New uniform response criteria are required to adequately assess clinical outcomes in myeloma. The European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry criteria have been expanded, clarified and updated to provide a new comprehensive evaluation system. Categories for stringent complete response and very good partial response are added. The serum free light-chain assay is included to allow evaluation of patients with oligo-secretory disease. Inconsistencies in prior criteria are clarified making confirmation of response and disease progression easier to perform. Emphasis is placed upon time to event and duration of response as critical end points. The requirements necessary to use overall survival duration as the ultimate end point are discussed. It is anticipated that the International Response Criteria for multiple myeloma will be widely used in future clinical trials of myeloma.
There is an increasing need for widely accepted, reproducible criteria to evaluate response in multiple myeloma.1, 2 Several different systems are currently in use, but are not exactly comparable. For example, the US cooperative groups ECOG and SWOG have differing systems, as do several European groups, such as the MRC (UK)3 and the IFM (France).4 In addition, the European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry/American Bone Marrow Transplant Registry (EBMT/IBMTR/ABMTR) developed widely used criteria, commonly referred to as the EBMT criteria.5 However, as discussed below, there is a need to update prior criteria.
The need for new uniform response criteria has been triggered by several factors (Table 1). The most pressing need is for criteria that facilitate precise comparisons between new treatment strategies. Better criteria are also required for use in the clinic at the individual patient level. In this setting, clarification of complete response (CR) is particularly important. As more active agents are available, there is a need to assess not just if response has occurred, but the exact magnitude of response. There is increased awareness of the distinction between surrogate end points such as reduction in M-component level and more clinical end points such as recovery of functional status or organ function, length of response and overall survival duration.6
Many of the commonly used criteria do not define CR stringently. In the EBMT criteria, CR does not require absence of monoclonal (M) plasma cells, but rather the reduction in plasma cells to 5% or less on bone marrow samples. This naturally results in the contamination of a subset of complete responders with normal polyclonal plasma cells in the marrow with those who still have M plasma cells. The latter are easily detected by kappa/lambda immunostaining or immunofluorescence studies using flow cytometry. Specific categories of CR with varying degrees of stringency allow greater precision in the definition of CR, enable comparison of the efficacy of various treatments including novel agents and csn permit the detection and monitoring of relapse more accurately. Existing criteria lack sufficient detail, which as a result allows substantial investigator discretion, and lead to inaccuracies in the estimated response rate. For example, the EBMT criteria require specific reductions in M-protein levels for each category of response, but the minimum level of M-protein that is required in the serum and urine to allow accurate response assessment is not specified. Similarly, it is not clear from prior criteria how patients with ‘unmeasurable’ levels of urine M-protein should be monitored for response evaluation.
Finally, present criteria allow limited assessment of response in patients with oligo-secretory or non-secretory myeloma.7 Response in these patients can now be assessed using the sensitive serum free light-chain (FLC) assay (Freelite, Binding Site). Incorporation of the serum FLC assay into the response criteria for myeloma allows inclusion and evaluation of these patients in clinical trials.
Development of new response and relapse criteria
The International Myeloma Working Group has developed new standard diagnostic criteria8 and a new International Staging System (ISS) for multiple myeloma,9 which are being widely accepted as the current standards for diagnosis and staging. The development of the new response criteria proposed in this manuscript started with a meeting of the International Myeloma Working Group (participants are listed at the end of the manuscript) during the 10th International Myeloma Workshop, Sydney, 10–14 April 2005. Based on the discussions and decisions made at this meeting, the criteria were formulated and drafted by two of the authors (BGD and SVR) and circulated to the members of the Working Group and revised. Final approval was made at a meeting of the International Myeloma Working Group at the Annual Meeting of the American Society of Hematology, Atlanta, GA, USA, December 2005 and subsequent reviews of this paper.
A summary of the important changes in the new criteria versus prior systems is provided in Table 2. It is important to point out that for patients with measurable M-protein levels in the serum and urine, the definitions of complete and partial response as well as disease progression match those used in the EBMT (Bladé) criteria. Therefore, although important clarifications are added, for all practical purposes, in trials that include only patients with measurable disease response rates and progression, estimates reported using the using the new International Myeloma Working Group criteria will be comparable to those using the EBMT criteria. This will allow easy comparison of rates reported in trials using the EBMT criteria with those using the new criteria. The most important changes in the new criteria are (1) addition of a new category of stringent CR that is of significant importance given rapid advances in therapy, (2) addition of response criteria for interpreting the serum FLC assay, which will enable numerous patients hitherto excluded from clinical trials for lack of measurable disease to enter and be evaluated on clinical trials, and (3) formal addition of a category of very good partial response (VGPR) to allow distinction of patients with excellent responses that may have outcomes similar to those patients considered to be in CR.
Diagnostic criteria for multiple myeloma
The need for clear baseline diagnostic criteria cannot be overemphasized. Three recent publications from the International Myeloma Working Group incorporate recommended methods for diagnosis, baseline staging and prognostic classifications as well as disease subtype identification.1, 8, 9 With these systems, the features of patients entering clinical trials can be clearly delineated. Table 3 summarizes the diagnostic criteria for active myeloma.
Changes in the M-component level are the principal indicators used for response evaluation.6 It is important to note that M-component is a surrogate marker and its use is accompanied by all the pitfalls that can potentially detract from such use including variations in marker synthesis, metabolism or release as well as myeloma cell heterogeneity with respect to M-component production.10 The major response categories include CR, partial response (PR), stable disease (SD), progressive disease (PD) and relapse from CR (see Tables 5 and 6).
Additional subcategories have been used by a number of investigators.3, 11 The subcategories of near complete response (nCR) and VGPR have been integrated into the new criteria under one single category termed ‘VGPR’. Importantly, the term ‘stable disease’ is not recommended for use as a measure of treatment efficacy; instead time to progression (TTP) and response duration estimates (see below) should be used in instances when the stability of disease with a particular therapy needs to be highlighted. TTP is calculated from the start of treatment and includes all patients entering the trial. Duration of response (DOR) is calculated from the time of first recorded achievement of a particular response level, that is, PR, VGPR, CR or sCR (see Table 5), and includes only responding patients. Although documentation of response requires a confirmatory measurement, the start time for DOR is the first date at which response was noted.
Important aspects of response assessment
Table 4 summarizes important practical details in response assessment. In addition, two specific points must be emphasized. Firstly, checking the M-component level at each cycle during induction is critically important in the evaluation of novel therapies to determine the speed of response, which may have clinical implications. For example, with several new regimens, response occurs rapidly and can be substantial within 1–2 months.12, 13 The second point is that the new criteria eliminate the need for consecutive confirmations 6 weeks apart currently required for response testing. A DOR of 6 weeks does not carry major clinical significance and is not a surrogate for durability of response. The main concern is to eliminate laboratory or other error; this can be carried out by the requirement of a confirmatory test at any time following the first test provided it is before any new/non-protocol therapy. The importance of response, that is, its durability, should be highlighted by reporting data on TTP and DOR. Thus plateau phase can be documented by indicating the TTP and/or DOR.1
Three other aspects pertaining to the serum FLC assay deserve emphasis. First, the serum FLC assay (Freelite, The Binding Site, Birmingham, UK) is a highly sensitive marker of light chains in circulation that are unbound to intact immunoglobulin, and the FLC ratio is an excellent indicator of clonality.14 Thus, normalizing of serum FLC ratio is a stricter indicator of CR, and may correlate well with extended response duration15 (Kumar S et al. Blood 2005; 106: 971a, abs 3479). Note that in patients with renal insufficiency, the levels of both the kappa and lambda may remain elevated, but the ratio normalizes with achievement of CR. Second, in order to minimize chance of error, FLC response is not assessable for patients who start with low baseline serum FLC assay levels below 10 mg/dl (<100 mg/l). Third, although the serum FLC assay is a very reliable test, it is important to closely monitor laboratory variation.16 Strict guidelines are required with regard to usage times for the serum FLC assay kits. It should also be noted that serum FLC assay testing might be useful in the prognostic and response evaluation of patients who also have a measurable serum and/or urine M-component in the future, given its recently reported prognostic value in M-gammopathy of undetermined significance (MGUS).17
The international Myeloma Working Group Uniform Response Criteria
The International Myeloma Working Group Uniform Response Criteria are listed in Table 5. Under CR two categories are listed: CR and stringent (sCR). The CR category is available for widespread use and provides continuity with prior systems. However, sCR, the more stringent category, allows more accurate assessment of new therapies. Many myeloma groups already use this latter category. It is now possible to specifically list and clearly identify which categories are used. The major goal is to foster studies evaluating correlations between stringent CR and durable response and prolonged survival.
VGPR, as defined in IFM trials,4 has been very slightly modified to also include what has been called nCR. Use of VGPR has several advantages including the reliance upon the 90% or higher regression cutoff, which is simpler to implement than use of immunofixation positivity versus negativity, an observer-dependent assessment. In addition, failure to achieve VGPR correlates with inferior outcome.1 The definition of PR except for inclusion of the FLC assay for the subgroup of patients with ‘unmeasurable’ disease is similar to the EBMT criteria. It is important to note that the FLC assay should not be used to assess response in patients with measurable levels of M-protein in either serum or urine. Such patients should be assessed using standard criteria; the serum light-chain assay is only applicable to those patients who do not have either 1 g/dl or higher M-protein in the serum or 200 mg/day or higher M-protein level in the urine. Less than PR is identified as SD, which can be clinically meaningful, but is not sufficient as an indicator of response benefit in new therapeutic trials. Reporting SD or response categories less than PR as meaningful is not recommended in clinical trials of new agents. Overall, the emphasis is upon simplicity, reproducibility and the awareness that very fine discriminations are frequently unreliable and not clinically meaningful.
The criteria for PD and relapse from CR are listed in Table 6. A category of clinical relapse has been added for optional assessment in clinical trials and for use in clinical practice. Progressive disease will continue to identify patients in whom the standard M-component (and related) criteria for relapse or disease progression have been met. Progressive disease is the end point that is used for calculating TTP and progression-free survival (PFS) in trials, and mirrors the EBMT criteria. One problem is that progression defined using these criteria may or may not reflect a need for therapy (or new therapy). Early re-treatment can be unnecessary, result in unwanted toxicities and underestimate the benefit of prior treatment, as true symptomatic relapse may not emerge until months or years later. Thus, discrete ‘event categories’ are required to identify relapse or progression requiring intervention. These ‘events’ are broadly the same as the CRAB categories used for diagnosis of myeloma. Various nuances and details related to use in the relapse setting are outlined in Table 6. Thus, where possible, reporting of time to re-treatment and/or time to clinical relapse would be useful; as mentioned earlier, these definitions will also be useful in clinical practice. It is anticipated that new trials will use clinical relapse as an end point and ‘time to clinical relapse’ as a hallmark of clinical utility of therapy.
The difficulties and nuances in evaluating myeloma-related events are well known. It is important to re-emphasize that myeloma must be the cause of events. Whatever additional testing is required to confirm myeloma relatedness is strongly encouraged. This may include magnetic resonance imaging, computed tomography and/or fluoro-18-deoxyglucose (FDG)/positron emission tomography (PET) imaging (Walker R et al. Blood 2004; 104: 217a, abs 758).18, 19
Survival end points
DOR is an important end point and can predict ultimate overall survival (Tricot G et al. Blood 2004; 104: 265a, abs 926).6, 20, 21, 22 Several different methods are used to calculate response duration and the impact of treatment.
PFS: PFS is the time from start of the treatment to disease progression or death. This encompasses all patients and has been considered a surrogate marker for overall survival duration. This is the recommended method to present trial results.
Event-free survival (EFS): The definition for EFS depends on how ‘event’ is defined. In some studies, this can be the same as PFS. EFS can also include additional ‘events’ that are considered to be of importance besides death, including serious drug toxicity. EFS is not recommended for general use unless specifically defined, as confusion can arise about the details of additional ‘events’. PFS is preferred.
TTP: This is the time from start of treatment to disease progression with deaths owing to causes other than progression not counted, but censored. This is a helpful method to discretely assess the durability of treatment benefit.
Disease-free survival (DFS): DFS applies to patients in CR, and is measured from the start of CR to the time of relapse from CR. This parameter has limited value in myeloma at present.
DOR: DOR applies to patients achieving at least PR by the criteria in Table 5, and is measured from start of achieving PR (first observation of PR before confirmation) to the time of disease progression, with deaths owing to causes other than progression not counted, but censored. This is an additional parameter for consideration in the assessment of new agents and/or new comprehensive treatment strategies. DOR and TTP are the recommended ways of establishing the durability of response. As noted above, investigators now have the option to consider ‘clinical relapse’ as a valuable end point.
Many recent myeloma trials have had response and/or TTP as the primary end points. However, overall survival and quality of life reflect the full impact of therapies. Several factors limit the use of overall survival as the ultimate end point.
Over 5 years of follow-up are required to assess benefit.
Initial response and TTP may or may not translate into overall survival benefit.
New agents used as part of induction, consolidation/transplant and/or maintenance are frequently used at time of relapse in the ‘control’ (non-use) arm of trials. Thus the comparison is with early versus later use. There has been no widely accepted plan or framework to control for this.
Additional new agents are now being introduced, which can further impact outcome assessment.
The problems involved are illustrated by several trials (Tricot G et al. Blood 2004; 104: 265a, abs 926)23, 24, 25 (Barlogie B et al. Blood 2004; 104: 156a, abs 538).26, 27, 28, 29 In the SWOG trial,26 high-dose cyclophosmide was utilized for stem cell harvesting in both arms of the trial and ultimately over half the patients in the non-transplant arm ended up being transplanted. Likewise, in a very recent trial reported by the Arkansas group,27 thalidomide was used as part of the TT-2 in one arm of the trial and produced a significantly higher CR rate and disease-free interval. However, overall survival was not improved. But, it is important to note that 83% of patients not in the thalidomide arm received thalidomide at relapse. Thus, again the study reflects an unplanned ‘early’ versus ‘later’ use of a therapeutic intervention, in this case thalidomide. In a more minor way, this was also an issue in the recently published28 results of the melphalan/prednisone (MP) versus MP thalidomide trial. In this case, there was survival benefit with addition of thalidomide. Only 21% of patients in the non-thaldiomide group had received thalidomide at the time of relapse. But, again, this was not a planned part of the trial. New trial designs to evaluate survival duration must accommodate these types of complexity. These details are further discussed in a recent review.1
The response criteria outlined in this paper are expected to be used widely in future clinical trials of myeloma. The major new additions to the response criteria are categories of stringent CR, VGPR and incorporation of the serum FLC assay to evaluate patients with oligo-secretory disease. The criteria also clarify several inconsistencies in prior response criteria, make confirmation of response and disease progression easier to perform with less chance of deviations, and define time to event end points that are critical in the evaluation of outcome.
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International myeloma working group:
Raymond Alexanian, MD Anderson, Houston, Texas
Kenneth Anderson, DFCI, Boston, Massachusetts
Michael Attal, Purpan Hospital, Toulouse, France
Herve Avet-Loiseau, Institute de Biologie, Nantes, France
Leif Bergsagel, Mayo Clinic Scottsdale
Joan Bladé, Hospital Clinica, Barcelona, Spain
Bart Barlogie, MIRT UAMS Little Rock, Arkanas
Regis Batille, Nantes, France
Meral Beksac, Ankara University, Turkey
Andrew Belch, Cross Cancer Institute, Canada
Mario Boccadoro, University of Torino
Michele Cavo, Bologna, Italy
Tony Child, United Kingdom
Ray Comenzo, Memorial-Sloan Kettering Cancer Center, New York
John Crowley, Cancer Research and Biostatistics, Seattle, Washington
William Dalton, H Lee Moffitt, Tampa, Florida
Faith Davies, Royal Marsden Hospital, London, England
Meletios Dimopoulos, Alexandra Hospital, Athens, Greece
Angela Dispenzieri, Mayo Clinic, Rochester, Minnesota
Brian Durie, Cedars-Sinai Outpatient Medical Center, Los Angeles, California
Theirry Facon, Centre Hospitalier Regional Universitaire de Lille, France
Dorotea Fantl, Buenos Aires, Argentina
Jean-Paul Fermand, Paris, France
Rafael Fonseca, Mayo Clinic Scottsdale, Scottsdale, Arizona
Gosta Gahrton, Karolinska Institutet, Stockholm , Sweden
Morie Gertz, Mayo Clinic
Hartmut Goldschmidt, Heidelberg, Germany
Philip Greipp, Mayo Clinic
Roman Hajek, Brno University, Brno, Czech Republic
Jean-Luc Harousseau, Institute de Biologie, Nantes, France
Kim Hawkins, Statistician, United Kingdom
Martin Hjorth, Data manager, Netherlands
Vania Hungria, Clinica San Germano, Sao Paolo, Brazil
Mohamad Hussein, The Cleveland Clinic, Cleveland, Ohio, USA
Peter Jacobs, South Africa
Mariana Juni, Fundaleu, Buenos Aires, Argentina
Douglas Joshua, Royal Prince Alfred Hospital, Sydney, Australia
Michael Katz, New York
Michio Kawano, Yamaguchi University, Ube, Japan
Shaji Kumar, Mayo Clinic
Robert Kyle, Mayo Clinic
Juan Lahuerta, Madrid, Spain
Henk Lokhorst, University Hospital, Utrecht, The Netherlands
Heinz Ludwig, Wilhelminenspital Der Stat Wien, Vienna
Jayesh Mehta, Northwestern University, Chicago
Giampaolo Merlini, University of Pavia, Pavia, Italy
Philippe Moreau, Nantes, France
Gareth Morgan, Royal Marsden Hospital, London
Antonio Palumbo, Cathedra Ematologia, Torino, Italy
Santiago Pavlovsky, Fundaleu, Buenos Aires, Argentina
Amara Nouel, Bolivar, Venezuela
Susie Novis, IMF, Los Angeles, California
Raymond Powles, Leukaemia & Myeloma, Wimbledon
Linda Pilarski, The University of Alberta, Edmonton Alberta, Canada
S Vincent Rajkumar, Mayo Clinic
Tony Reiman, Cross Cancer Institute, Canada
Paul Richardson, Dana Farber Cancer Institute, Boston, Massachusetts
Angelina Rodriquez Morales, Bonco MetroPolitano de Sangre, Caracas, Venezuela
Kazuyuki Shimizu, Nagoya City Midori General Hospital, Nagoya, Japan
David Siegel, Hackensack, Cancer Center, Hackensack, New Jersey
Guido Tricot, MIRT UAMS, Little Rock, Arkansas
Jesus San Miguel, University of Salamanca
Seema Singhal, Northwestern University
Pieter Sonneveld, Erasmus University Hospital, Rotterdam, The Netherlands
Keith Stewart, Mayo Clinic Scottsdale
Patrizia Tosi, Bologna, Italy
Ingemar Turesson, Malmo, Sweden
Ivan Van Riet, Brussels Vrija University
David Vesole, St Vincent's Comprehensive Cancer Center, New York
Donna Weber, MD Anderson, Houston, Texas
Jan Westin, University of Gothenberg, Sweden
Keith Wheatley, University of Birmingham, Edgbaston, Birmingham, UK
Brian Van Ness, University of Minnesota