Leukemia (2006), 17
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LEADING ARTICLE
International uniform response criteria for multiple myeloma
BGM Durie1, J-L Harousseau2, JS Miguel3, J BladeŽ4, 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
The need for new uniform response criteria has been triggered
assess clinical outcomes in myeloma. The European Group
by several factors (Table 1). The most pressing need is for criteria
for Blood and Bone Marrow Transplant/International Bone
that facilitate precise comparisons between new treatment
Marrow Transplant Registry criteria have been expanded,
clarified and updated to provide a new comprehensive evalua-
strategies. Better criteria are also required for use in the clinic
tion system. Categories for stringent complete response and
at the individual patient level. In this setting, clarification of
very good partial response are added. The serum free light-
complete response (CR) is particularly important. As more active
chain assay is included to allow evaluation of patients with
agents are available, there is a need to assess not just if response
oligo-secretory disease. Inconsistencies in prior criteria are
has occurred, but the exact magnitude of response. There is
clarified making confirmation of response and disease progres-
increased awareness of the distinction between surrogate end
sion easier to perform. Emphasis is placed upon time to event
and duration of response as critical end points. The require-
points such as reduction in M-component level and more
ments necessary to use overall survival duration as the ultimate
clinical end points such as recovery of functional status or
end point are discussed. It is anticipated that the International
organ function, length of response and overall survival
Response Criteria for multiple myeloma will be widely used in
duration.6
future clinical trials of myeloma.
Many of the commonly used criteria do not define CR
Leukemia advance online publication, 20 July 2006;
stringently. In the EBMT criteria, CR does not require absence of
doi:10.1038/sj.leu.2404284
Keywords: myeloma; response criteria; staging; survival duration;
monoclonal (M) plasma cells, but rather the reduction in plasma
uniform criteria; clinical outcomes
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
Introduction
kappa/lambda immunostaining or by immunofluorescence
studies using flow cytometry. Specific categories of CR with
There is an increasing need for widely accepted, reproducible
varying degrees of stringency allow greater precision in the
criteria to evaluate response in multiple myeloma.1,2 Several
definition of CR, enable comparison of the efficacy of various
different systems are currently in use, but are not exactly
treatments including novel agents and can permit the detection
comparable. For example, the US cooperative groups ECOG
and monitoring of relapse more accurately. Existing criteria lack
and SWOG have differing systems, as do several European
sufficient detail, which as a result allows substantial investigator
groups, such as the MRC (UK)3 and the IFM (France).4 In
discretion, and leads to inaccuracies in the estimated response
addition, the European Group for Blood and Bone Marrow
rate. For example, the EBMT criteria require specific reductions
Transplant/International Bone Marrow Transplant Registry/
in M-protein levels for each category of response, but the
American Bone Marrow Transplant Registry (EBMT/IBMTR/
minimum level of M-protein that is required in the serum and
ABMTR) developed widely used criteria, commonly referred to
urine to allow accurate response assessment is not specified.
as the EBMT criteria.5 However, as discussed below, there is a
Similarly, it is not clear from prior criteria how patients with
need to update prior criteria.
`unmeasurable' levels of urine M-protein should be monitored
for response evaluation.
Correspondence: Dr BGM Durie, Aptium Oncology Inc., Cedars-Sinai
Finally, present criteria allow limited assessment of response
Outpatient Cancer Center, 8201 Beverly Boulevard, Los Angeles, CA
in patients with oligo-secretory or non-secretory myeloma.7
90048, USA or Dr SV Rajkumar, Division of Hematology, Mayo
Response in these patients can now be assessed using the
Clinic, 200 First Street SW, Rochester, MN 55905, USA.
sensitive serum free light-chain (FLC) assay (Freelite, Binding
E-mails: bdurie@aptiumoncology.com or rajkumar.vincent@mayo.edu.
29
Site). Incorporation of the serum FLC assay into the response
For members of the International Myeloma Working Group, see
criteria for myeloma allows inclusion and evaluation of these
Appendix A.
Received 8 May 2006; accepted 11 May 2006
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
Criteria
K
Facilitate precise comparisons of efficacy between new
treatment strategies in trials
K
For patients with measurable levels of serum and urine monoclonal
K
Incorporation of the serum FLC assay to include assessment of
protein levels, the criteria for CR, PR and progressive disease
patients with oligo-secretory and non-secretory diseasea
remain unchanged. (Tables 5 and 6)
K
Stricter definitions for CR
K
Clarification and revision of important practical details of response
K
Provide clarifications, improve detail and correct
evaluation (Table 4)
inconsistencies in prior response criteria
Elimination of mandatory 6 weeks wait time to confirm
achievement of response
Abbreviations: CR, complete response; FLC, free light chain.
a
Introduction of a similar non-time-dependent confirmation for
Oligo- and non-secretory myeloma identifies patients without
relapse and/or disease progression
sufficient M-component in serum and/or urine to monitor response
Clarification of the `start time' for duration of response evaluation
(see Table 4: definitions of measurable disease).
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
Elimination of the minor response category
standard diagnostic criteria8 and the new International Staging
K
Incorporation of response criteria for the serum FLC assay to
System (ISS) for multiple myeloma,9 which are being widely
enable assessment of response in patients with non- or oligo-
accepted as the current standards for diagnosis and staging. The
secretory disease (Tables 5 and 6)
development of the new response criteria proposed in this
K
Clarification that criteria for progressive disease (rather than criteria
manuscript started with a meeting of the International Myeloma
for `relapse from CR') are to be used for calculation of time to
Working Group (participants are listed at the end of the
progression and progression-free survival in patients who are
in CR. Criteria for relapse from CR are to be used only if DFS is
manuscript) during the 10th International Myeloma Workshop,
calculated and reported
Sydney, 1014 April 2005. Based on the discussions and
K
Introduction of new category of clinical relapse or progressive
decisions made at this meeting, the criteria were formulated and
disease (Table 6)
drafted by two of the authors (BGD and SVR) and circulated to
Introduces clinical relapse as a new optional end point
the members of the Working Group and revised. Final approval
was made at a meeting of the International Myeloma Working
Abbreviations: CR, complete response; DFS, disease-free survival;
EBMT, European Group for Blood and Bone Marrow Transplant; FLC,
Group at the Annual Meeting of the American Society of
free light chain; IBMTR, International Bone Marrow Transplant Registry;
Hematology, Atlanta, GA, USA, December 2005 and subse-
PR, partial response; sCR, stringent complete response; VGPR, very
quent reviews of this paper.
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
(BladeŽ) 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 progres-
Changes in the M-component level are the principal indicators
sion, estimates reported using the using the new International
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
as well as myeloma cell heterogeneity with respect to
(1) addition of a new category of stringent CR that is of signifi-
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 5 and 6).
will enable numerous patients hitherto excluded from clinical
Additional subcategories have been used by a number of
trials for lack of measurable disease to enter and be evaluated on
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 classi-
Although documentation of response requires a confirmatory
fications as well as disease subtype identification.1,8,9 With
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
3
Table 3
Diagnostic criteria for multiple myeloma requiring
Table 4
Practical details of response evaluation
systemic therapy
Laboratory tests for measurement of M-protein
Presence of an M-componenta in serum and/or urine plus clonal
Serum M-protein level is quantitated using densitometry on SPEP
plasma cells in the bone marrow and/or a documented clonal
except in cases where the SPEP is felt to be unreliable such as in
plasmacytoma
patients with IgA monoclonal proteins migrating in the beta
region. If SPEP is not available or felt to be unreliable (e.g., in
PLUS one or more of the following:b
some cases of IgA myeloma) for routine M-protein quantitation
Calcium elevation (411.5 mg/dl) [42.65 mmol/l]
during therapy, then quantitative immunoglobulin levels on
Renal insufficiency (creatinine 42 mg/dl) [177 mmol/l or more]
nephelometry or turbidometry can be accepted. However, this
Anemia (hemoglobin o10 g/dl or 2 g/dl onormal) (hemoglobin
must be explicitly reported, and only nephelometry can be used
o12.5 mmol/lc or 1.25 mmol/lonormal)
for that patient to assess response and SPEP and nephelometric
Bone disease (lytic lesions or osteopenia)
values cannot be used interchangeably.
Urine M-protein measurement is estimated using 24-h UPEP only.
aIn patients with no detectable M-component, an abnormal serum FLC
Random or 24 h urine tests measuring kappa and lambda light
ratio on the serum FLC assay can substitute and satisfy this criterion.
chain levels are not reliable and are not recommended
For patients, with no serum or urine M-component and normal serum
FLC ratio, the baseline bone marrow must have X10% clonal plasma
Definitions of measurable disease
cells; these patients are referred to as having `non-secretory myeloma'.
Response criteria for all categories and subcategories of response
Patients with biopsy-proven amyloidosis and/or systemic light chain
except CR are applicable only to patients who have `measurable'
deposition disease (LCDD) should be classified as `myeloma with
disease defined by at least one of the following three measurements:
documented amyloidosis' or `myeloma with documented LCDD,'
Serum M-protein X1 g/dl (X10 gm/l)[10 g/l]
respectively if they have X30% plasma cells and/or myeloma-related
Urine M-protein X200 mg/24 h
bone disease.
Serum FLC assay: Involved FLC level X10 mg/dl (X100 mg/l)
bMust be attributable to the underlying plasma cell disorder.
provided serum FLC ratio is abnormal
cNote: Hemoglobin of 10 g/dl is 12.5 mmol/l [or 100 g/l].
Response criteria for CR are applicable for patients who have
Important aspects of response assessment
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,
Table 4 summarizes important practical details in response
and cannot be assessed for any of the other response categories
assessment. Two specific points must be emphasized. Firstly,
checking the M-component level at each cycle during induction
Follow-up to meet criteria for PR or SD
is critically important in the evaluation of novel therapies to
It is recommended that patients undergoing therapy be tracked
determine the speed of response, which may have clinical
monthly for the first year of new therapy and every other month
thereafter
implications. For example, with several new regimens, response
Patients with `measurable disease' as defined above need to be
occurs rapidly and can be substantial within 12 months.12,13
followed by both SPEP and UPEP for response assessment and
The second point is that the new criteria eliminate the need for
categorization
consecutive confirmations 6 weeks apart currently required for
Except for assessment of CR, patients with measurable disease
response testing. A DOR of 6 weeks does not carry major
restricted to the SPEP will need to be followed only by SPEP;
clinical significance and is not a surrogate for durability of
correspondingly, patients with measurable disease restricted to
the UPEP will need to be followed only by UPEPa
response. The main concern is to eliminate laboratory or other
Patients with measurable disease in either SPEP or UPEP or both
error; this can be carried out by the requirement of a
will be assessed for response only based on these two tests and
confirmatory test at any time following the first test provided it
not by the FLC assay. FLC response criteria are only applicable to
is before any new/non-protocol therapy. The importance of
patients without measurable disease in the serum or urine, and to
response, that is, its durability, should be highlighted by
fulfill the requirements of the category of stringent CR
reporting data on TTP and DOR. Thus plateau phase can be
To be considered CR, both serum and urine immunofixation must be
carried out and be negative regardless of the size of baseline
documented by indicating the TTP and/or DOR.1
M-protein in the serum or urine; patients with negative UPEP
Three aspects pertaining to the serum FLC assay deserve
values pretreatment still require UPEP testing to confirm CR and
emphasis. First, the serum FLC assay (Freelite, The Binding Site,
exclude light chain or BenceJones escape
Birmingham, UK) is a highly sensitive marker of light chains in
Skeletal survey is not required for assessment of response unless
circulation that are unbound to intact immunoglobulin, and the
clinically indicated, but is recommended once a year in clinical
FLC ratio is an excellent indicator of clonality.14 Thus, normal-
practice; bone marrow is required only for categorization of CR,
and for patients with non-secretory disease
izing of serum FLC ratio is a stricter indicator of CR, and may
correlate well with extended response duration15 (Kumar S et al.
Abbreviations: CR, complete response; FLC, free light chain; PR,
Blood 2005; 106: 971a, abs 3479). Note that in patients with
partial response; SD, stable disease; SPEP, serum protein electro-
renal insufficiency, the levels of both the kappa and lambda may
phoresis; UPEP, urine protein electrophoresis.
aFor good clinical practice patients should be periodically screened for
remain elevated, but the ratio normalizes with achievement of
light chain escape with UPEP or serum FLC assay.
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
The international Myeloma Working Group Uniform
closely monitor laboratory variation.16 Strict guidelines are
Response Criteria
required with regard to usage times for the serum FLC assay kits.
It should also be noted that serum FLC assay testing might
The International Myeloma Working Group Uniform Response
be useful in the prognostic and response evaluation of patients
Criteria are listed in Table 5. Under CR two categories are
who also have a measurable serum and/or urine M-component
listed: CR and stringent (sCR). The CR category is available
in the future, given its recently reported prognostic value in
for widespread use and provides continuity with prior systems.
M-gammopathy of undetermined significance (MGUS).17
However, sCR, the more stringent category, allows more
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
Not meeting criteria for CR, VGPR, PR or progressive disease
response; stability of disease is best described by
providing the time to progression estimates)
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
The criteria for PD and relapse from CR are listed in Table 6.
groups already use this latter category. It is now possible
A category of clinical relapse has been added for optional
to specifically list and clearly identify which categories
assessment in clinical trials and for use in clinical practice.
are used. The major goal is to foster studies evaluating
Progressive disease will continue to identify patients in whom
correlations between stringent CR and durable response and
the standard M-component (and related) criteria for relapse or
prolonged survival.
disease progression have been met. Progressive disease is the
VGPR, as defined in IFM trials,4 has been very slightly
end point that is used for calculating TTP and progression-free
modified to also include what has been called nCR. Use of
survival (PFS) in trials, and mirrors the EBMT criteria. One
VGPR has several advantages including the reliance upon the
problem is that progression defined using these criteria may or
90% or higher regression cutoff, which is simpler to implement
may not reflect a need for therapy (or new therapy). Early re-
than use of immunofixation positivity versus negativity, an
treatment can be unnecessary, result in unwanted toxicities and
observer-dependent assessment. In addition, failure to achieve
underestimate the benefit of prior treatment, as true sympto-
VGPR correlates with inferior outcome.1 The definition of PR
matic relapse may not emerge until months or years later. Thus,
except for inclusion of the FLC assay for the subgroup of patients
discrete `event categories' are required to identify relapse or
with `unmeasurable' disease is similar to the EBMT criteria. It is
progression requiring intervention. These `events' are broadly
important to note that the FLC assay should not be used to assess
the same as the CRAB categories used for diagnosis of myeloma.
response in patients with measurable levels of M-protein in
Various nuances and details related to use in the relapse setting
either serum or urine. Such patients should be assessed using
are outlined in Table 6. Thus, where possible, reporting of time
standard criteria; the serum light-chain assay is only applicable
to re-treatment and/or time to clinical relapse would be useful;
to those patients who do not have either 1 g/dl or higher
as mentioned earlier, these definitions will also be useful in
M-protein in the serum or 200 mg/day or higher M-protein level
clinical practice.
in the urine. Less than PR is identified as SD, which can be
The difficulties and nuances in evaluating myeloma-related
clinically meaningful, but is not sufficient as an indicator of
events are well known. It is important to re-emphasize that
response benefit in new therapeutic trials. Reporting SD or
myeloma must be the cause of events. Whatever additional
response categories less than PR as meaningful is not
testing is required to confirm myeloma relatedness is strongly
recommended in clinical trials of new agents. Overall, the
encouraged. This may include magnetic resonance imaging,
emphasis is upon simplicity, reproducibility and the awareness
computed tomography and/or fluoro-18-deoxyglucose (FDG)/
that very fine discriminations are frequently unreliable and not
positron emission tomography (PET) imaging (Walker R et al.
clinically meaningful.
Blood 2004; 104: 217a, abs 758).18,19
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Response criteria for multiple myeloma
BGM Durie et al
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Table 6
International Myeloma Working Group uniform response criteria: disease progression and relapse
Relapse subcategory
Relapse criteria
Progressive diseasea
Progressive Disease: requires any one or more of the following:
To be used for calculation of time to progression and
progression-free survival end points for all patients
Increase of X25% from baseline in
including those in CR (includes primary progressive
Serum M-component and/or (the absolute increase must be X0.5 g/dl)b
disease and disease progression on or off therapy)
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
Any one or more of the following:
studied is DFS)d
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.
Survival end points
DOR: DOR applies to patients achieving at least PR by the
criteria in Table 5, and is measured from start of achieving PR
End points such as PFS, TTP and DOR can predict ultimate
(first observation of PR before confirmation) to the time of
overall survival (Tricot G et al. Blood 2004; 104: 265a, abs
disease progression, with deaths owing to causes other than
926).6,2022 Several different methods are used to calculate
progression not counted, but censored. This is an additional
response duration and the impact of treatment.
parameter for consideration in the assessment of new agents
and/or new comprehensive treatment strategies. DOR and
PFS: PFS is the time from start of the treatment to disease
TTP are the recommended ways of establishing the durability
progression or death. This encompasses all patients and has
of response.
been considered a surrogate marker for overall survival dura-
tion. This is the recommended method to present trial results.
Event-free survival (EFS): The definition for EFS depends on
Overall survival
how `event' is defined. In some studies, this can be the same
as PFS. EFS can also include additional `events' that are
Many recent myeloma trials have had response and/or TTP as
considered to be of importance besides death, including
the primary end points. However, overall survival and quality of
serious drug toxicity. EFS is not recommended for general use
life reflect the full impact of therapies. Several factors limit the
unless specifically defined, as confusion can arise about the
use of overall survival as the ultimate end point.
details of additional `events'. PFS is preferred.
TTP: This is the time from start of treatment to disease
Over 5 years of follow-up are required to assess benefit.
progression with deaths owing to causes other than progres-
Initial response and TTP may or may not translate into overall
sion not counted, but censored. This is a helpful method to
survival benefit.
assess the durability of treatment benefit.
New agents used as part of induction, consolidation/
Disease-free survival (DFS): DFS applies to patients in CR,
transplant and/or maintenance are frequently used at time
and is measured from the start of CR to the time of relapse
of relapse in the `control' (non-use) arm of trials. Thus the
from CR. This parameter has limited value in myeloma at
comparison is with early versus later use. There has been no
present.
widely accepted plan or framework to control for this.
Leukemia
Response criteria for multiple myeloma
BGM Durie et al
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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
myeloma. N Engl J Med 2003; 348: 26092617.
The problems involved are illustrated by several trials.2329 In a
12 Oakervee HE, Popat R, Curry N, Smith P, Morris C, Drake M et al.
recent trial reported by the Arkansas group,27 thalidomide was
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,
myeloma. Br J Haematol 2005; 129: 755762.
overall survival was not improved. But, it is important to note
13 Drayson M, Tang LX, Drew R, Mead GP, Carr-Smith H, Bradwell
AR. Serum free light chain measurements for identifying and
that 83% of patients not in the thalidomide arm received
monitoring patients with nonsecretory multiple myeloma. Blood
thalidomide at relapse. Thus, the study reflects an unplanned
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)
myeloma. Lancet 2003; 361: 489491.
versus MP thalidomide trial. New trial designs to evaluate
15 Mead GP, Carr-Smith HD, Drayson MT, Morgan GJ, Child A,
Bradwell AR. Serum free light chains for monitoring multiple
survival duration must accommodate these types of complexity.
myeloma. Br J Haematol 2004; 126: 348354.
These details are further discussed in a recent review.1
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
17 Rajkumar
SV,
Kyle
RA,
Therneau
TM,
Melton
III
LJ,
Bradwell AR, Clark RJ et al. Serum free light chain ratio is an
used widely in future clinical trials of myeloma. The major new
independent
risk
factor
for
progression
in
monoclonal
additions to the response criteria are categories of stringent CR,
gammopathy of undetermined significance. Blood 2005; 106:
VGPR and incorporation of the serum FLC assay to evaluate
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 con-
tomography in diagnosis and management of multiple myeloma
firmation of response and disease progression easier to perform
and its variants. Arch Int Med 1985; 145: 14511452.
19 Durie BGM, Waxman AD, D'Angeloa A, William CM. Whole
with less chance of deviations, and define time to event end
body F-FDG18 PET identifies high-risk myeloma. J Nucl Med 2002;
points that are critical in the evaluation of outcome.
43: 14571463.
20 Durie BGM. Is magnitude of initial response predictive for survival
in multiple myeloma? Ann Oncol 1999; 2: 166169.
21 Lahuerta JJ, Martinez-Lopez J, de la Serna J, Blade J, Grande C,
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Leukemia
Response criteria for multiple myeloma
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7
Appendix A.
International myeloma working group:
Michio Kawano, Yamaguchi University, Ube, Japan
Shaji Kumar, Mayo Clinic, Rochester, Minnesota, USA
Raymond Alexanian, MD Anderson Center, Houston, Texas, USA
Robert Kyle, Mayo Clinic, Rochester, Minnesota, USA
Kenneth Anderson, DFCI, Boston, Massachusetts, USA
Juan Lahuerta, Madrid, Spain
Michael Attal, Purpan Hospital, Toulouse, France
Henk Lokhorst, University Hospital, Utrecht, The Netherlands
Herve Avet-Loiseau, Institute de Biologie, Nantes, France
Heinz Ludwig, Wilhelminenspital Der Stat Wien, Vienna
Leif Bergsagel, Mayo Clinic Scottsdale, Arizona, USA
Jayesh Mehta, Northwestern University, Chicago, USA
Joan BladeŽ, Hospital Clinica, Barcelona, Spain
Giampaolo Merlini, University of Pavia, Pavia,
Bart Barlogie, MIRT UAMS Little Rock, Arkansas, USA
Italy
Regis Batille, Institute de Biologie, Nantes, France
Philippe Moreau, Nantes, France
Meral Beksac, Ankara University, Turkey
Gareth Morgan, Royal Marsden Hospital, London,
Andrew Belch, Cross Cancer Institute, Canada
United Kingdom
Mario Boccadoro, University of Torino, Italy
Antonio Palumbo, Cathedra Ematologia, Torino, Italy
Michele Cavo, Bologna, Italy
Santiago Pavlovsky, Fundaleu, Buenos Aires, Argentina
Tony Child, Leeds General Hospital, Leeds, United Kingdom
Amara Nouel, Bolivar, Venezuela
Ray Comenzo, Memorial-Sloan Kettering Cancer Center,
Susie Novis, IMF, Los Angeles, California, USA
New York, USA
Raymond Powles, Leukaemia & Myeloma, Wimbledon,
John Crowley, Cancer Research and Biostatistics, Seattle,
United Kingdom
Washington, USA
Linda Pilarski, The University of Alberta, Edmonton Alberta,
William Dalton, H Lee Moffitt, Tampa, Florida, USA
Canada
Faith Davies, Royal Marsden Hospital, London, England
S Vincent Rajkumar, Mayo Clinic, Rochester, Minnesota,
Meletios Dimopoulos, Alexandra Hospital, Athens, Greece
USA
Angela Dispenzieri, Mayo Clinic, Rochester, Minnesota, USA
Tony Reiman, Cross Cancer Institute, Canada
Brian Durie, Cedars-Sinai Outpatient Medical Center,
Paul Richardson, Dana Farber Cancer Institute, Boston,
Los Angeles, California, USA
Massachusetts, USA
Thierry Facon, Centre Hospitalier Regional Universitaire
Angelina Rodriquez Morales, Bonco MetroPolitano de
de Lille, France
Sangre, Caracas, Venezuela
Dorotea Fantl, Hospital Italiano, Buenos Aires, Argentina
Kazuyuki Shimizu, Nagoya City Midori General Hospital,
Jean-Paul Fermand, Paris, France
Nagoya, Japan
Rafael Fonseca, Mayo Clinic Scottsdale, Scottsdale, Arizona,
David Siegel, Hackensack, Cancer Center, Hackensack,
USA
New Jersey, USA
Gosta Gahrton, Karolinska Institutet, Stockholm , Sweden
Guido Tricot, MIRT UAMS, Little Rock, Arkansas, USA
Morie Gertz, Mayo Clinic, Rochester, Minnesota, USA
Jesus San Miguel, University of Salamanca, Salamanca,
Hartmut Goldschmidt, University of Heidelberg, Heidelberg,
Spain
Germany
Seema Singhal, Northwestern University, Chicago, Illinois,
Philip Greipp, Mayo Clinic, Rochester, Minnesota, USA
USA
Roman Hajek, Brno University, Brno, Czech Republic
Pieter Sonneveld, Erasmus University Hospital, Rotterdam,
Jean-Luc Harousseau, Institute de Biologie, Nantes, France
The Netherlands
Kim Hawkins, University of Leeds, United Kingdom
Keith Stewart, Mayo Clinic Scottsdale, Scottsdale, Arizona,
Martin Hjorth, Rotterdam, The Netherlands
USA
Vania Hungria, Clinica San Germano, Sao Paolo, Brazil
Patrizia Tosi, Bologna, Italy
Mohamad Hussein, The Cleveland Clinic, Cleveland, Ohio,
Ingemar Turesson, Malmo, Sweden
USA
Ivan Van Riet, Brussels Vrija University
Peter Jacobs, South Africa
David Vesole, St Vincent's Comprehensive Cancer Center,
Sundar Jagannath, St Vincent's Comprehensive Cancer
New York, USA
Center, New York, USA
Donna Weber, MD Anderson, Houston, Texas, USA
Mariana Juni, Fundaleu, Buenos Aires, Argentina
Jan Westin, University of Gothenberg, Sweden
Douglas Joshua, Royal Prince Alfred Hospital, Sydney, Australia
Keith Wheatley, University of Birmingham, Edgbaston,
Michael Katz, International Myeloma Foundation, Los
Birmingham, UK
Angeles, California, USA
Brian Van Ness, University of Minnesota, Minnesota, USA
Leukemia