment in myeloma. We have highlighted the limitations of current criteria, and corrected any inadvertent errors that have been identified in the various published criteria over time. The paper also provides input in areas where there is controversy or lack of clarity.


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This study was supported by Grants CA62242 and CA107476 from the National Cancer Institute.

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  1. Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA

    • R A Kyle
    •  & S V Rajkumar


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