Document xpx5QmO4mw2D46VaEp4Kz9EQ

REPRINT OF LEADING ARTICLE: International uniform response criteria for multiple myeloma Received 8 May 2006; Accepted 11 May 2006; Published online 20 July 2006. The International Myeloma Working Group The International Myeloma Foundation LEADING ARTICLE Leukemia (2006), 17 & 2006 Nature Publishing Group All rights reserved 0887-6924/06 $30.00 www.nature.com/leu International uniform response criteria for multiple myeloma BGM Durie1, J-L Harousseau2, JS Miguel3, J Blade4, B Barlogie5, K Anderson6, M Gertz7, M Dimopoulos8, J Westin9, P Sonneveld10, H Ludwig11, G Gahrton12, M Beksac13, J Crowley14, A Belch15, M Boccadaro16, I Turesson17, D Joshua18, D Vesole19, R Kyle7, R Alexanian20, G Tricot5, M Attal21, G Merlini22, R Powles23, P Richardson24, K Shimizu25, P Tosi26, G Morgan27 and SV Rajkumar7 on behalf of the International Myeloma Working Group29 1Aptium Oncology, Inc., Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA, USA; 2Institute de Biologie, Nantes, France; 3University of Salamanca, Salamanca, Spain; 4Hospital Clinica, Barcelona, Spain; 5MIRT UAMS, Little Rock, Arkansas, USA; 6DFCI, Boston, MA, USA; 7Mayo Clinic, Rochester, MN, USA; 8Alexandra Hospital, Athens, Greece; 9University of Gothenberg, Gothenberg, Sweden; 10Rotterdam, The Netherlands; 11Wilhelminenspital Der Stat Wien, Vienna, Austria; 12Karolinska Institutet, Stockholm, Sweden; 13Ankara University, Turkey; 14Cancer Research and Biostatistics, Seattle, WA, USA; 15Cross Cancer Institute, Canada; 16University of Torino, Torino, Italy; 17University of Malmo, Malmo, Sweden; 18Royal Prince Alfred Hospital, Sydney, Australia; 19St Vincent's Comprehensive Cancer Center, New York, NY, USA; 20MD Anderson, Houston, TX, USA; 21Purpan Hospital, Toulouse, France; 22University of Pavia, Pavia, Italy; 23The Leukemia and Myeloma Program, Wimbledon, UK; 24Dana Farber Cancer Institute, Boston, MA, USA; 25Nagoya City Midori General Hospital, Nagoya, Japan; 26University of Bologna, Bologna, Italy and 27Royal Marsden Hospital, London, UK 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 lightchain 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. Leukemia (2006) 0, 000000. doi:10.1038/sj.leu.2404284 Keywords: myeloma; response criteria; staging; survival duration; uniform criteria; clinical outcomes Introduction 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. Correspondence: Dr BGM Durie, Aptium Oncology Inc., Cedars-Sinai Outpatient Cancer Center, 8201 Beverly Boulevard, Los Angeles, CA 90048, USA or Dr SV Rajkumar, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mails: bdurie@aptiumoncology.com or rajkumar.vincent@mayo.edu. 29For members of the International Myeloma Working Group, see Appendix A. Received 8 May 2006; accepted 11 May 2006 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 by 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 can permit the detection and monitoring of relapse more accurately. Existing criteria lack sufficient detail, which as a result allows substantial investigator discretion, and leads 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. Response criteria for multiple myeloma BGM Durie et al 2 Table 1 Rationale for the development of uniform response criteria Table 2 Summary of similarities and specific changes introduced in the New Uniform Response Criteria compared to the EBMT/IBMTR K Facilitate precise comparisons of efficacy between new Criteria treatment strategies in trials K Incorporation of the serum FLC assay to include assessment of patients with oligo-secretory and non-secretory diseasea K Stricter definitions for CR K Provide clarifications, improve detail and correct inconsistencies in prior response criteria K For patients with measurable levels of serum and urine monoclonal protein levels, the criteria for CR, PR and progressive disease remain unchanged. (Tables 4 and 5) K Clarification and revision of important practical details of response evaluation (Table 4) Elimination of mandatory 6 weeks wait time to confirm Abbreviations: CR, complete response; FLC, free light chain. aOligo- and non-secretory myeloma identifies patients without sufficient M-component in serum and/or urine to monitor response (see Table 4: definitions of measurable disease). achievement of response Introduction of a similar non-time-dependent confirmation for relapse and/or disease progression Clarification of the `start time' for duration of response evaluation Requirement of XPR as response requirement for new drug trials Allow use of quantitative immunoglobulin levels in patients in Development of new response and relapse criteria whom the M-protein measurements are unavailable or unreliable K Introduction of new response categories (Table 5) sCR and VGPR The International Myeloma Working Group has developed new standard diagnostic criteria8 and the new International Staging System (ISS) for multiple myeloma,9 which are being widely accepted as the current standards for diagnosis and staging. The Elimination of the minor response category K Incorporation of response criteria for the serum FLC assay to enable assessment of response in patients with non- or oligosecretory disease (Tables 4 and 5) 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, 1014 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. K Clarification that criteria for progressive disease (rather than criteria for `relapse from CR') are to be used for calculation of time to progression and progression-free survival in patients who are in CR. Criteria for relapse from CR are to be used only if DFS is calculated and reported K Introduction of new category of clinical relapse or progressive disease (Table 6) Introduces clinical relapse as a new optional end point Abbreviations: CR, complete response; DFS, disease-free survival; EBMT, European Group for Blood and Bone Marrow Transplant; FLC, free light chain; IBMTR, International Bone Marrow Transplant Registry; PR, partial response; sCR, stringent complete response; VGPR, very good partial response. 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 be clearly delineated. Table 3 summarizes the diagnostic criteria and urine, the definitions of complete and partial response as for active myeloma. well as disease progression match those used in the EBMT (Blade) criteria. Therefore, although important clarifications are Response categories 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 Changes in the M-component level are the principal indicators used for response evaluation.6 It is important to note that Myeloma Working Group criteria will be comparable to those M-component is a surrogate marker and its use is accompanied using the EBMT criteria. This will allow easy comparison of rates by all the pitfalls that can potentially detract from such use reported in trials using the EBMT criteria with those using the including variations in marker synthesis, metabolism or release new criteria. The most important changes in the new criteria are (1) addition of a new category of stringent CR that is of signifi- as well as myeloma cell heterogeneity with respect to M-component production.10 The major response categories cant importance given rapid advances in therapy, (2) addition include CR, partial response (PR), stable disease (SD), progres- of response criteria for interpreting the serum FLC assay, which sive disease (PD) and relapse from CR (see Tables 4 and 5). will enable numerous patients hitherto excluded from clinical trials for lack of measurable disease to enter and be evaluated on Additional subcategories have been used by a number of investigators.3,11 The subcategories of near complete response clinical trials, and (3) formal addition of a category of very good (nCR) and VGPR have been integrated into the new criteria partial response (VGPR) to allow distinction of patients with under one single category termed `VGPR'. Importantly, the term excellent responses that may have outcomes similar to those `stable disease' is not recommended for use as a measure of patients considered to be in CR. 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 Diagnostic criteria for multiple myeloma needs to be highlighted. TTP is calculated from the start of treatment and includes all patients entering the trial. Duration of The need for clear baseline diagnostic criteria cannot be response (DOR) is calculated from the time of first recorded overemphasized. Three recent publications from the Inter- achievement of a particular response level, that is, PR, VGPR, national Myeloma Working Group incorporate recommended CR or sCR (see Table 5), and includes only responding patients. methods for diagnosis, baseline staging and prognostic classifications as well as disease subtype identification.1,8,9 With Although documentation of response requires a confirmatory measurement, the start time for DOR is the first date at which these systems, the features of patients entering clinical trials can response was noted. Leukemia Response criteria for multiple myeloma BGM Durie et al Table 3 Diagnostic criteria for multiple myeloma requiring systemic therapy Presence of an M-componenta in serum and/or urine plus clonal plasma cells in the bone marrow and/or a documented clonal plasmacytoma PLUS one or more of the following:b Calcium elevation (411.5 mg/dl) [42.65 mmol/l] Renal insufficiency (creatinine 42 mg/dl) [177 mmol/l or more] Anemia (hemoglobin o10 g/dl or 2 mg onormal) (hemoglobin o12.5 mmol/lc or 1.25 mmol/lonormal) Bone disease (lytic lesions or osteopenia) aIn patients with no detectable M-component, an abnormal serum FLC ratio on the serum FLC assay can substitute and satisfy this criterion. For patients, with no serum or urine M-component and normal serum FLC ratio, the baseline bone marrow must have X10% clonal plasma cells; these patients are referred to as having `non-secretory myeloma'. Patients with biopsy-proven amyloidosis and/or systemic light chain deposition disease (LCDD) should be classified as `myeloma with documented amyloidosis' or `myeloma with documented LCDD,' respectively if they have X30% plasma cells and/or myeloma-related bone disease. bMust be attributable to the underlying plasma cell disorder. cNote: Hemoglobin of 10 g/dl is 12.5 mmol/l [or 100 g/l]. Important aspects of response assessment Table 4 summarizes important practical details in response assessment. 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 12 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 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 (o100 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 Table 4 Practical details of response evaluation Laboratory tests for measurement of M-protein Serum M-protein level is quantitated using densitometry on SPEP except in cases where the SPEP is felt to be unreliable such as in patients with IgA monoclonal proteins migrating in the beta region. If SPEP is not available or felt to be unreliable (e.g., in some cases of IgA myeloma) for routine M-protein quantitation during therapy, then quantitative immunoglobulin levels on nephelometry or turbidometry can be accepted. However, this must be explicitly reported, and only nephelometry can be used for that patient to assess response and SPEP and nephelometric values cannot be used interchangeably. Urine M-protein measurement is estimated using 24-h UPEP only. Random or 24 h urine tests measuring kappa and lambda light chain levels are not reliable and are not recommended Definitions of measurable disease Response criteria for all categories and subcategories of response except CR are applicable only to patients who have `measurable' disease defined by at least one of the following three measurements: Serum M-protein X1 g/dl (X10 gm/l)[10 g/l] Urine M-protein X200 mg/24 h Serum FLC assay: Involved FLC level X10 mg/dl (X100 mg/l) provided serum FLC ratio is abnormal Response criteria for CR are applicable for patients who have abnormalities on one of the three measurements. Note that patients who do not meet any of the criteria for measurable disease as listed above can only be assessed for stringent CR, and cannot be assessed for any of the other response categories Follow-up to meet criteria for PR or SD It is recommended that patients undergoing therapy be tracked monthly for the first year of new therapy and every other month thereafter Patients with `measurable disease' as defined above in the SPEP and UPEP need to be followed by both SPEP and UPEP for response assessment and categorization Except for assessment of CR, patients with measurable disease restricted to the SPEP will need to be followed only by SPEP; correspondingly, patients with measurable disease restricted to the UPEP will need to be followed only by UPEPa Patients with measurable disease in either SPEP or UPEP or both will be assessed for response only based on these two tests and not by the FLC assay. FLC response criteria are only applicable to patients without measurable disease in the serum or urine, and to fulfill the requirements of the category of stringent CR To be considered CR, both serum and urine immunofixation must be carried out and be negative regardless of the size of baseline M-protein in the serum or urine; patients with negative UPEP values pretreatment still require UPEP testing to confirm CR and exclude light chain or BenceJones escape Skeletal survey is not required for assessment of response unless clinically indicated, but is recommended once a year in clinical practice; bone marrow is required only for categorization of CR, and for patients with non-secretory disease Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, stable disease; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis. aFor good clinical practice patients should be periodically screened for light chain escape with UPEP or serum FLC assay. 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 3 Leukemia Response criteria for multiple myeloma BGM Durie et al 4 Table 5 International Myeloma Working Group uniform response criteria: CR and other response categories Response subcategory Response criteriaa sCR CR as defined below plus Normal FLC ratio and Absence of clonal cells in bone marrowb by immunohistochemistry or immunofluorescencec CR Negative immunofixation on the serum and urine and Disappearance of any soft tissue plasmacytomas and p5% plasma cells in bone marrowb VGPR Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level o100 mg per 24 h PR X50% reduction of serum M-protein and reduction in 24-h urinary M-protein by X90% or to o200 mg per 24 h If the serum and urine M-protein are unmeasurable,d a X50% 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, X50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was X30% In addition to the above listed criteria, if present at baseline, a X50% reduction in the size of soft tissue plasmacytomas is also required SD (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 CR, VGPR, PR or progressive disease Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, stable disease; sCR, stringent complete response; VGPR, very good partial response. aAll response categories require two consecutive assessments made at anytime before the institution of any new therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not required to satisfy these response requirements. bConfirmation with repeat bone marrow biopsy not needed. cPresence/absence of clonal cells is based upon the k/l ratio. An abnormal k/l ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is k/l of 44:1 or o1:2. dRefer to Table 4 for definitions of measurable disease. 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 retreatment 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. 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 Leukemia Response criteria for multiple myeloma BGM Durie et al Table 6 International Myeloma Working Group uniform response criteria: disease progression and relapse Relapse subcategory Relapse criteria Progressive diseasea To be used for calculation of time to progression and progression-free survival end points for all patients including those in CR (includes primary progressive disease and disease progression on or off therapy) Progressive Disease: requires any one or more of the following: Increase of X25% from baseline in Serum M-component and/or (the absolute increase must be X0.5 g/dl)b Urine M-component and/or (the absolute increase must be X200 mg/24 h Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels. The absolute increase must be 410 mg/dl. Bone marrow plasma cell percentage: the absolute % must be X10%c Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas Development of hypercalcemia (corrected serum calcium 411.5 mg/dl or 2.65 mmol/l) that can be attributed solely to the plasma cell proliferative disorder Clinical relapsea Clinical relapse requires one or more of: Direct indicators of increasing disease and/or end organ dysfunction (CRAB features)b It is not used in calculation of time to progression or progression-free survival but is listed here as as something that can be reported optionally or for use in clinical practice 1. Development of new soft tissue plasmacytomas or bone lesions 2. Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and at least 1 cm) increase as measured serially by the sum of the products of the cross-diameters of the measurable lesion 3. Hypercalcemia (411.5 mg/dl) [2.65 mmol/l] 4. Decrease in hemoglobin of X2 g/dl [1.25 mmol/l] (see Table 3 for further details) 5. Rise in serum creatinine by 2 mg/dl or more [177 mmol/l or more] Relapse from CRa(To be used only if the end point studied is DFS)d Any one or more of the following: Reappearance of serum or urine M-protein by immunofixation or electrophoresis Development of X5% plasma cells in the bone marrowc Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion, or hypercalcemia see below) Abbreviations: CR, complete response; DFS, disease-free survival. aAll relapse categories require two consecutive assessments made at anytime before classification as relapse or disease progression and/or the institution of any new therapy. bFor progressive disease, serum M-component increases of X1 gm/dl are sufficient to define relapse if starting M-component is X5 g/dl. cRelapse from CR has the 5% cutoff versus 10% for other categories of relapse. dFor purposes of calculating time to progression and progression-free survival, CR patients should also be evaluated using criteria listed above for progressive disease. 5 Survival end points End points such as PFS, TTP and DOR can predict ultimate overall survival (Tricot G et al. Blood 2004; 104: 265a, abs 926).6,2022 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 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. Overall survival 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. Leukemia Response criteria for multiple myeloma BGM Durie et al 6 Additional new agents are now being introduced, which can 11 Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, further impact outcome assessment. Irwin D et al. A phase II study of bortezomib in relapsed, refractory The problems involved are illustrated by several trials.2329 In a recent trial reported by the Arkansas group,27 thalidomide was myeloma. N Engl J Med 2003; 348: 26092617. 12 Oakervee HE, Popat R, Curry N, Smith P, Morris C, Drake M et al. PAD combination therapy (PS-341/bortezomib, doxorubicin and used as part of the TT-2 in one arm of the trial and produced a dexamethasone) for previously untreated patients with multiple 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, the study reflects an unplanned myeloma. Br J Haematol 2005; 129: 755762. 13 Drayson M, Tang LX, Drew R, Mead GP, Carr-Smith H, Bradwell AR. Serum free light chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma. Blood 2001; 97: 29002902. `early' versus `later' use of a therapeutic intervention, in this case 14 Bradwell AR, Carr-Smith HD, Mead GP, Harvey TC, Drayson MT. thalidomide. In a more minor way, this was also an issue in the Serum testing for assessment of patients with BenceJones recently published28 results of the melphalan/prednisone (MP) versus MP thalidomide trial. New trial designs to evaluate survival duration must accommodate these types of complexity. These details are further discussed in a recent review.1 myeloma. Lancet 2003; 361: 489491. 15 Mead GP, Carr-Smith HD, Drayson MT, Morgan GJ, Child A, Bradwell AR. Serum free light chains for monitoring multiple myeloma. Br J Haematol 2004; 126: 348354. 16 Hassoun H, Reich L, Klimek VM, Dhodapkar M, Cohen A, Kewalramani T et al. Doxorubicin and dexmaethasone followed by thalidomide and dexamethasone is an effective well Conclusions tolerated initial therapy for multiple myeloma. Br J Hematol 2006; 132: 155. 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 17 Rajkumar SV, Kyle RA, Therneau TM, Melton III LJ, Bradwell AR, Clark RJ et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005; 106: 812817. patients with oligo-secretory disease. The criteria also clarify 18 Kyle RA, Schreiman JS, McLeod RA, Beabout JW. Computed 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. tomography in diagnosis and management of multiple myeloma and its variants. Arch Int Med 1985; 145: 14511452. 19 Durie BGM, Waxman AD, D'Angeloa A, William CM. Whole body F-FDG PET identifies high-risk myeloma. J Nucl Med 2002; 43: 14571463. 20 Durie BGM. Is magnitude of initial response predictive for survival in multiple myeloma? Ann Oncol 1999; 2: 166169. References 21 Lahuerta JJ, Martinez-Lopez J, de la Serna J, Blade J, Grande C, Alegra A et al. Remission status defined by immunofixation versus electrophoresis following autologus transplantation has a major 1 Durie BGM. New approaches to treatment for multiple myeloma: impact on the outcome of multiple myeloma patients. Br J durable remission and quality of life as primary goals. Clin Haematol 2000; 109: 438446. Lymphoma Myeloma 2005; 6: 181190. 22 Riccardi A, Mora O, Tinelli C, Porta C, Danova M, Brugnatelli S 2 Rajkumar SV, Dispenzieri A. Evaluation and monitoring of et al. Response to first-line chemotherapy and long-term survival in response to therapy in multiple myeloma. Haematologica 2005; patients with multiple myeloma: results of the MM87 prospective 90: 13051308. randomized protocol. Eur J Cancer 2003; 39: 3137. 3 Child JA, Morgan G, Davies F, Owen RG, Bell SE, Hawkins K et al. 23 Cavo M, Zamagni E, Tosi P, Tacchetti P, Cellini C, Cangini D et al. High-dose chemotherapy with hematopoietic stem cell Superiority of thalidomide and dexamethasone over vincristine rescue for multiple myeloma. N Engl J Med 2003; 348: doxorubicindexmaethasone (VAD) as primary therapy in pre- 18751883. paration for autologous transplantation for multiple myeloma. 4 Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG Blood 2005; 106: 359. et al. Single versus double autologous stem-cell transplantation for 24 Richardson PG, Sonneveld P, Schuster MW, Irwin D, multiple myeloma. N Engl J Med 2003; 26: 24952502. Stadtmauer E, Facon T et al. Bortezomib or high-dose dexametha- 5 Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G sone for relapsed multiple myeloma. N Engl J Med 2005; 352: et al. Criteria for evaluating disease response and progression in 24872498. patients with multiple myeloma treated by high-dose therapy and 25 Rajkumar SV, Dispenzieri A. Evaluation and monitoring of haemopoietic stem cell transplantation. Br J Haematol 1998; 102: response to therapy in multiple myeloma. Haematologica 2005; 11151123. 90: 13051308. 6 Durie BGM, Jacobson J, Barlogie B, Crowley J. Magnitude of res- 26 Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, ponse with myeloma frontline therapy does not predict outcome: Hurd DD et al. Standard chemotherapy compared with high importance of time to progression in Southwest Oncology Group dose chemoradiotherapy for multiple myeloma: final results chemotherapy trials. J Clin Oncol 2004; 22: 18571863. of phase III US Intergroup trial S9321. J Clin Oncol 2006; 24: 7 Dispenzieri A, Kyle RA, Lacy MQ, Rajkumar SV, Therneau TM, 929936. Larson DR et al. POEMS syndrome: definitions and long-term 27 Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, outcome. Blood 2003; 101: 24962506. van Rhee F et al. Thalidomide and hematopoietic-cell 8 International Myeloma Working Group. Criteria for the classifica- transplantation for multiple myeloma. N Engl J Med 2006; 354: tion of monoclonal gammopathies, multiple myeloma and related 10211030. disorders: a report of the International Myeloma Working Group. 28 Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea Br J Haematol 2003; 121: 749757. V et al. Oral melphalan and prednisone therapy plus thalidomide 9 San Miguel J, Greipp PR, Durie BGM, Crowley J, Barlogie B, Blade compared with melphalan and prednisone alone in elderly J et al. International staging system for multiple myeloma. J Clin patients with multiple myeloma: a randomized controlled trial. Oncol 2005; 23: 34123420. Lancet 2006; 367: 825831. 10 Durie BGM. Staging and kinetics in multiple myeloma. In: Salmon 29 Alexanian R, Weber D, Giralt S, Dimopoulos M, Delasalle K, SE (ed). Clinics in Haematology: Myeloma and Related Disorders, Smith T et al. Impact of complete remission with intensive therapy Vol. 2, Number 1, WB Saunders Company, Ltd: Alden Press, in patients with responsive multiple myeloma. Bone Marrow Ocford, 1982, pp 318. Transplant 2001; 27: 10371043. Leukemia Response criteria for multiple myeloma BGM Durie et al Appendix A. International myeloma working group: Ray Alexanian, MD Anderson Center, Houston, Texas, USA Kenneth Anderson, DFCI, Boston, Massachusetts, USA Michael Attal, Purpan Hospital, Toulouse, France Herve Avet-Loiseau, Institute de Biologie, Nantes, France Leif Bergsagel, Mayo Clinic Scottsdale, Arizona, USA Joan Blade, Hospital Clinica, Barcelona, Spain Bart Barlogie, MIRT UAMS Little Rock, Arkansas, USA Regis Batille, Institute de Biologie, Nantes, France Meral Beksac, Ankara University, Turkey Andrew Belch, Cross Cancer Institute, Canada Mario Boccadoro, University of Torino, Italy Michele Cavo, Bologna, Italy Tony Child, Leeds General Hospital, Leeds, United Kingdom Ray Comenzo, Memorial-Sloan Kettering Cancer Center, New York, USA John Crowley, Cancer Research and Biostatistics, Seattle, Washington, USA William Dalton, H Lee Moffitt, Tampa, Florida, USA Faith Davies, Royal Marsden Hospital, London, England Meletios Dimopoulos, Alexandra Hospital, Athens, Greece Angela Dispenzieri, Mayo Clinic, Rochester, Minnesota, USA Brian Durie, Cedars-Sinai Outpatient Medical Center, Los Angeles, California, USA Thierry Facon, Centre Hospitalier Regional Universitaire de Lille, France Dorotea Fantl, Hospital Italiano, Buenos Aires, Argentina Jean-Paul Fermand, Paris, France Rafael Fonseca, Mayo Clinic Scottsdale, Scottsdale, Arizona, USA Gosta Gahrton, Karolinska Institutet, Stockholm , Sweden Morie Gertz, Mayo Clinic, Rochester, Minnesota, USA Hartmut Goldschmidt, University of Heidelberg, Heidelberg, Germany Philip Greipp, Mayo Clinic, Rochester, Minnesota, USA Roman Hajek, Brno University, Brno, Czech Republic Jean-Luc Harousseau, Institute de Biologie, Nantes, France Kim Hawkins, University of Leeds, United Kingdom Martin Hjorth, Rotterdam, The Netherlands Vania Hungria, Clinica San Germano, Sao Paolo, Brazil Mohamad Hussein, The Cleveland Clinic, Cleveland, Ohio, USA Peter Jacobs, South Africa Sundar Jagannath, St Vincent's Comprehensive Cancer Center, New York, USA Mariana Juni, Fundaleu, Buenos Aires, Argentina Douglas Joshua, Royal Prince Alfred Hospital, Sydney, Australia Michael Katz, International Myeloma Foundation, Los Angeles, California, USA Michio Kawano, Yamaguchi University, Ube, Japan Shaji Kumar, Mayo Clinic, Rochester, Minnesota, USA Robert Kyle, Mayo Clinic, Rochester, Minnesota, USA Juan Lahuerta, Madrid, Spain Henk Lokhorst, University Hospital, Utrecht, The Netherlands Heinz Ludwig, Wilhelminenspital Der Stat Wien, Vienna Jayesh Mehta, Northwestern University, Chicago, USA Giampaolo Merlini, Italy Philippe Moreau, Nantes, France GianPaolo Merlini, Pavia, Italy Gareth Morgan, Royal Marsden Hospital, London, United Kingdom Antonio Palumbo, Cathedra Ematologia, Torino, Italy Santiago Pavlovsky, Fundaleu, Buenos Aires, Argentina Amara Nouel, Bolivar, Venezuela Susie Novis, IMF, Los Angeles, California, USA Raymond Powles, Leukaemia & Myeloma, Wimbledon, United Kingdom Linda Pilarski, The University of Alberta, Edmonton Alberta, Canada S Vincent Rajkumar, Mayo Clinic, Rochester, Minnesota, USA Tony Reiman, Cross Cancer Institute, Canada Paul Richardson, Dana Farber Cancer Institute, Boston, Massachusetts, USA 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, USA Guido Tricot, MIRT UAMS, Little Rock, Arkansas, USA Jesus San Miguel, University of Salamanca, Salamanca, Spain Seema Singhal, Northwestern University, Chicago, Illinois, USA Pieter Sonneveld, Erasmus University Hospital, Rotterdam, The Netherlands Keith Stewart, Mayo Clinic Scottsdale, Scottsdale, Arizona, USA Patrizia Tosi, Bologna, Italy Ingemar Turesson, Malmo, Sweden Ivan Van Riet, Brussels Vrija University David Vesole, St Vincent's Comprehensive Cancer Center, New York, USA Donna Weber, MD Anderson, Houston, Texas, USA Jan Westin, University of Lund, Sweden Keith Wheatley, University of Birmingham, Edgbaston, Birmingham, UK Brian Van Ness, University of Minnesota, Minnesota, USA 7 Leukemia