SWOG ONCOLOGY RESEARCH PROFESSIONAL (ORP) MANUAL RESPONSE ASSESSMENT MYELOMA CHAPTER 11C REVISED: SEPTEMBER 2016

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1 MYELOMA Quantitative Markers-Myeloma Assessment Quantitative markers are biochemicals that are recorded in tests on body fluids such as serum and urine. Applicable Disease Sites The myeloma disease site uses markers in quantified disease assessment. The markers examined are the serum M protein, urine M protein, and serum free light chain levels. These markers are assessed regularly to see by what percentage they have increased or decreased from their value at baseline. In addition, in patients whose markers indicate that they are responding to treatment, the bone marrow is also assessed for a decrease in the plasma cells. Response Assessment Specific criteria for assessing response are found in Section 10.0 of each protocol. The two versions of the response criteria listed below are representative of the versions that are used most often. In 2006, the International Myeloma Working Group published the International Uniform Response Criteria for Multiple Myeloma, on which the first version listed is based. This version of the criteria is standard in all SWOG multiple myeloma protocols activated after January 1, The second version listed is representative of the criteria used in some SWOG multiple myeloma protocols activated prior to January 1, Since the criteria used are unique to each protocol, the protocol must be consulted prior to assessing response. Response Assessment for Studies Activated Since January 1, 2006 This version of the response criteria is based on the International Uniform Response Criteria for Multiple Myeloma, and is standard in all protocols activated after January 1, Measurability of Disease Measurable Disease: Measurable, quantifiable protein criteria must be present. Acceptable protein criteria are: Serum M protein 1 g/dl ( 10 g/l), quantified by using densitometry on serum protein electrophoresis (SPEP). AND / OR Urine M protein [Bence-Jones Protein] 200 mg/24 hrs (> 0.2 g/24 hrs), quantified by 24-hour urine protein electrophoresis (UPEP). AND/OR Bone marrow plasma cells 30% Chapter 11C - Page 1 ORP Manual Version 3.0

2 OR Patients who have both serum M protein levels < 1 g/dl AND urine M protein levels < 200 mg/24 hrs at baseline may be followed by serum free light chain (FLC) assay if involved free light chain level 10 mg/dl ( 100mg/L). Oligosecretory and Non-secretory Disease: Patients that do not meet the criteria for measurable disease above may only be assessed for the following objective statuses: Stringent Complete Response, Stable, and Progression. Criteria for Objective Status scr CR VGPR PR STA Stringent Complete Response: Meets all of the criteria for Complete Response (CR) and normal serum free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence Complete Response: Disappearance of all evidence of serum and urine M proteins on immunofixation electrophoresis studies and 5% plasma cells in bone marrow and disappearance of any soft tissue plasmacytomas Very Good Partial Response: Meets all of the criteria for Partial Response (PR) and Serum and urine M proteins detectable by immunofixation but not on electrophoresis or 90% reduction in serum M protein and urine M protein < 100 mg/24 hrs. Partial Response: If the patient had soft tissue plasmacytomas present at baseline and they were assessed at this disease assessment: 50% reduction in size of soft tissue plasmacytomas and If the patient had 30% plasma cells in bone marrow at baseline and a bone marrow biopsy was done: 50% reduction in plasma cells and 50% reduction in serum M protein and reduction in urine M protein 90% or to < 200 mg/24hr or If patient had serum M protein < 1 g/dl, urine M protein < 200 mg/24 hrs, and an involved serum free light chain level 10 mg/dl at baseline: 50% decrease in the difference between involved and uninvolved serum free light chain levels Stable Disease: Patient does not meet criteria for Stringent Complete Response, Complete Response, Very Good Partial Response, Partial Response, or Progression. Chapter 11C - Page 2 ORP Manual Version 3.0

3 PROG Progression: Any one or more of the following: Serum M protein increase 25% from baseline (or an increase of 1 g/dl if serum M protein was 5 g/dl at baseline), with an absolute increase of 0.5 g/dl or Urine M protein increase 25% from baseline, with an absolute increase of 200 mg/24 hrs or If patient had serum M protein < 1 g/dl, urine M protein < 200 mg/24 hrs, and an involved serum free light chain level 10 mg/dl at baseline: 25% increase in the difference between involved and uninvolved serum free light chain level, with an absolute increase of 10 mg/dl or Bone marrow plasma cell percentage increase 25% from baseline, with the absolute plasma cell % 10% or New bone lesions or soft tissue plasmacytomas, or definite increase in size of existing bone lesions or soft tissue plasmacytomas or Development of hypercalcemia (corrected serum calcium > 11.5 mg/dl or 2.65 mmol/l that can be attributed solely to multiple myeloma Notes M protein may also be known by the following synonyms: M-spike, monoclonal protein, myeloma protein, monoclonal paraprotein, M-component. Urine M protein measurement is estimated using 24-hour urine protein electrophoresis (UPEP) only. Random or 24-hour urine tests measuring kappa and lambda light chain levels are not reliable and are not recommended. Patients with measurable disease in both the serum and urine (serum M protein 1g/dL and urine M protein 200 mg/24h) at baseline need to be followed by both SPEP and UPEP for response assessment. Except for assessment of Complete Response, patients with measurable disease restricted to the serum (serum M protein 1 g/dl and urine M protein < 200 mg/24h) at baseline may be followed by SPEP only. Likewise, except for assessment of Complete Response, patients with measurable disease restricted to the urine (serum M protein < 1 g/dl and urine M protein 200 mg/24h) at baseline may be followed by UPEP only. Patients with serum M protein 1 g/dl and/or urine M protein 200 mg/24h at baseline will be assessed for response based on SPEP and/or UPEP results only. Except for assessment of Stringent Complete Response, serum free light chain (FLC) assay response requirements are only applicable to patients who had serum M protein < 1 g/dl, urine M protein < 200 mg/24 hrs, and an involved serum free light chain level 10 mg/dl at baseline. A normal serum free light chain ratio is required for all patients for a Stringent Complete Response. To qualify for a Complete Response, both serum and urine immunofixation must be carried out and must be negative, regardless of the size of the baseline M protein in the serum or urine. Skeletal survey is not required for assessment of response unless clinically indicated, but is recommended once a year in clinical practice. Stringent Complete Response, Complete Chapter 11C - Page 3 ORP Manual Version 3.0

4 Response, Very Good Partial Response, Partial Response, and Stable Disease all require no known evidence of progressive or new bone lesions if radiographic studies were performed, but radiographic studies are not required to satisfy these response requirements. The size of the soft tissue plasmacytomas is defined as the sum of the products of the crossdiameters of each plasmacytoma. The size of the bone lesions will be determined in a similar manner. A definite increase in the size is defined as a 50% increase (and at least 1 cm 2 ) of this sum. Criteria for Best Response This is calculated from a sequence of objective status evaluations. scr CR VGPR PR UsCR UCR UVGPR Stringent Complete Response: An objective status of Stringent Complete Response on at least two sequential disease assessments. Only one bone marrow biopsy, done during one of these two disease assessments, is required to confirm the response. Complete Response: An objective status of Complete Response on at least two sequential disease assessments. Only one bone marrow biopsy, done during one of these two disease assessments, is required to confirm the response. Very Good Partial Response: An objective status of Very Good Partial Response on at least two sequential disease assessments. Partial Response: An objective status of Partial Response on at least two sequential disease assessments. Unconfirmed scr: One objective status of Stringent Complete Response (based on evidence from serum and urine studies and, if drawn, bone marrow biopsy) but the confirmation studies are either not done, or when done, do not meet the requirements necessary to confirm response. This must be documented before progression and at least three weeks after registration. Unconfirmed CR: One objective status of Complete Response (based on evidence from serum and urine studies and, if drawn, bone marrow biopsy) but the confirmation studies are either not done, or when done, do not meet the requirements necessary to confirm response. This must be documented before progression and at least three weeks after registration. Unconfirmed VGPR: One objective status of Very Good Partial Response, but the confirmation studies are either not done, or when done, do not meet the requirements necessary to confirm response. This must be documented before progression and at least three weeks after registration. Chapter 11C - Page 4 ORP Manual Version 3.0

5 UPR STA INC NASS Unconfirmed PR: One objective status of Partial Response, but the confirmation studies are either not done, or when done, do not meet the requirements necessary to confirm response. This must be documented before progression and at least three weeks after registration. Stable / No Response: At least one objective status of Stable at least three weeks after registration, but not qualifying as any of the above. If radiographic studies were performed there should be no known progressive or new bone lesions. Increasing Disease: First objective status recorded (other than Unknowns or those before three weeks) of Progression, provided this occurs within eight weeks of registration. Inadequate Assessment, Response Unknown: Progression greater than eight weeks after registration and either all objective statuses prior to registration are unknown or the only known objective statuses occurred less than three weeks after registration. Response Assessment for Studies Activated Prior to January 1, 2006 This version of the response criteria is representative of the criteria used in some SWOG multiple myeloma protocols activated prior to January 1, Please note that prior to January 1, 2006 SWOG did not have a standard multiple myeloma response criteria, so you MUST consult section 10.0 of the treatment protocol prior to assessing patient response. Measurability of Disease Measurable Disease: Measurable, quantifiable protein criteria must be present. Acceptable protein criteria are quantifiable ( 1.0 g/dl [10.0 g/l] serum M-protein of IgG, IgA, IgD, IgE isotype and/or urine M-protein [Bence-Jones Protein] ( 200 mg/24 [ 0.2 g/24 hrs]). Patients with IgM peaks must have either 20% bone marrow plasmacytosis or > 3 lytic lesions on the skeletal survey. Chapter 11C - Page 5 ORP Manual Version 3.0

6 Criteria for Objective Status CR Complete Remission: Absence of bone marrow or blood findings of multiple myeloma. This includes disappearance of all evidence of serum and urine M-proteins on immunofixation electrophoresis studies. Normalization of serum concentrations of normal immunoglobulins is not required for CR. There must also be no evidence of increasing anemia. Bone marrow cellularity must be 20% with plasma cells 5%. REM Remission: A 75% reduction in the serum M-protein, and if a urine M- protein (Bence-Jones protein) is present, either a 90% reduction in this protein, or a urine M-protein < 0.2 g/day. Bone marrow plasma cells must be 5%. PR STA PROG REL Partial Remission: A 50% reduction in the serum M-protein, and if present, a 50% reduction in the urine M-protein (Bence-Jones protein). Bone marrow plasma cells must not be increased from baseline level. Stable / No Remission: A < 50% reduction in the serum M-protein, or if the patient has light-chain disease only, a < 50% reduction in the urine M-protein (Bence-Jones protein). Patients not qualifying for remission or progression. Progression: In patients with no confirmed Partial Remission, Remission, or Complete Remission, Progression is defined as a > 25% increase from baseline in myeloma protein production or other signs of disease progression such as hypercalcemia, etc. Relapse: In patients with a confirmed Partial Remission, Remission, or Complete Remission (The patient must have had an objective status of Partial Remission, Remission, or Complete Remission on two successive disease assessments performed at least six weeks apart - with or without a bone marrow biopsy.), Relapse is defined as the first occurrence of any of the following: 1) a myeloma protein increase by100% from the lowest level recorded on study, provided the absolute magnitude of this increase is at least 1 g/dl for a serum monoclonal protein or at least 500 mg/24 hrs of urine M-protein; 2) a myeloma protein increase above the response criteria for PR (see criteria for Partial Remission), with the same requirements for the absolute magnitude of the protein increase; 3) reappearance of any myeloma peak that had disappeared while on protocol treatment, provided it meets the same requirements listed above; 4) increase in the size and number of lytic bone lesions recognized on radiographs. Chapter 11C - Page 6 ORP Manual Version 3.0

7 Notes In all remissions, the serum calcium must remain normal, and where a skeletal survey is required, the size and number of lytic lesions must not increase. Criteria for Best Response This is calculated from a sequence of objective status evaluations. CR REM PR UCR UREM UPR STA Complete Remission: An objective status of Complete Remission on at least two disease assessments performed at a minimum of six weeks apart. A bone marrow biopsy and a skeletal survey must be done during one of these two disease assessments. The skeletal survey must either show recalcification or no change in osteolytic lesions. Remission: An objective status of Remission on at least two disease assessments performed at a minimum of six weeks apart. A bone marrow biopsy must be done during one of these two disease assessments. If the patient has new symptoms of pain, a skeletal survey must also be done. Partial Remission: An objective status of Partial Remission on at least two disease assessments performed at a minimum of six weeks apart. A bone marrow biopsy must be done during one of these two disease assessments. If the patient has new symptoms of pain, a skeletal survey must also be done. Unconfirmed CR: One objective status of Complete Remission based on evidence from serum and urine protein, with or without a bone marrow biopsy, documented before progression and at least three weeks after registration, but the confirmation studies are either not done, or when done, do not meet the requirements necessary to confirm response. Unconfirmed REM: One objective status of Remission based on evidence from serum and urine protein, with or without a bone marrow biopsy, documented before progression and at least three weeks after registration, but the confirmation studies are either not done, or when done, do not meet the requirements necessary to confirm response. Unconfirmed PR: One objective status of Partial Remission based on evidence from serum and urine protein, with or without a bone marrow biopsy, documented before progression and at least three weeks after registration, but the confirmation studies are either not done, or when done, do not meet the requirements necessary to confirm response. Stable / No Remission: At least one objective status of Stable at least three weeks after registration, but not qualifying as any of the above. Chapter 11C - Page 7 ORP Manual Version 3.0

8 INC NASS Increasing Disease: First objective status recorded (other than Unknowns or those before three weeks) of Progression, provided this occurs within eight weeks of registration. Inadequate Assessment, Response Unknown: Progression greater than eight weeks after registration and either all objective statuses prior to registration are unknown or the only known objective statuses occurred less than three weeks after registration. Baseline and Follow-up Studies In order to assess the patient s response to treatment, it is crucial that we get an accurate depiction of the patient s disease status at baseline. And since each patient s disease markers may display in a different manner in the serum, urine, and bone marrow, all patients must have all of these sites assessed at baseline. Once on study, however, the follow-up tests required to assess the patient s response to treatment may differ from patient to patient, depending on what their disease status was at baseline. The disease marker that is examined in the urine is the urine M protein, which is also sometimes called Bence-Jones protein. This protein is assessed by using two different tests: urine electrophoresis (UPEP) and urine immunofixation electrophoresis (UIFE). The UIFE checks for the presence of the M protein and identifies what type of protein it is, and the UPEP measures the amount of M protein that is present. For SWOG studies, both of these tests must be performed on 24 hour urine samples, and the M protein must be quantified (given a numerical value) on the UPEP. Urine M protein measurements obtained from UPEPs done on random urine samples, or quantified from urine tests that only measure urine kappa and lambda lights chain levels, are not considered reliable and the values obtained from these tests will not be accepted by SWOG. At baseline, these tests must be done within 28 days prior to registration. In the serum, the disease marker that is examined is the serum M protein. Like in the urine, this protein is assessed by two tests: serum protein electrophoresis (SPEP) and serum immunofixation electrophoresis (SIFE). The SIFE checks for the presence and identity of the serum M protein, and the SPEP quantifies the amount of serum M protein present. For SWOG studies, the serum M protein must be quantified on the SPEP. At baseline, these tests must be done within 28 days prior to registration. In both the serum and urine, the immunofixation tests (SIFE and UIFE) are more sensitive to the presence of M protein than the protein electrophoresis tests (SPEP and UPEP). So sometimes the results from the SPEP or UPEP will indicate that there is no M protein, or that if an M protein is present it is too little to be quantified, but the SIFE or UIFE done on the same sample will indicate that an M protein is present. This is why the response criteria above specify that for a patient to be in a complete response or complete remission, both the protein electrophoresis and the immunofixation tests must be done on the serum and urine, and all tests must be negative for the presence of M protein. Chapter 11C - Page 8 ORP Manual Version 3.0

9 Additionally, the response criteria based on the International Uniform Response Criteria for Multiple Myeloma now allows for patient response to be assessed by following a patient s serum free light chain levels. These are measured by a serum free light chain assay, which is also known as a Freelite test. As explained in the criteria above, if at baseline the patient s serum M protein is < 1 g/dl and urine M protein is < 200 mg/24 hr, the patient may still be considered to have measurable disease if their involved free light chain level is 10 mg/dl. The patient will then be assessed for response based on the results from follow-up serum free light assays. For these patients, at baseline this test must be done within 28 days prior to registration. Patients who are considered to have measurable disease based on their serum and/or urine M protein levels will only need to have a free light chain assay performed when it appears that the patient has entered a stringent complete response. Bone marrow biopsies are done to assess how much of the bone marrow is comprised of plasma cells and one must be performed within 28 days prior to registration. Additional followup bone marrow biopsies may be required during the study to confirm a patient s response. Multiple Myeloma Response Exercises The following are exercises in determining patient response to treatment. Please note that the first two exercises are based on the response criteria for studies activated since January 1, The last two exercises are based on the criteria for studies activated prior to January 1, These exercises distinguish between objective status and best response. Objective status refers to the patient s response at each scheduled assessment. Best response is determined from a sequence of objective status evaluations and refers to the patient s most favorable response over all assessments up to that time point. In multiple myeloma response assessment you will often have to calculate the percent change in a value from baseline. To calculate this percent change, please use the following formula: (current value baseline value) X 100 baseline value Chapter 11C - Page 9 ORP Manual Version 3.0

10 Exercises for Studies Activated Since January 1, 2006 Exercise 1 Parameter Prestudy Week 6 Week 12 Week 18 Serum M protein 1.2 g/dl 0.5 g/dl 0.1 g/dl 0 g/dl % change from baseline -58.3% -91.7% -100% Serum IFE present present present present Urine M protein 350 mg/24h 190 mg/24h 80 mg/24h 70 mg/24h % change from baseline -45.7% -77.1% -80% Urine IFE present present present present Serum calcium 9.5 mg/dl 9.8 mg/dl 9.9 mg/dl 9.6 mg/dl BM plasma cell % 20% Plasmacytomas none Objective Status PR VGPR VGPR Best Response at Time Point UPR UVGPR VGPR Best Response Overall VGPR Note that at week 6, while the urine M protein had only decreased 45.7% from baseline, the absolute value of the urine M protein was < 200 mg/24h, and thus the patient still met the criteria for an objective status of Partial Response (PR). Exercise 2 Parameter Prestudy Week 6 Week 12 Week 18 Serum M protein 0.3 g/dl 0.1 g/dl 0 g/dl Serum IFE present present present Urine M protein 0 mg/24h 0 mg/24h Urine IFE absent absent Serum FLC involved lambda lambda lambda Serum FLC kappa 0.01 mg/dl 0.15 mg/dl 0.22 mg/dl Serum FLC lambda 298 mg/dl 103 mg/dl 1.28 mg/dl Serum FLC (involved mg/dl uninvolved) mg/dl mg/dl % change in (involved -65.5% -99.6% uninvolved) from baseline Serum calcium 10.4 mg/dl 10.1 mg/dl 9.8 mg/dl BM plasma cell % 35% 5% % change in BM plasma cell % -85.7% from baseline Plasmacytomas none none Objective Status PR VGPR Best Response at Time Point UPR UVGPR Best Response Overall UVGPR Chapter 11C - Page 10 ORP Manual Version 3.0

11 At baseline this patient s serum M protein was < 1 g/dl, and the urine M protein was < 200 mg/24h. However, the serum free light chain assay showed an involved free light chain, in this case lambda, that was 10 mg/dl. So this patient is considered to have measurable disease, and is followed by serum free light chain assay. Please note that an objective status could not be determined for the week 12 assessment. Since this patient is being followed by serum free light chain assay, if this test is not done we cannot determine how the patient is responding to treatment. You should always make sure to do all tests that section 10 requires for your patient (SPEP and/or UPEP or serum free light chain assay) at every disease assessment. The week 18 assessment was very close to qualifying as a Complete Response (CR), but the serum immunofixation electrophoresis test showed that the serum M protein was still present. Thus, the objective status for this assessment was a Very Good Partial Response (VGPR). Exercises for Studies Activated Prior to January 1, 2006 Exercise 3 Parameter Prestudy Week 6 Week 12 Week 18 Serum M protein 8.2 g/dl 1.2 g/dl 0 g/dl 0 g/dl % change from baseline -85.4% -100% -100% Serum IFE present present absent absent Urine M protein 180 mg/24h 50 mg/24h 0 mg/24h 0 mg/24h Urine IFE present present absent absent BM plasma cell % 18% 3% BM cellularity % 70% 50% Bone lesions 1 none Increasing anemia? yes yes no no Objective Status REM CR CR Best Response at Time Point UREM UCR CR Best Response Overall CR The week 18 assessment confirmed that the patient was experiencing a Complete Remission (CR). Please note that for the week 18 best response to be categorized as a CR a bone marrow biopsy and a skeletal survey had to be done in addition to the serum and urine studies. Chapter 11C - Page 11 ORP Manual Version 3.0

12 Exercise 4 Parameter Prestudy Week 6 Week 12 Week 18 Serum M protein 0 g/dl 0 g/dl 0 g/dl 0 g/dl Serum IFE absent absent present present Urine M protein 480 mg/24h 216 mg/24h 365 mg/24h 615 mg/24h % change from baseline -55% -24% +28.1% Urine IFE present present present present BM plasma cell % 22% BM cellularity % 80% Bone lesions multiple Objective Status PR STA PROG Best Response at Time Point UPR UPR UPR Best Response Overall UPR At week 18 this patient s urine M protein level increased by 28.1%, which qualified this patient for an objective status of progression. Please note that in many protocols the study calendar may request that other extra tests, like a bone marrow biopsy, be done when the patient has progressed. Chapter 11C - Page 12 ORP Manual Version 3.0