M-PROTEIN AND RESPONSE IN MULTIPLE MYELOMA
M-protein in multiple myeloma Plasma cells produce immunoglobulins (also called gammaglobulins), which consist of a heavy chain (IgG, IgA, IgM, IgD or IgE) and a light chain (kappa or lambda) linked together. One plasma cell produces one type of immunoglobulin (for instance, IgA kappa or IgG kappa). Normally the body contains a variety of different plasma cells (“polyclonal”), so the immunoglobulins in the serum are also all different (polyclonal). In the case of multiple myeloma, the malignant cells are all copies of the same plasma cell (they are “monoclonal”). Therefore the malignant plasma cells all produce the same (monoclonal) immunoglobulin. This monoclonal immunoglobulin is called M-protein or paraprotein and also consists of a heavy chain (most often IgG or IgA but also IgM, IgD or IgE) and a light chain (kappa or lambda). The amount of monoclonal immunoglobulin in the serum is used to measure the tumor load. The malignant cells may also produce free light chains, no longer bound to a heavy chain. These free light chains can be quantified in serum, however, most of the light chains are excreted in the urine. Light chains in urine are called urine M-protein or Bence-Jones. In case of light chain disease, the malignant plasma cells no longer produce complete immunoglobulines but only produce a light chain (kappa or lambda). In light chain disease the amount of urine M-protein (Bence-Jones) or amount of Free Light Chains (FLC-values) in serum are used to measure the tumor load. In case of non-secreting myeloma the malignant plasma cells do not produce quantifiable amounts of monoclonal immunoglobulin or free light chains. Consequently the tumorload can not be measured by the amount of M-protein in serum or urine, but instead is measured by the amount of plasma cells in bone marrow smears or, if bone marrow smears are not available, the amount of plasma cells in bone marrow biopsy.
M-protein in Serum To determine the disease status in multiple myeloma, the amount of monoclonal immunoglobulin in the serum is measured in g/l. Generally the quantity of monoclonal immunoglobulin that is produced by the malignant cells is far greater than the amount of “normal” immunoglobulin produced by “healthy” plasma cells. Sometimes the lab will only measure the total amount of immunoglobulin of the type produced by the malignant cells (total involved Ig), which includes a portion of normal immunoglobulin.
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Example: In a patient with multiple myeloma, the malignant plasma cells produce vast amounts of monoclonal IgG kappa. The serum M-protein is only the monoclonal IgG kappa. Total involved Ig is monoclonal IgG plus normal (polyclonal) IgG. Consequently the value total involved Ig cannot be less than the value serum M-protein. When the patient is in CR, there should be no more measurable monoclonal immunoglobulin, while total involved Ig may still be present: in that case it consists only of the portion normal immunoglobulin. It is not always clear from a lab report if it shows serum M-protein or total involved Ig. When in doubt, check with the lab. It is also possible to measure the amount of free light chains in serum (Free Light Chains, FLC). Generally either the kappa or lambda chain has high levels. The serum FLC levels are used as response criteria if serum and urine M-protein are not measurable. In order to confirm (s)CR the FLC ratio between kappa and lambda (kappa:lambda) should be within the ‘normal’ range: 0.26-1.65. Protein electrophoresis of serum is a quantitative test and measures the amount of M-protein in serum. Immunofixation of serum is a qualitative test to identify which type of monoclonal immunoglobulin is present and is either positive or negative. When the amount of monoclonal immunoglobulin measured by protein electrophoresis has become so low that it can no longer be measured, immunofixation can still be positive. To confirm a CR, immunofixation of serum must be negative. Sometimes the lab uses another method, namely Immunosubstraction. This method is less accurate. Please contact the HDC in case this method is used to confirm CR.
M-protein in urine Urine M-protein is the amount of free light chains (kappa or lambda) in the urine. The most reliable method is by measuring the total amount in a 24 hr urine collection, but it can also be measured in a single sample as g/l. The values measured in 24 hr urine collection are more reliable, and hence to be preferred. In patients with light chain disease, urine M-protein measured in 24 hr urine is the main parameter to determine disease status. Only in case urine M-protein values are not available FLC values in serum can be used.
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M-PROTEIN AND RESPONSE IN MULTIPLE MYELOMA
Protein electrophoresis of urine is a quantitative test and measures the amount of M-protein in urine. Immunofixation of urine is a qualitative test to identify which type of monoclonal immunoglobulin is present and is either positive or negative. When the amount of monoclonal immunoglobulin measured by protein electrophoresis has become so low that it can no longer be measured, immunofixation can still be positive. To confirm a CR, immunofixation of urine must be negative.
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M-PROTEIN AND RESPONSE IN MULTIPLE MYELOMA
Evaluation of response and relapse in multiple myeloma trials For the more recent HOVON multiple myeloma trials starting with HO86 the response criteria have been changed compared to the older multiple myeloma trials. This document is based on the criteria established by the International Myeloma Working Group (IMWG), published 21APR2010. These criteria were adapted from the International Uniform Response Criteria for Multiple Myeloma by BGM Durie et al. (Leukemia (2006) 1-7). The changes compared to the old trials are: -
the disappearance of Minimal Response (MR);
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the disappearance of Progression from MR/PR;
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the addition of stringent complete response (sCR);
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the addition of free light chain values and ration in serum (FLC);
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the change from response category NC into stable disease (SD);
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the change of the required confirmation of relapse or disease progression and/or the institution of any new therapy within six weeks into requirement of two consecutive assessments at any time before classification as relapse or disease progression and/or the institution of any new therapy;
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The disappearance of response citerias bone plasmacytima and lytic bone lesions.
The possible responses are: PR (Partial Response), VGPR (Very Good Partial Response) CR (Complete Response) and sCR (stringent Complete Response). The possible relapse categories are Relapse from (s)CR and PD (Progressive Disease). If neither of the response or relapse categories are met response should be SD (Stable Disease).
Partial Response A new PR requires all of the following: -
serum M-protein reduction of 50 % compared to On Study value (immunofixation of serum need not be negative);
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urine M-protein reduction of 90 % compared to On Study or urine M-protein < 0.2 g/24hrs (immunofixation of urine need not be negative); urine M-protein unknown is only accepted if MM is not light chain disease or if MM is light chain disease and serum FLC values are available;
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if only FLC values are available: 50% decrease in the difference between involved and uninvolved FLC values;
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if serum and urine M-protein are not measurable, and serum free light assay is also not measurable, 50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was 30%. This does not apply to the HO86 and HO87;
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soft tissue plasmacytomas area reduction of 50 % compared to On Study;
When the previous response was PR and none of the criteria for progressive disease are met, response remains PR.
Very Good Partial Response A new VGPR requires all of the following: -
all criteria of PR are met plus the following:
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serum M-protein reduction of 90 % compared to On Study value (immunofixation of serum need not be negative);
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urine M-protein < 0.1 g/24hrs (immunofixation of urine need not be negative); urine Mprotein unknown is only accepted if MM is not light chain disease or if MM is light chain disease and serum FLC values are available;
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if only FLC values are available: >90% decrease in the difference between involved and uninvolved FLC values;
When the previous response was VGPR and none of the criteria for progressive disease are met, response remains VGPR.
Complete Response A new CR requires all of the following: -
all criteria of VGPR are met plus the following:
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serum M-protein = 0; serum M-protein unknown is only accepted if immunofixation serum is negative;
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immunofixation serum is negative;
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urine M-protein = 0; urine M-protein unknown is only accepted if immunofixation urine is negative;
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immunofixation urine is negative; immunofixation urine not done is only accepted if last known immunofixation was negative;
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M-PROTEIN AND RESPONSE IN MULTIPLE MYELOMA
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last known plasma cells in bone marrow < 5 %. Confirmation of value plasma cells in bone marrow is not needed;
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disappearance of any soft tissue plasmacytoma;
When the previous response was CR and none of the criteria for relapse are met, response remains CR.
Stringent Complete Response A new sCR requires all of the following: -
all criteria of CR are met plus the following:
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normal FLC ratio (0.26-1.65);
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absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence;
When the previous response was (s)CR and none of the criteria for relapse are met, response remains (s)CR.
Relapse from (s)CR A Relapse from (s)CR must be reported if the previous response was (s)CR and any of the following: -
serum M-protein > 0 or positive immunofixation serum;
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urine M-protein > 0 or positive immunofixation urine;
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plasma cells in bone marrow 5 %;
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development of new soft tissue plasmacytoma(s);
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appearance of new skeletal lesion(s) and/or increase in number or size of skeletal lesion(s) or bone plasmacytoma(s) compared to last known value;
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hypercalcaemia.
All relapse categories require two consecutive assessments made at anytime before classification as relapse and/or the institution of any new therapy. Otherwise response may remain (s)CR. In case of sCR: relapse from sCR is possible on the basis of a positive result of immunohistochemistry or immunofluorescence of bone marrow aspirate or biopsy.
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A relapse must also be reported if the previous response was relapse and the criteria for (s)CR, VGPR, PR, and SD are not met.
Clinical Relapse In the IMWG criteria ‘Clinical Relapse’ is also defined. It is not used in calculation of time to progression or progression-free survival (e.g. in HOVON studies). It is listed in the IMWG criteria as something that can be reported optionally or for use in clinical practice. For your information the criteria for Clinical Relapse are listed below: Clinical relapse requires one or more of: Direct indicators of increasing disease and/or end organ dysfunction (CRAB features). -
Development of new soft tissue plasmacytomas or bone lesions;
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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;
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Hypercalcemia (> 11.5 mg/dL) [2.65 mmol/L];
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Decrease in haemoglobin of ≥ 2 g/dL [1.25 mmol/L];
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Rise in serum creatinine by 2 mg/dL or more [177 mmol/L or more].
Progressive disease (PD) PD must be reported if the previous response was either VGPR, PR, SD or PD and any of the following: -
serum M-protein increase of > 5 g/l and > 25 % compared to nadir (increase of 10 g/L is sufficient for PD if starting M-protein is 50 g/L;
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urine M-protein increase of > 0.2 g/24hrs and > 25 % compared to nadir;
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if only FLC values are available: the absolute increase in the difference between involved and uninvolved FLC values must be >10 g/L;
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plasma cells in bone marrow increase of > 25 % compared to nadir; the absolute percentage must be 10%;
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Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas;
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Development of hypercalcaemia (corrected serum calcium >11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder.
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All relapse categories require two consecutive assessments made at anytime before classification as relapse and/or the institution of any new therapy. Otherwise response may remain VGPR, PR or SD. PD must also be reported if the previous response was PD and the criteria for (s)CR, VGPR, PR, and SD are not met.
Stable disease SD requires the following: -
not meeting criteria for (s)CR, VGPR, PR or progressive disease
Conventions used in response evaluation -
When on protocol treatment all responses are compared to baseline values at On Study.
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When a patient goes off protocol, all responses are still compared to On Study values until a relapse or progression (including the moment of going off treatment) is reported in follow up. At that time the values at relapse, progression or start of treatment off protocol become the new baseline values. Since these responses are no longer relevant for the study’s endpoints they will be accepted at face value with the exception of CR or in case of unclarities.
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Nadir is defined as the lowest value for a certain parameter since baseline. So it is the lowest value since On Study, until a relapse or progression is reported in follow up, when a new baseline is set and a new nadir can be established.
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Once immunofixation of serum or urine is negative, it is considered to remain negative until proven otherwise (by positive immunofixation or presence of M-protein in blood or urine).
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When immunofixation serum or urine is negative, serum M-protein or urine M-protein is considered 0.
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If immunofixation is not done it is considered positive if all previous immunofixations were either positive or not done.
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When immunofixation serum or urine is positive, but serum M-protein or urine M-protein is not quantifiable because it is less than the detection limit, serum M-protein or urine Mprotein is considered very low but not completely absent.
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Plasma cells in bone marrow will be taken from aspirate; only if aspirate is unknown the biopsy results are taken as substitute.
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When plasma cells in bone marrow were normal at the previous evaluation (including On Study) they will be considered still normal if they are unknown or not repeated.
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If number of soft tissue plasmacytoma is unknown, it is regarded as not present.
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If area of soft tissue plasmacytoma is unknown, it is regarded as not increased.
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When only one value in centimeters is given for size of largest soft tissue plasmacytoma this value is squared to obtain the area, when two values are given these are multiplied to obtain the area.
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If skeletal lesions are unknown they will be considered not increased.
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If the number of skeletal lesions increases, but all other criteria for (s)CR, VGPR or PR are met and serum M-protein (or urine M-protein in case of light chain disease or plasma cells in bone marrow in case of non-secreting myeloma) is decreased compared to the previous evaluation (including On Study) response can still be (s)CR, VGPR or PR.
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If the number of skeletal lesions increases, but serum M-protein (or urine M-protein in case of light chain disease or plasma cells in bone marrow in case of non-secreting myeloma) is increased but less than 5 g/L compared to the previous evaluation (including On Study) response can not be (s)CR, VGPR or PR.
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The development of compression fractures does not exclude (s)CR, VGPR or PR and also may not indicate relapse from (s)CR or progressive disease (PD).
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If number of bone plasmacytoma is unknown, it is regarded as not present.
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If area of bone plasmacytoma is unknown, it is regarded as not increased.
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When the tumor mass of a bone plasmacytoma disappears a skeletal lesion may remain that is not to be distinguished from a lytic bone lesion. This is not to be interpreted as an increase in skeletal lesions and therefore does not indicate relapse from (s)CR or progressive disease (PD).
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Hypercalcaemia: calcium adjusted for albumin (add 0.02 mmol/l for every g/l albumin below 40) > 2.8 mmol/l not attributable to any other cause; no hypercalcaemia until proven otherwise, so if calcium is unknown hypercalcaemia is considered absent.
Order of responses -
PD is progressive disease and can follow after VGPR, PR, SD or PD.
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After CR a response can only remain CR or become a relapse; the loss of CR to relapse overrules all other responses.
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After sCR a response can only remain sCR or become a relapse; the loss of sCR to relapse overrules all other responses.
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After VGPR a response can only remain VGPR, improve to (s)CR or become progressive disease; the loss of VGPR to progressive disease overrules all other responses.
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After PR a response can only remain PR, improve to (s)CR or VGPR or become progressive disease; the loss of PR to progressive disease overrules all other responses.
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Usually a relapse or progressive disease will prompt the end of protocol treatment and the end of response evaluation compared to On Study values. However, in some protocols (not HO86 and HO87) it is allowed to continue protocol treatment and it is possible to go from relapse or progressive disease to SD, PR, VGPR or (s)CR (compared to On Study values). When the next response evaluation after a relapse or progressive disease during protocol treatment does not comply with SD, PR, VGPR or (s)CR compared to On Study, the response remains relapse or progressive disease.
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During follow up the moment of relapse, progressive disease or start treatment off protocol creates a new baseline value to which responses are compared.
Conventions about order of responses mentioned above result in the following possible response orders: Previous response
Present response (s)CR
VGPR
PR
SD
PD
(s)CR
x
VGPR
x
x
PR
x
x
x
SD
x
x
x
x
x
PD
x
x
x
x
x
Relapse
x
x
x
x
x
Relapse x
x x
x
x = response allowed
Remission status in follow up The remission status in follow up should always match the last known response evaluation. For specific study agreements see the relevant sections in the protocol.
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