Q1 What is your occupation/role? (select all that apply) Answered: 310 Skipped: 4 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

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1 Q1 What is your occupation/role? (select all that apply) Answered: 310 Skipped: 4 ANSWER CHOICES Pathologist Total Respondents: 310 Pathologist Physician (non-radiolo... Medical Director Technologist/Te chnician QA/QC Coordinator Laboratory Manager Industry Other (please specify) Physician (non-radiology, non-pathology) Medical Director Technologist/Technician QA/QC Coordinator Laboratory Manager Industry Other (please specify) 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% RESPONSES # OTHER (PLEASE SPECIFY) DATE 58.06% % % % % % % % 37 1 patient with MM 2/22/ :32 PM 2 Clinical Scientist 2/22/ :44 AM 3 Clinical Chemistry Trainee 2/22/ :14 AM 4 PhD Clinical Scientist; Technical Director 2/20/ :49 PM 5 Clinical Chemistry fellow 2/20/ :23 PM 6 Clinical Biochemist 2/20/2019 8:44 AM 1 / 35

2 7 Clinical Chemist 2/20/2019 8:13 AM 8 Technical Director 2/19/ :59 PM 9 Laboratory supervisor 2/15/ :14 PM 10 Non-physician medical director 2/13/ :35 AM 11 Laboratory Consultant 2/13/2019 9:15 AM 12 Medical Director, Laboratory Medicine (DABCC) 2/13/2019 9:14 AM 13 consultant, molecular diagnostics 2/12/ :57 AM 14 Biochemistry Fellow 2/12/2019 9:39 AM 15 Clinical Chemist 2/10/2019 9:22 PM 16 Technical Director -Chemistry 2/7/ :19 PM 17 Content specialist 2/7/ :19 AM 18 Laboratory Director 2/7/2019 8:26 AM 19 Hematology PhD Medical laboratory Scientist 2/7/2019 5:05 AM 20 Principal Scientist 2/6/2019 4:24 PM 21 Chief of Clinical Immunology 2/6/2019 4:17 PM 22 Biochemist 2/6/2019 9:58 AM 23 Chemical Pathologist 2/6/2019 9:44 AM 24 Clinical Biochemist 2/6/2019 8:20 AM 25 Clinical chemistry fellow 2/6/2019 7:10 AM 26 Clinical biochemist 2/6/2019 5:55 AM 27 Clinical Chemist 2/5/2019 6:42 PM 28 Clinical Chemist 2/4/2019 3:29 PM 29 x 1/31/2019 2:05 PM 30 Clinical Chemist 1/31/2019 9:18 AM 31 Clinical Biochemist 1/31/2019 8:55 AM 32 Ph.D., D(ABMLI) 1/31/2019 7:56 AM 33 Part time senior Neuropathologist 1/30/2019 8:22 PM 34 Clinical Chemist 1/30/2019 7:26 PM 35 Clinical Biochemist 1/30/2019 5:42 PM 36 PhD clinical chemist 1/30/2019 4:19 PM 37 Director, Medical Affairs 1/30/2019 2:46 PM Disclaimer The information, data, and draft recommendations provided by the College of American Pathologists are presented for informational and public feedback purposes only. The draft recommendations and supporting documents will be removed on March 1, The draft recommendations along with the public comments received and completed evidence review will be reassessed by the expert panel in order to formulate the final recommendations. These draft materials should not be stored, adapted, or redistributed in any manner. 2 / 35

3 Q2 Which of the following best describes your practice setting? (select one) ANSWER CHOICES University hospital/aca... Voluntary, non-profit... Proprietary hospital City/County/Sta te hospital Veterans hospital Army/Air Force/Navy... National/corpor ate laboratory Regional/local independent... Public Health, non-hospital Clinic, group, or doctor... N/A industry or vendor Other (please specify) University hospital/academic medical center Voluntary, non-profit hospital Answered: 308 Skipped: 6 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% RESPONSES 48.05% % % 17 Proprietary hospital City/County/State hospital Veterans hospital 4.87% % 10 Army/Air Force/Navy hospital National/corporate laboratory 0.97% % 13 3 / 35

4 Regional/local independent laboratory (except clinic or group practice and not owned by a national corporation(s)) Public Health, non-hospital Clinic, group, or doctor office laboratory 6.49% % % 9 N/A industry or vendor Other (please specify) 4.55% % 19 TOTAL 308 # OTHER (PLEASE SPECIFY) DATE 1 District general university hopsital (UK) 2/22/ :44 AM 2 Private Community Laboratory 2/20/2019 8:44 AM 3 Private Laboratory 2/14/2019 2:43 AM 4 consultant, molecular diagnostics 2/12/ :57 AM 5 Product Specialist (Technical Sales) 2/11/2019 8:09 AM 6 Integrated Health Care system 2/7/2019 1:35 PM 7 HMO organization 2/7/ :19 PM 8 Nonprofit organization 2/7/ :19 AM 9 Healthcare System with 5 hospitals and numerous physician practices including a large oncology practice with multiple regional offices 2/6/2019 4:17 PM 10 Contract research organization 2/6/ :32 AM 11 Large Health System 2/5/2019 6:42 PM 12 x 1/31/2019 2:05 PM 13 Consultant 1/31/2019 7:03 AM 14 PRIVATE CLINICAL LABORATORY 1/31/2019 1:12 AM 15 Research Institute on Brain Development 1/30/2019 8:22 PM 16 Nonacademic hospital based cancer center 1/30/2019 3:25 PM 17 Retired 1/30/2019 3:13 PM 18 A for profit lab owned by an academic hospital 1/30/2019 2:55 PM 19 Global clinical trials lab 1/30/2019 2:46 PM Disclaimer The information, data, and draft recommendations provided by the College of American Pathologists are presented for informational and public feedback purposes only. The draft recommendations and supporting documents will be removed on March 1, The draft recommendations along with the public comments received and completed evidence review will be reassessed by the expert panel in order to formulate the final recommendations. These draft materials should not be stored, adapted, or redistributed in any manner. 4 / 35

5 Q3 Draft Recommendation Statement 1Clinical care providers should order both serum protein electrophoresis (SPE) and serum free light chains (sflc) assay for the initial detection of monoclonal protein in all patients with suspected monoclonal gammopathies (MG).Strength of Recommendation (SOR): Strong ANSWER CHOICES Agree as written Agree as written Agree with suggested... Disagree. Include... Does not pertain to m... Agree with suggested modifications Disagree. Include comments in the box below Does not pertain to my area of expertise or practice Answered: 174 Skipped: 140 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 77.01% % % % 5 TOTAL 174 # COMMENTS DATE 1 I think this should depend on the level of suspicion that an MG may be present. If suspicion is high, a serum IFE should also be ordered for the initial detection, as the sflc assay could be completely within normal limits despite an MG being present. Likewise, if suspicion is high for a plasma cell dyscrasia, I think urine studies should be ordered during the initial diagnostic work-up. 2 Serum and urine electrophoresis should be used for the initial investigation of suspected monoclonal gammopathy 3 In the event of initial testing of a clinically suspicous patient, start with SPE. If a peak is detectd that is greater than 100mg/dl then proceed to serum IFE or IT. Urine studies should also be collected for UPE and UIFE or UIT. then proceed to SFLC if the clinical information is lacking or patient demonstrates a myeloma defining event RESPONSES 2/22/ :51 PM 2/22/ :13 AM 2/21/2019 8:31 AM 4 Initial detection can be in two stages: (1) SPEP; (2) sflc, if SPEP is not abnormal 2/20/2019 9:12 AM 5 / 35

6 5 Might not need both tests in the setting of follow up. "Patients with suspected monoclonal gammopathies" technically by definition would include a patient with a history of MG. 2/15/2019 4:20 PM 6 sflc does not add value. An abnormal K/L ratio is not diagnostic of MG and a normal K/L ratio does not exclude MG. 36% of tertiary care patients without MG have an abnormal K/L ratio. 30% of patients with MG have a normal K/L ratio. sflc does not add value. Examination of urine is more useful. 7 The SPEP is insufficiently sensitive by itself, without immunofixation, to identify small bands or those superimposed on the peaks of other protein fractions. Serum FLCs are very helpful and should be done, but do not replace the sensitivity of immunofixation. 2/13/2019 4:48 PM 2/13/2019 1:47 PM 8 Would add serum immunofixation to recommendation 2/12/2019 5:56 PM 9 Both tests provide presumptive finding and do not ID the monoclocnal. Furthermore, both tests have high false negative and positive rates. 10 The only reservation I have is that SPE is not as sensitive as sife for detection of M proteins, both in terms of detecting low absolute amounts of M protein and in potential overlap of M proteins with normal bands. So a negative SPE result will not definitively rule out the possiblity of an M protein. In cases of high clinical suspicion a serum IFE may be better. 2/12/2019 5:00 PM 2/11/2019 6:41 AM 11 In my country (Belgium), sflc is not reimbursed in this indication. 2/10/2019 9:36 AM 12 urine for Bence Jones proteins 2/9/ :59 PM 13 positive findings in SPE could reflex to sflc with similar outcome 2/8/2019 7:25 AM 14 SPE, serum IFE and sflc is required in the screening panel to cover 95% sensitivity. SPE and sflc alone are inadequate. 2/7/2019 3:25 PM 15 In our country the cost of sflc is a limitation and the test is not widely available 2/7/2019 9:06 AM 16 with measurement of Immunoglobulins. 2/7/2019 5:14 AM 17 Serum immunofixation should be included. 2/6/2019 4:32 PM 18 Include a serum immunofixation along with SPE 2/6/ :01 AM 19 sflc has a very false positive and false negative rate to be of use in initial diagnosis 2/6/2019 6:43 AM 20 In the Guidelines 1 and 2: One is stating that SPE and Free light should be ordered for initial detection and Second is stating that all Abnormal SPE should be confirmed with Immunofixation. 21 The SFLC reference ranges should be modified for patients with renal impairment. Results in these patients are often misinterpreted. 22 The initial detection should be with a serum immunofixation and serum free light chain assay. Then abnormality suspicious for presence of a monoclonal gammopathy should be confirmed with SPE and 24 hour urine for protein electrophoresis and immunofixation. 23 Agree, but caution that coupling sflc and SPE could lead to massive overutilization, as SPE alone is overutilized when there is minimal clinical suspicion for monoclonal gammopathy. 2/5/2019 6:27 AM 2/2/ :30 AM 1/31/ :09 AM 1/31/2019 9:37 AM 24 SPE alone 1/31/2019 9:04 AM 25 add serum IFE 1/31/2019 8:39 AM 26 It would be more useful to include urine analysis. An abnormal K/L: ratio is neither diagnostic of MG nor does a normal value exclude MG. 36% of tertiary care patients without MG have an abnormal K/L ratio. More than 30% of patients with MG have a normal K/L ratio. 1/31/2019 6:55 AM 27 and urine gel and immunofixs 1/31/2019 6:47 AM 28 ADD IMMUNOGLOBULINES G A M AND KAPPA LINKED AND LAMBDA LINKED ASSAYS 1/31/2019 1:35 AM 29 Serum free light chain analysis is not available in all clinical laboratories. Furthermore, not all insurer providers will cover sflc in the screening (for the initial detection of monoclonal protein). Disclaimer The information, data, and draft recommendations provided by the College of American Pathologists are presented for informational and public feedback purposes only. The draft recommendations and supporting documents will be removed on March 1, The draft recommendations along with the public comments received and completed evidence review will be reassessed by the expert panel in order to formulate the final recommendations. These draft materials should not be stored, adapted, or redistributed in any manner. 6 / 35 1/30/2019 6:02 PM

7 Q4 Draft Recommendation Statement 2Laboratorians should confirm a SPE abnormality suspicious for a presence of a monoclonal gammopathy with serum immunofixation electrophoresis (IFE).SOR: Strong ANSWER CHOICES Agree as written Agree as written Agree with suggested... Disagree. Include... Does not pertain to m... Agree with suggested modifications Disagree. Include comments in the box below Does not pertain to my area of expertise or practice Answered: 174 Skipped: 140 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 80.46% % % % 6 TOTAL 174 # COMMENTS DATE 1 in the case of suspicious band on SPE, hypogramma or restriction < 100 mg/dl then the next step should be to test by IF or IT, SFLC, UPE and UIF or UIT 2/21/2019 8:31 AM 2 Does this place the responsibility of ordering the IFE on the laboratory?self-referral issues? 2/20/ :18 AM 3 Laboratorians should confirm a SPE abnormality suspicious for a presence of a monoclonal gammopathy with serum immunofixation electrophoresis (IFE) or equivalent method (ex. immunosubtraction or MALDI-TOF MS). 4 Should allow other newer techonolgies such as immunotyping/immunosubtraction and MALDI (mass spectrophotometry) 5 Would rephrase to include confirmation by newer technologies such as mass spectrometric isotyping RESPONSES 2/20/2019 8:20 AM 2/18/ :13 AM 2/15/2019 4:46 PM 6 Capillary-based immunotyping technology should also be an acceptable method for confirmation. As-written, the implication is that only gel-based typing is acceptable. 2/15/2019 1:54 PM 7 Serum immunofixation should be included in initial evaluation 2/12/2019 5:56 PM 7 / 35

8 8 With both IFE and sflc 2/10/2019 9:37 PM 9 "and sflc";comment: aprox 66% of non-secretor MM can be detected by sflc only 2/8/2019 3:42 AM 10 Does this include immunotyping (capillary procedures) or specifically gel electrophoresis immunofixation? 2/6/2019 4:52 PM 11 See above, as frequently SPE is normal but IFE detects a monoclonal protein. Especially true with IgA, and minor IgG or IgM. 2/6/2019 4:32 PM 12 or immunotyping and IFE if negative. 2/6/ :06 AM 13 A suspicious or questionable SPE should be reflexd with IFE and sflc 2/6/ :04 AM 14 If there is clear M-spike seen, then it should be reflexed to IFE. If there are indefinitive bands, and suspicious clinical indications, IFE should be reflexed. 2/5/2019 2:11 PM 15 or immunosubstraction 2/5/ :47 AM 16 or with immunotyping? 2/2/2019 4:18 PM 17 "should confirm all initial SPE abnormalities..." 2/2/2019 1:40 PM 18 As written it seems to preclude other identification methods such as immunosubtraction 1/31/2019 2:17 PM 19 The initial detection should be with a serum immunofixation and serum free light chain assay. Then abnormality suspicious for presence of a monoclonal gammopathy should be confirmed with SPE and 24 hour urine for protein electrophoresis and immunofixation. 20 Laboratorians should confirm a SPE abnormality suspicious for a presence of a monoclonal gammopathy with sflc and serum immunofixation electrophoresis (IFE). 1/31/ :09 AM 1/31/ :54 AM 21...suspicious for "the" presence... 1/31/2019 9:37 AM 22 Suggest a reflex order to IFE is available so the laboratory can add the test when appropriate. 1/31/2019 9:28 AM 23 only with order from clinican...not reflexed. not the labs job to "order" stuff 1/31/2019 6:47 AM 24 MALDI-TOF to confirm - another acceptable method 1/30/2019 5:43 PM Disclaimer The information, data, and draft recommendations provided by the College of American Pathologists are presented for informational and public feedback purposes only. The draft recommendations and supporting documents will be removed on March 1, The draft recommendations along with the public comments received and completed evidence review will be reassessed by the expert panel in order to formulate the final recommendations. These draft materials should not be stored, adapted, or redistributed in any manner. 8 / 35

9 Q5 Draft Recommendation Statement 3Laboratorians and/or clinical care providers should follow-up an abnormal sflc ratio for the presence of a monoclonal gammopathy with a serum IFE. SOR: Conditional ANSWER CHOICES Agree as written Agree as written Agree with suggested... Disagree. Include... Does not pertain to m... Comments Agree with suggested modifications Disagree. Include comments in the box below Does not pertain to my area of expertise or practice Comments Answered: 174 Skipped: % % % % % 0 TOTAL 174 # COMMENTS DATE There are no responses. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% RESPONSES 9 / 35

10 Q6 Comments Answered: 41 Skipped: 273 # RESPONSES DATE 1 I think the recommendation should state that the follow-up of an abnormal sflc ratio should include an SPE (if one has not been done already) along with a concurrent serum IFE. 2 SFLC should not be part of initial investigations. May be done when diagnosis of MM made but would have already done IFE by then. 3 Don't see how that can be placed on the laboratorian as we don't always know that sflc has been run. 4 would modify statement to include urine protein electrophoresis as a followup test for an abnormal serum free light chain ratio 2/22/ :51 PM 2/22/ :13 AM 2/21/ :50 AM 2/21/ :25 AM 5 Should a urine IFE or quant light chains also be done? 2/20/ :55 PM 6 Laboratorians and/or clinical care providers should follow-up an abnormal sflc ratio for the presence of a monoclonal gammopathy with a serum IFE or equivalent method (ex. immunosubtraction or MALDI-TOF MS). 2/20/2019 8:20 AM 7 Serum free light chain both kappa and lambda ratio is highly recommended. 2/19/ :50 AM 8 Less sure about this one - there can be mild abnormalities in the ratio unrelated to monoclonal gammopathy. Might suggest "persistently abnormal sflc ratio" or setting a threshold for the degree of abnormality rather than a blanket recommendation for all abnormal ratios 2/15/2019 4:46 PM 9 Might not need both tests in the setting of follow up. 2/15/2019 4:20 PM 10 Capillary-based immunotyping technology should also be an acceptable method for confirmation. As-written, the implication is that only gel-based typing is acceptable. 2/15/2019 1:54 PM 11 sflc is not a useful test and should not be part of the screening process. 2/13/2019 4:48 PM 12 Serum AND Urine IFE recommended 2/13/2019 1:13 PM 13 SPEP with serum IFE if indicated by pathologist, not just serum IFE stand alone test 2/13/ :11 AM 14 If not already ordered, the serum and urine PEP should be performed. Any abnormal findings should reflex to IFE for either sample as confirmation and clonal identification. If negative, serum IgD and IgE anti-sera should be used to r/o these monoclonal gammopathies. 2/13/2019 9:35 AM 15 See statement #2 2/12/2019 5:56 PM 16 If so, we should simply screen with IFE alone. It will be more cost effective! 2/12/2019 5:00 PM 17 Due to lower sensitivity of IFE, IFE may not reveal the cause of abnormal sflc. 2/10/2019 9:37 PM 18 IFE is less sensitive than sflc. 2/10/2019 9:36 AM 19 unless requested with initial order. 2/8/2019 7:25 AM 20 The recommendation is not clear. It is not clear if the recommendation is for MG follow-up or if it is upon a incidental finding of abnormal sflc ratio 21 Serum IFE should be included in the initial screen along with sflc. We see many cases where serum IFE is positive but sflcs are not. There are published papers supporting this observation. sflc is useful as an adjunct test, but there are cases where sflc and serum IFEs do not overlap. For this reason, SPE, serum IFE and sflc, all 3 may needed in the screening panel. 22 This would be redundant if Statement 1 and 2 were followed. If SPE and flc assays were done and the SPE showed an MG, IFE would be done. Statement 3 would therefore only have any independent meaning if the SPE were negative and the flc assay was abnormal, and in that case the IFE would not be indicated since there was no abnormality to characterize. The correct approach in that case would be to do a UPE, not an IFE. 2/8/2019 3:42 AM 2/7/2019 3:25 PM 2/7/ :25 AM 10 / 35

11 23 The follow-up shouldn t be done with IFE (not quantitative and less sensitive). We think it should be done with the involved FLC 2/7/2019 9:06 AM 24 The follow up has to be done with SPE and sflc 2/7/2019 5:43 AM 25 Rule out Bence-Jones proteinuria 2/7/2019 5:14 AM 26 If ratio is only mildly abnormal and patient has renal involvement, other clinical and laboratory parameters may account for the abnormal ratio and IFE is not needed. 2/6/2019 4:32 PM 27 Many times on M band in FLC diseases. 2/6/2019 2:52 PM 28 IFE should be included on initial screening so followup order for serum IFE would not be necessary. I have seen many cases of positive IFE with negative sflc ratio. The order for an IFE should not depend on result of sflc. 2/6/ :01 AM 29 provided the abnormality exceeds a small variance due to significant azotemia. 2/6/ :06 AM 30 SPE and sflc should be the first requests in suspect patients with MG. Reflex ( Immunofixation,Immunotyping) must follow a suspect or questionable SPE. 2/6/ :04 AM 31 sflc is not a useful screening test and should not be used in the first place. 2/6/2019 6:43 AM 32 It might be helpful to provide further guidance such as a numerical value for an abnormal -- and clinically meaningful -- sflc ratio to warrant additional testing with IFE/immunotyping. Laboratories have different cut-off values for normal sflc ranges, which result in varying normal (and abnormal) sflc ratios. Is enough evidence to direct a sflc ratio greater than 'x' that would have a clinically high pre-test probability of detecting the presence of a monoclonal gammopathy with serum IFE/IT? 2/2/2019 4:18 PM 33 "...with a serum and urine IFE." 2/2/2019 1:40 PM 34 I think that the predictive value of a very slightly abnormal sflc ratio is low. I would agree that a markedly abnormal sflc ratio should be followed up on. Again as written this seems to preclude immunosubtraction and urine PEP/IFE. 35 The initial detection should be with a serum immunofixation and serum free light chain assay. Then abnormality suspicious for presence of a monoclonal gammopathy should be confirmed with SPE and 24 hour urine for protein electrophoresis and immunofixation. 36 A threshold for abnormal should be indicated. The sflc ratio is often slightly abnormal when both FL and FK are elevated (e.g. renal disease) and would not require follow-up IFE without clear clinical indications of monoclonal gammopathy. Also note logistical concerns, where only some (or maybe none) of the clinical care providers can directly order IFE. 1/31/2019 2:17 PM 1/31/ :09 AM 1/31/2019 9:37 AM 37 Initial screen does not include sflc 1/31/2019 9:04 AM 38 As state above abnormal sflc ratio has more than 30% false positive and equal number of false negative and is not a useful assay for diagnosis of MG. 1/31/2019 6:55 AM 39 take out lab...only the clinician can should/order...the lab should not be ordering for them 1/31/2019 6:47 AM 40 IF KAPPA AND LAMBA ARE BOTH OF IT INCREASED WITH AN ABNORMAL RATIO FOLLOW UP WITH SERUM IFE AND URINE IFE 41 See previous comment - regarding use of MALDI-TOF for identification of monoclonal protein or serum IFE Disclaimer The information, data, and draft recommendations provided by the College of American Pathologists are presented for informational and public feedback purposes only. The draft recommendations and supporting documents will be removed on March 1, The draft recommendations along with the public comments received and completed evidence review will be reassessed by the expert panel in order to formulate the final recommendations. These draft materials should not be stored, adapted, or redistributed in any manner. 11 / 35 1/31/2019 1:35 AM 1/30/2019 5:43 PM

12 Q7 Draft Recommendation Statement 4Clinical care providers should order SPE, sflc, and urine IFE for the initial detection of monoclonal protein in all patients with suspected amyloid light chain (AL) amyloidosis.sor: Strong ANSWER CHOICES Agree as written Agree as written Agree with suggested... Disagree. Include... Does not pertain to m... Agree with suggested modifications Disagree. Include comments in the box below Does not pertain to my area of expertise or practice Answered: 174 Skipped: 140 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 77.59% % % % 10 TOTAL 174 # COMMENTS DATE 1 I believe that since amyloidosis can accompany myeloma in which a whole immunoglobin M- protein is also present, a serum IFE needs to be included, or the work-up is incomplete. Also, I think the recommendation should state that a UPE (24-hour collection - if one has not been done already) should be ordered along with a concurrent urine IFE. 2 Serum and urine electrophoresis should still be used for the initial investigation of patients with AL amyloidosis. SFLC may be helpful as a follow up test. 3 At our institution, urines are all run by protein electrophoresis prior to immunofixation so would consider modifying the phrase to reflect this testing algorithm that providers should do a order SPE, sflc and UPEP (and perform urine IFE when appropriate if the UPEP is abnormal). While the IFE is more sensitive, it is unclear whether a nonquantifiable urine light chain detected only by IFE yields useful clinical information. RESPONSES 2/22/ :51 PM 2/22/ :13 AM 2/21/ :25 AM 4 with the addition of serum IFE 2/21/2019 8:31 AM 5 Agree although SPE could potentially be omitted, how often is it positive when FLC & urine IFE are normal? 2/15/2019 4:46 PM 12 / 35

13 6 Capillary-based immunotyping technology should also be an acceptable method for confirmation. As-written, the implication is that only gel-based typing is acceptable. 2/15/2019 1:54 PM 7 sflc does not add value. The number of false positive and false negative results is too high for sflc to be a bona fide laboratory test. 8 Urine UPEP (24 hour strongly preferred) with IFE if indicated by pathologist, not just standalone urine IFE, not random urine testing 2/13/2019 4:48 PM 2/13/ :11 AM 9 sflc, SPEP and UPEP (urine IFE for abnormal UPEP) 2/13/2019 9:35 AM 10 Would use serum IFE with urine IFE or sflc 2/12/2019 5:56 PM 11 SPE does not add anything here. Suggest a staggered approach starting with IFE, if negative but clinical suspicion remains high, do sflc; if still negative, then urine IFE. 2/12/2019 5:00 PM hour not random urine 2/7/2019 6:32 PM 13 There are few studies of the gain in sensitivity of adding the urine IFE in this case. I would like to see the confidence intervals for the gain in sensitivity of adding the urine IFE. 2/6/ :01 AM 14 SPE ans sflc with Reflex serum testing. 2/6/ :04 AM 15 sflc is of dubious value. 2/6/2019 6:43 AM 16 it is not necesary 2/6/2019 5:59 AM 17 Do not agree urine IFE should be used in the initial detection. 2/5/2019 2:11 PM 18 Per NCCN guidelines urine protein electrophoresis is recommended. Should this also be ordered? 2/2/2019 4:18 PM 19 The urine must be a 24 hour specimen. 2/1/ :33 AM 20 Again, the serum immunofixation, sflc and urine IFE should be the initial test. serum immunofixation is more sensitive than SPE 1/31/ :09 AM 21 If we could add light chain quantification in urine also 1/31/2019 9:39 AM 22 sflc usually does not add value. 1/31/2019 6:55 AM 23 As sflc analysis is not available in all clinical laboratories, I would sugest to say sflc AND/OR uife. 1/30/2019 6:02 PM 24 IFE or MALDI-TOF 1/30/2019 5:43 PM Disclaimer The information, data, and draft recommendations provided by the College of American Pathologists are presented for informational and public feedback purposes only. The draft recommendations and supporting documents will be removed on March 1, The draft recommendations along with the public comments received and completed evidence review will be reassessed by the expert panel in order to formulate the final recommendations. These draft materials should not be stored, adapted, or redistributed in any manner. 13 / 35

14 Q8 Draft Recommendation Statement 5Clinical care providers should NOT order heavy/light chain isotype assay (HLC) for initial detection of monoclonal protein in patients with suspected MG.SOR: Strong ANSWER CHOICES Agree as written Agree as written Agree with suggested... Disagree. Include... Does not pertain to m... Agree with suggested modifications Disagree. Include comments in the box below Does not pertain to my area of expertise or practice Answered: 174 Skipped: 140 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% RESPONSES 82.76% % % % 20 TOTAL 174 # COMMENTS DATE 1 Ratio should be known in order to confirm myelomas 2/19/ :50 AM 2 Not for initial screen, although may be useful as a secondary assay. 2/11/2019 6:41 AM 3 IFE is better 2/7/2019 5:14 AM 4 Test may be useful pending the result of screening tests but should not be initial screening assay. 1/31/2019 9:28 AM 5 First SPE than free light chain assay 1/31/2019 1:16 AM 6 It depends of the clinical disease 1/30/2019 8:26 PM 14 / 35

15 Q9 Draft Recommendation Statement 6In patients with intact monoclonal proteins by SPE, laboratorians should use measurement of the M spike for quantification within the gamma region. SOR: Conditional ANSWER CHOICES Agree as written Agree as written Agree with suggested... Disagree. Include... Does not pertain to m... Agree with suggested modifications Disagree. Include comments in the box below Does not pertain to my area of expertise or practice Answered: 174 Skipped: 140 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 72.41% % % % 13 TOTAL 174 # COMMENTS DATE 1 Should be consistent with techique used, i.e. perpendicular drop or tangent skimming, not a mixture of both. Tangent skimming preferred technique for gamma region bands. 2 A caveat should be added that laboratorians should be consistent with their method of quantification and report changes and provide rebaselining when (if) method changes. 3 In very rare instances, we have a very large and narrow m-spike and the quantification is inaccurate because it is outside of the dynamic range of our scanner. This happens very rarely, so i would modify the statement to say "In most patients with intact monoclonal proteins..." 4 Not al lm-spikes are in the gamma region. the m spike should be quantitated wherever it is located. 5 Ideally, the term "M-spike" would not be used. Consider replacement with better language eg. monoclonal immunoglobulin (see Canadian recommendations by the CSCC 2018, Clin Biochem) RESPONSES 2/22/ :13 AM 2/21/ :27 AM 2/21/ :25 AM 2/20/ :55 PM 2/20/2019 9:12 AM 6 In patients with intact monoclonal proteins by SPE, laboratorians should use measurement of the M spike for quantification in any region provided that the M-spike is clearly distinguishable. 2/20/2019 8:20 AM 7 This should be done in all regions, including the beta region when obviously present. 2/18/ :13 AM 15 / 35

16 8 For some patients it might be beneficial to monitor quant Ig as well, e.g., if there's a second peak that comes & goes over time 2/15/2019 4:46 PM 9 Quantitative immunoglobulin testing is more accurate, if there is not one standard for how the total protein used in density estimation is derived. Example: if total protein is measured with nephelometry, it is usually more accurate than colorimetry/dye-based total protein quants. The colorimetric quant's fluctuate with dye-binding error. So I do NOT accept a standard of estimating M-spike density based off this potentially-variable parameter. 10 M spike is outdated and confusing terminology. Paraprotein is more accurate. Paraproteins may be biclonal or oligoclonal. The "spike" refers to the electrophoretic pattern but clonality is determined by IFX. 11 "M spike" is terminology that should be avoided, it is confused with IgM. There is a long history of using it but in the laboratory it is a paraprotein and not necessarily a myeloma related protein. 2/15/2019 1:54 PM 2/15/ :35 AM 2/14/2019 7:38 AM 12 or beta region (some M-spikes are not in gamma) 2/13/ :11 AM 13 The effect of background proteins on the M quantification applies to both beta and gamma region and depends on the relative sizes of the M-spike and the background proteins. SPE location is not the determining factor. 2/12/2019 5:00 PM 14 Quantitation by neph/turb is more accurate 2/11/2019 7:05 AM 15 unless the m-spike is below 0.5g/dL 2/8/2019 3:42 AM 16 Not all M spikes are in gamma region 2/7/2019 6:32 PM 17 We also give estimation of M-component when there are clear spikes in beta regions (only when it exceeds the normal range of beta region) with an additional statement indicating that quantitation is only approximation as it overlaps with B region 2/7/2019 3:25 PM 18 Is there a recommendation to integrate by tangent skimming vs. perpendicular drop? 2/6/2019 4:52 PM 19 If the measurements are done in the same laboratory, since measuring of M-spike is subjective and operator dependent. This may lead to variations of +/ mg/dl. 20 In patients with intact monoclonal proteins by SPE, laboratorians should use measurement of the M spike for quantification. 2/6/2019 4:32 PM 2/6/2019 2:52 PM 21 Some monoclonal spikes aren't in the gamma region 2/2/2019 1:40 PM 22 While this is the standard, there is considerable variation due to placement of markers for calculation of area under the curve by different technologists. This problem is greatest in 'broadbased' spikes. However, as things stand with M-spike being part of diagnostic/monitoring algorithms, we are stuck with this. 23 As long as there is no signification background polyclonal immunoglobulins present relative to the the concentration of the m-component 1/31/ :50 PM 1/31/2019 2:05 PM 24 To be strong not conditional 1/31/2019 9:39 AM 25 This applies to any monoclonal protein that can be detected in the gamma region, whether intact or free. 1/31/2019 9:37 AM 26 M spike may be any where from alpha-1 to gamma 1/31/2019 9:04 AM 27 Criteria for perfoming quantification by integral analysis should be established. 1/31/2019 7:18 AM 28 measure in any region...beta or even alphas 1/31/2019 6:47 AM Disclaimer The information, data, and draft recommendations provided by the College of American Pathologists are presented for informational and public feedback purposes only. The draft recommendations and supporting documents will be removed on March 1, The draft recommendations along with the public comments received and completed evidence review will be reassessed by the expert panel in order to formulate the final recommendations. These draft materials should not be stored, adapted, or redistributed in any manner. 16 / 35

17 Q10 Draft Recommendation Statement 7In patients with intact monoclonal proteins by SPE, laboratorians should use total IgA for the quantification of the IgA monoclonal proteins outside the gamma region. SOR: Conditional ANSWER CHOICES Agree as written Agree as written Agree with suggested... Disagree. Include... Does not pertain to m... Agree with suggested modifications Disagree. Include comments in the box below Does not pertain to my area of expertise or practice Answered: 174 Skipped: 140 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 55.17% % % % 20 TOTAL 174 # COMMENTS DATE 1 This recommendation, I believe is too all inclusive. We commonly see patients that have betamigrating M-proteins that are clearly separated from the normal beta bands, i.e. between the two bands. It might be better to state that if the monoclonal protein can not be clearly distinguished from the normal beta bands, that the total IgA concentration may be useful for quantification. 2 Concentration of measured total IgA unlikely to bear any resemblance to monoclonal concentration. Monoclonal proteins do not react equimolarly with polyclonal antisera. 3 An additional statement should be made that except for IgA, quantification of total Igs is of limited utility. RESPONSES 2/22/ :51 PM 2/22/ :13 AM 2/21/ :27 AM 4 What about IgM or IgZG monoclonals outside the gamma region? They do occur. 2/20/ :55 PM 5 We usually report it as semiquantitative if it is not in the gamma region! 2/20/ :27 PM 6 If reporting out this way, would only do so with a disclaimer/explanation as to the methodology 2/20/ :18 AM 17 / 35

18 7 There can be situations where monoclonal proteins outside the gamma region can be uniquely quantified without influence of fractional background proteins. 8 We observe monoclonal peaks outside of the gamma region that are distinguishable from background proteins. We believe they should be quantitated by SPE. 2/20/2019 9:12 AM 2/20/2019 8:20 AM 9 Both an M-spike in the beta region and IgA quantification will contain a normal protein fraction. There is not strong evidence that following IgA quants in these cases improve patient outcomes. 10 Not sure why this would be limited to just IgA. It can be a pain to figure out what part of the beta is MPT for any isotype, if the M-spike overlaps it 2/18/ :13 AM 2/15/2019 4:46 PM 11 I submit that IgM should similarly be quantified. 2/15/2019 1:54 PM 12 Prefer a comment suggesting that clinicians order and follow IgA levels rather than performing reflex testing and using results to quantify an IgA monoclonal band which may have an excess of light chains. 13 This is much more conditional than other recommendations here. Some IgAs run in gamma region and can be quantiated adequately from the SPEP. 14 M spike in the beta region should be measured and results are useful for tracking the change in level. 15 Both total IgA and peak measurements of IgA monoclonal gaoathies provide relative comparable results to confirm responses to new therapies. 2/15/ :35 AM 2/14/ :34 PM 2/13/2019 4:48 PM 2/13/2019 3:30 PM 16 Agree- reduces overestimation of the M component by superimposed protein fractions. 2/13/2019 1:47 PM 17 bands outside the gamma region should not be quantified, clinicians should follow the serum total IgA concentration to monitor 18 It makes no difference between the two; both carry a high degree of uncertainty wrt the actual amount of monoclonal proteins present. 19 Depends somewhat on the location of hte M protein. On split beta gels, you can occasionally get an M protein that migrates between the two beta bands, allowing fairly accurate quantitation. For M proteins in the beta region, we routinely comment when they overlap the normal betas that "due to overlap with beta proteins quantiation will overestimate the amount of M protein present". 2/13/2019 9:35 AM 2/12/2019 5:00 PM 2/11/2019 6:41 AM 20 Use measured IgA M-protein 2/10/2019 9:37 PM 21 It is possible to quantify it using SPE in B region as well. 2/10/2019 9:36 AM 22 or preferably the respective Hevylite Assay, if available 2/8/2019 3:42 AM 23 Could use either total IgA or measurement of M spike. 2/7/ :25 AM 24 In addition to quantification of the M spike? 2/6/2019 4:52 PM 25 In techniques that split Beta-1 and Beta-2 regions, sometimes accurate quantitation of the spike is possible. Must be done on a case by case basis. 26 quantitative IgA value from nephelometry may be useful for monitoring; but quantitative value for IgA may not correlate with values obtained from electrophoretic scan. 27 In patients with intact monoclonal proteins by SPE, laboratorians should use total IgA for the quantification of the IgA monoclonal proteins is hard to quantified. 2/6/2019 4:32 PM 2/6/2019 3:33 PM 2/6/2019 2:52 PM 28 I feel that SPEP still represents a better measure than total 2/6/2019 2:28 PM 29 There is no evidence that this practice leads to better clinical outcomes than other approaches to quantifying monoclonal proteins. 2/6/ :01 AM 30 The peak in beta region can be quantified and results are useful in monitoring progress 2/6/2019 6:43 AM 31 why? 2/6/2019 5:59 AM 32 Normally we see IgA co-migrating with beta globulins and we report total beta globulin concentration in our laboratory. I do agree using total IgA concentration in these cases, but reporting total beta globulins may also be an option. 2/5/2019 2:11 PM 33 Some peaks do not overlap with the serum fractions and are easy to quantify 2/5/ :47 AM 34 Should quantitate M-Spike from SPE when possible and clear 2/5/2019 6:27 AM 18 / 35

19 35 I would suggest that if the IgA band does not overlap with other normal bands it may be possible to quantitate the spike 36 Are the total IgA methods imfluenced by degree of IgA polymerization? Also concern about background polyclonal IgA in patients with GI tract inflammation 1/31/2019 2:17 PM 1/31/2019 2:05 PM 37 Monoclonal IgA can also be estimated by subtracted normal average concentration of beta 1 or Beta 2 band size in many cases. 1/31/ :06 AM 38 To be strong 1/31/2019 9:39 AM 39 Total IgA along with M-spike quantification may be appropriate depending on the degree of overlap between the M-spike and the normal background beta-globulins. 40 The SPE should indicate that any monoclonal protein outside of the gamma region should be quantified by the total Ig. IgG can also occur outside gamma in rare cases, as can IgM. 1/31/2019 9:37 AM 1/31/2019 9:28 AM 41 IgA is usually in the Beta to fast gamma region 1/31/2019 9:04 AM 42 Depends on how well can demarcate spike on SPE 1/31/2019 8:04 AM 43 Since not all beta region M-proteins are IgA, clinicians should be directed to include direct quantification of all beta region gammopathies. 44 M spike in the beta region should be measured and results are useful for tracking the change in level. 1/31/2019 7:18 AM 1/31/2019 6:55 AM 45 we can add HLC 1/30/ :43 PM 46 Recommendation should not be restricted to IgA. Though IgA is the Ig more frequently comigrating with the beta globulins, IgM and IgG also can migrate outside the gamma region. Recommendation should be for all Ig. 1/30/2019 6:02 PM 47 Hevylites is a good predictor of monoclonal in outside gamma región 1/30/2019 5:57 PM 48 No 1/30/2019 5:55 PM 49 Does this recommend or automatically reflex to using the total IgA for quantification 1/30/2019 5:43 PM Disclaimer The information, data, and draft recommendations provided by the College of American Pathologists are presented for informational and public feedback purposes only. The draft recommendations and supporting documents will be removed on March 1, The draft recommendations along with the public comments received and completed evidence review will be reassessed by the expert panel in order to formulate the final recommendations. These draft materials should not be stored, adapted, or redistributed in any manner. 19 / 35

20 Q11 Draft Recommendation Statement 8Laboratorians should report both quantitative levels and kappa/lambda ratio when the sflc assay is performed.sor: Conditional ANSWER CHOICES Agree as written Agree as written Agree with suggested... Disagree. Include... Does not pertain to m... Agree with suggested modifications Disagree. Include comments in the box below Does not pertain to my area of expertise or practice Answered: 174 Skipped: 140 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 89.08% % % % 6 TOTAL 174 # COMMENTS DATE 1 sflc assay does not add value. It is neither diagnostic of any condition, nor does it exclude any condition. 2/13/2019 4:48 PM 2 and if the ratio or quantities exceed the IMWG guidelines, report that as well. 2/6/ :06 AM 3 sflc assy does not add value and is not a useful test. 2/6/2019 6:43 AM 4 Renal impairment should alter reference ranges. 2/2/ :30 AM 5 Please also report that K - L difference as this is the criteria used for disease progression in international myeloma working group guidelines. 6 This should be a strong recommendation, as this assay can only be interpreted accurately when all values are available. RESPONSES 2/1/ :33 AM 1/31/ :28 PM 7 To be strong 1/31/2019 9:39 AM 8 sflc assay does not add value. It is neither diagnostic of any condition, nor does it exclude any condition. 1/31/2019 6:55 AM 20 / 35

21 Q12 Draft Recommendation Statement 9Clinical care providers should use abnormal sflc ratio, and 1.5 g/dl (15 g/l) value of intact monoclonal proteins as criteria for higher risk of progression in patients with monoclonal gammopathy.sor: Conditional ANSWER CHOICES Agree as written Agree as written Agree with suggested... Disagree. Include... Does not pertain to m... Agree with suggested modifications Disagree. Include comments in the box below Does not pertain to my area of expertise or practice Answered: 174 Skipped: 140 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 66.67% % % % 34 TOTAL 174 # COMMENTS DATE 1 This only applies to IgG monoclonals, lower cut-off used for IgA and IgM bands 2/22/ :13 AM 2 THIS IS NOT A GOOD IDEA. THESE CUT-OFFS WERE PROPOSED IN RETROSPECTIVE MAYO CLINIC STUDIES FOCUSING ON MGUS. GIVEN THAT THESE ASSAYS ARE USED IN MGUS, SMM, AND MYELOMA IT WILL BE CONFUSING. THE FACT THAT THE CUT-OFFS ARE DERIVED FROM RETROSPECTIVE DATABASES MAKE THEM NON-OPTIMAL AND QUITE UNCERTAIN. 3 With emphasis on intact monoclonal proteins, no mention is made of reflexing to IgD and IgE when only light chains are found. Not all laboratories currently have that protocol. We do and have found a number of IgD and IgE monoclonal proteins. RESPONSES 2/20/2019 8:20 AM 2/15/ :35 AM 4 Abnormal sflc ratio does not add value. It is not uncommon to see kappa dominant K/L ratio in patients with lambda chain associated MG. 2/13/2019 4:48 PM 5 Defer to hem/onc clinician 2/13/2019 3:58 PM 21 / 35

22 6 The original study also included Ig isotype. Also, these criteria apply to risk prediction in MGUS and not any monoclonal gammopathic conditions. 2/12/2019 5:00 PM 7 May use the criteria 2/10/2019 9:37 PM 8 Agree provided that the statement is rewritten to emphasize that BOTH criteria are required. 2/7/ :25 AM 9 I feel other genetic markers should be used and other markers 2/6/2019 2:28 PM 10 Abnormal sflc ratio is not useful. What would you make of a kappa dominant k/l ratio in a patient with IgG lambda monoclonal Ig? 2/6/2019 6:43 AM 11 And heavy chain type 2/5/ :31 AM 12 Also include a non-igg isotype M-protein, as per Rajkumar paper. 2/1/ :33 AM 13 Seems hard to use this as written. Is this both abnormal ratio AND spike >1.5 or is it either one? Also, is there a lower limit of the sflc ratio below which it is not as informative? 1/31/2019 2:17 PM 14 Would also include non-igg type monoclonal protein as a risk factor. 1/31/ :28 PM 15 Abnormal sflc ratio does not add value. It is not uncommon to see kappa dominant K/L ratio in patients with lambda chain associated MG. 16 CONSIDER EVALUATING DIFFERENCE AND RATIO OF INVOLVED SFLC AND NOT INVOLVED SFLC Disclaimer The information, data, and draft recommendations provided by the College of American Pathologists are presented for informational and public feedback purposes only. The draft recommendations and supporting documents will be removed on March 1, The draft recommendations along with the public comments received and completed evidence review will be reassessed by the expert panel in order to formulate the final recommendations. These draft materials should not be stored, adapted, or redistributed in any manner. 1/31/2019 6:55 AM 1/31/2019 1:35 AM 22 / 35

23 Q13 Draft Recommendation Statement 10Clinical care providers may use the non-igg isotype as a risk factor for progression to multiple myeloma or a B-cell lymphoproliferative disorder.sor: Conditional ANSWER CHOICES Agree as written Agree as written Agree with suggested... Disagree. Include... Does not pertain to m... Comments Agree with suggested modifications Disagree. Include comments in the box below Does not pertain to my area of expertise or practice Comments Answered: 174 Skipped: % % % % % 0 TOTAL 174 # COMMENTS DATE There are no responses. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% RESPONSES 23 / 35

24 Q14 Comments Answered: 6 Skipped: 308 # RESPONSES DATE 1 Cut-off of 10g/L used as risk factor for IgA and IgM monoclonals, IgD or IgE monoclonals risk factors irrespective of concentration and urine free light chain monoclonal >0.5g/L. 2 THIS IS NOT A GOOD IDEA. THESE CUT-OFFS WERE PROPOSED IN RETROSPECTIVE MAYO CLINIC STUDIES FOCUSING ON MGUS. GIVEN THAT THESE ASSAYS ARE USED IN MGUS, SMM, AND MYELOMA IT WILL BE CONFUSING. THE FACT THAT THE CUT-OFFS ARE DERIVED FROM RETROSPECTIVE DATABASES MAKE THEM NON-OPTIMAL AND QUITE UNCERTAIN. 2/22/ :13 AM 2/20/2019 8:20 AM 3 Same comment regarding testing for IgD and IgE 2/15/ :35 AM 4 The statement itself is true but what is the purpose of this in isolation? 2/12/2019 5:00 PM 5 I prefer to remove not to cause misleading 1/31/2019 9:39 AM 6 This should be clarified if it refers to only IgA. 1/31/2019 9:28 AM Disclaimer The information, data, and draft recommendations provided by the College of American Pathologists are presented for informational and public feedback purposes only. The draft recommendations and supporting documents will be removed on March 1, The draft recommendations along with the public comments received and completed evidence review will be reassessed by the expert panel in order to formulate the final recommendations. These draft materials should not be stored, adapted, or redistributed in any manner. 24 / 35

25 Q15 Draft Recommendation Statement 11Clinical care providers may use immunoparesis as a risk factor for progression to multiple myeloma or a B-cell lymphoproliferative disorder.sor: Conditional ANSWER CHOICES Agree as written Agree as written Agree with suggested... Disagree. Include... Does not pertain to m... Agree with suggested modifications Disagree. Include comments in the box below Does not pertain to my area of expertise or practice Answered: 174 Skipped: 140 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 55.75% % % % 61 TOTAL 174 # COMMENTS DATE 1 Needs clarification on concept of immunoparesis 2/21/ :27 AM 2 THIS IS NOT A GOOD IDEA. THESE CUT-OFFS WERE PROPOSED IN RETROSPECTIVE MAYO CLINIC STUDIES FOCUSING ON MGUS. GIVEN THAT THESE ASSAYS ARE USED IN MGUS, SMM, AND MYELOMA IT WILL BE CONFUSING. THE FACT THAT THE CUT-OFFS ARE DERIVED FROM RETROSPECTIVE DATABASES MAKE THEM NON-OPTIMAL AND QUITE UNCERTAIN. 2/20/2019 8:20 AM 3 Defer to hem/onc clinician 2/13/2019 3:58 PM 4 recommend using "hypogammaglobulinemia" instead of "immunoparesis" 2/13/ :11 AM 5 The statement itself may be true but is there a point in repeating what's been known for decades? 2/12/2019 5:00 PM 6 immunoparesis in the presence of a monoclonal peak should be reported as a pattern strongly suggestive of multiple myeloma. RESPONSES 2/6/ :06 AM 7 A definition of immunoparesis should be given 2/5/ :47 AM 8 Recent paper and my opinion suggests otherwise 1/31/2019 8:39 AM 25 / 35