Jo Gilbertson
Good afternoon and welcome to Noridian's Open Public Meeting. My name is Jo Gilbertson and I am one of the Medical Policy Specialists at Noridian Healthcare Solutions.

Today we'll be discussing multiple MolDX proposed LCDs.

Next slide.

Noridian is presenting the three following proposed LCDs:

MolDX: Next Generation Sequencing for Hematologic Malignancies and Suspected Hematologic Malignancies, DL40427.

MolDX: Transcriptional Biomarkers for Therapeutic Decision Making in Renal Carcinoma, DL40435.

MolDX: Genome-Wide Molecular Methodologies for the Detection of Copy Number Alterations and Structural Variants in Hematologic Neoplasms (DL40411)

Before we begin this meeting, I would like to make a few of the following announcements. This meeting will be recorded. Our recording and written transcript will be posted on our website following today's meeting. All lines are currently being muted and will remain muted throughout the meeting. Only those who registered to present will be allowed to comment on the proposed LCDs today. If closed captioning as needed, please click the closed caption icon on the bottom right hand of the corner of your screen. For those of you that are presenting, your comments with slides or verbal comments. You are being allotted 15 minutes to make comments. Your lines will be open when it is your turn to speak. Please be prepared to begin your comments immediately when called upon. Make sure you are not on mute within your own system or we will not be able to hear your comments. Please speak clearly to ensure the system will be able to translate into captions for display. You will hear the moderator's voice when one minute remaining. If you reach the end of your 15 minute time limit, your line will be muted and we will continue to the next proposed policy.

By signing in today, you are giving consent to use to the use of your recorded voice and your comment. Please be mindful of sharing any personal health information during your presentation. In addition to comments that are made today, all comments should also be submitted in writing to ensure that all cited literature can be fully reviewed and considered during the LCD development process. Commentors who reference public studies, articles, or other supporting evidence should submit a complete copy of each cited document with their comments. References provided without an accompanying full text copy may not be considered if the full text cannot be obtained for review. All written comments received will be recorded in response to comments article.

I'll now turn this meeting over to Dr. Rajadhyaksha. You may begin.

Next slide.

Dr. Aparna Rajadhyaksha
Thank you, Jo.

This is Dr. Aparna Rajadhyaksha representing Noridian. Our first LCD is MolDX: Next-Generation Sequencing for Hematologic Malignancies and Suspected Hematologic Malignancies.

Next slide, please.

This policy describes and clarifies coverage for Lab-Developed tests and FDA-approved or cleared clinical lab tests utilizing Next-Generation Sequencing (NGS) in cancer. This policy scope is specific for hematologic malignancies and suspected hematologic malignancies. It is exclusive of solid tumor testing, circulating tumor cell DNA, and other cancer-related indications for NGS, such as germline testing, minimal residual disease, or response to therapy.

Next slide, please.

So for the coverage guidance, we have the patient has one of the following. A. A confirmed hematologic malignancy in accordance with the current national or international consensus diagnostic guidelines and is undergoing evaluation at the time of initial diagnosis, disease progression, transformation, representing an a priori change in genetic content or clinical relapse or, an undiagnosed but highly suspected hematologic malignancy in accordance with current national or international consensus guidelines as above, and a standard evaluation to rule out benign or reactive causes has been performed as documented in the medical record.

Next slide, please.

Two, at least one of the following is true. Molecular profiling is required for definitive disease classification according to the current WHO or ICC frameworks and classification has not yet been fully established by other non-NGS genetic testing; or molecular profiling is necessary to direct immediate clinical management, inclusive of targeted therapy selection, decisions regarding treatment intensity or determination of hematopoietic stem cell transplantation eligibility as established by national clinical practice guidelines, such as those from NCCN, has not been established by any other non-NGS testing.

Next slide, please.

Three, the patient has not been previously tested for the same or similar genetic content for clinically actionable genetic information for the same intended use.

Four, the test is being used in a patient who is part of the population in which the test was analytically validated and according to the intended use of the test.

Five, the assay performance include at least the minimum genes and genomic positions required for the identification of clinically relevant FDA approved therapies with a companion diagnostic biomarker, as well as other biomarkers known to be necessary for clinical decision making for its intended use that can be reasonably detected by the test. Because these genes and variants will change as the literature and drug indications evolve, they are listed separately in the associate documents such as the MolDX technical assessment forms.

Six, the test has completed a technical assessment by MolDX to verify that analytic validity, clinical validity, and clinical utility standards are met for the stated indications of the test, next slide, please.

So at this point, I will ask Dr. Ghobrial and or Dr. Sperling to give their comments for this LCD, for this proposed LCD. Sorry. Thank you.

Dr. Irene Ghobrial
Thank you. Good afternoon. We are again thankful for the Noridian Medical Directors for hearing us. And my name is Irene Ghobrial. I'm a Professor of Medicine at Dana-Farber Cancer Institute. And I have here with me Adam Sperling, who's an assistant professor at Stanford University. Adam.

Dr. Adam Sperling
Yeah, thank you for inviting us to present our comments.

Dr. Irene Ghobrial
Next slide, please.

We introduced ourselves, but I just want to say that I've been practicing in multiple myeloma for over 21 years at Dana-Farber Cancer Institute now, working in the area of myeloma, but also precursors with MGUS and smoldering myeloma. Adam?

Dr. Adam Sperling
Yeah, so I'm also a researcher and clinician. I recently moved to Stanford, but I'm the also studying both multiple myeloma and precursors, and I'm the leader of myeloma translational research here at Stanford Cancer Institute.

Dr. Irene Ghobrial
Next slide, please.

This is our disclosures, and we want to highlight here that I'm a founder and board member and consultant for Predicta Bioscience and then consulting for many other pharmaceutical companies. Adam.

Dr. Adam Sperling
Yeah, I think the only relevant disclosure here is that I've consulted for Predicta Biosciences as well.

Dr. Irene Ghobrial
Next slide, please.

So we just want to first say thank you for providing this MolDX LCD because it does provide a lot of benefit for our patients with multiple myeloma, and for many years, we've been working as translational researchers as well as clinicians seeing patients with multiple myeloma. And we've been using FISH, which has been providing for us some benefit, but not full benefit for understanding the genomic changes that occur in our patients but also guiding therapy and helping us understand how to classify our patients. Recently, the International Myeloma Society, as well as NCCN guidelines have changed this, and we are now indicating that we need NGS for providing care for our patients. We do want to highlight three specific areas that we want to discuss with the directors here. The first one is the coverage for smoldering myeloma, which is not currently provided specifically in the plasma cell neoplasms for an ICD-10.

The second one will be related to the specimen types and just clarifying that bone marrow, blood, and extra medullary sites could be involved in multiple myeloma.

And the third one will be the timing of defining who is relapsing and progressing so that we can provide therapy at the timing of those patients and not be exactly at the six months' time point. Next slide.

The first one that we want to discuss here is the recommendation for the NGS, which, as you indicated, is providing for all plasma cell neoplasms, including multiple myeloma, plasma cell leukemia, and others. And all of these are usually provided within ICD-10 of C90. However, there is a problem with that is that when we see patients with smoldering myeloma, and I'll go through that in the next few slides, we currently code them with an ICD-10 of D47.2, which is not under the multiple myeloma ICD-10. And that's critical because we will not be able to cover our patients who are currently in need for this NGS testing. Next slide.

And this is just giving you some highlight of why smoldering myeloma is very critical. So the precursors to multiple myeloma are two of them. One of them is called MGUS, monoclonal gammopathy of undetermined significance. And then when it progresses, it goes to smoldering myeloma. And then those patients progress to active multiple myeloma. Genomically, there is no difference between smoldering myeloma and active multiple myeloma. The only difference is when they develop end organ damage, which is fractures in their bones or anemia or renal failure. When we're seeing patients with smoldering myeloma, we're trying to define whether they have active disease because we treat them specifically for active myeloma. But even high risk smoldering myeloma right now is being treated with daratumumab.

Last year, we just received FDA approval for the first drug to be approved for smoldering myeloma, and that is Daratumumab. But there are many other drugs being tested right now for potential approval in the future. And this is important because we are treating patients with this ICD-10, which is different than the one that is for multiple myeloma. And currently, it is critical for us to decide whether they're high risk or not. Next slide.

Now, this gives you the alterations that we see in smoldering myeloma, which are exactly the same that we see in multiple myeloma. And you see many manuscripts that were published by others as well as our groups that show that indeed these can highlight for you who is high risk and who has the high chance of progressing to active multiple myeloma. Next slide.

And I'm highlighting here that these alterations are actually important to be detected by NGS. We cannot detect those by FISH. So translocations can be defined by FISH, but here we need NRAS, KRAS mutations, which are single nucleotide variants, as well as MYC alterations. And these are essential for us to show by NGS, and they are predictors of outcome, whether those patients would progress rapidly to overt myeloma and whether we decide to treat them with their tumumab (incoherent) or other drugs in the future. And as you can see from this, most of those studies were done by either whole genome sequencing or whole exome sequencing and not by targeted sequencing panels. Adam?

Dr. Adam Sperling
Yeah, I think it just highlights that NGS is really required as we begin, as we risk stratify patients with smoldering multiple myeloma. Risk stratification is now essential because we have therapies for high-risk patients. And so it's just important that we be able to accurately stratify our patients so we can just define those who will benefit from therapy.

Dr. Irene Ghobrial
Next slide.

And this is just giving you again that NCCN guidelines for smoldering myeloma does have the part of multi-gene panel testing. And we are now trying to clarify further that indeed next generation sequencing is critical for those patients. Next slide.

We'll move on to our second one, which is about the type of specimen that we're looking for, whether it's not just bone marrow, but also blood or extramedullary site. And I'll give Adam the opportunity to discuss this one.

Dr. Adam Sperling
Yeah, so this is really our second point, which is to explicitly recognize the clinically appropriate invalidated specimen types associated with plasma cell neoplasms. So I think right now the current DL number doesn't specify the specimen types, we want to make sure that this is included. And so we would propose including language that includes bone marrow, peripheral blood, or extramedullary sites that are suspected of harboring the hematologic malignancy for cases where the assay is validated for that type of specimen. And so we don't want to make a you know, blanket equivalence between specimen types, but really just that in individual patients, it may be appropriate to obtain samples from specific specimen types. So next slide, please.

So why is this important? So multiple myeloma is a, can be a patchy disease. It often includes the, you know, involves bone marrow, but not always. It can either, sometimes be patchy within the bone marrow itself. And these PET scans show some of that where you can see focal uptake within regions within bone, or it can actually be extramedullary disease, so disease outside the bone marrow. And in many cases in patients that have extramedullary disease, often the bone marrow burden can be quite low. And then, of course, there can also be circulating cells. Multiple groups have shown this. And these circulating cells actually represent the tumor sites. And so I think it's important that we be able to obtain samples from whatever site, wherever site there is disease. So that might be bone marrow in some patients. It might be a focal lesion in the bone in another patient. It could be an extramedullary site you know, a soft tissue plasmacytoma in another patient. And in some patients where we can't obtain, either safely obtain a biopsy of a site or where the bone marrow is not clearly involved, we can actually obtain samples from the peripheral blood.

Dr. Irene Ghobrial
And I just want to highlight that circulating tumor cells are prognostic in our patients with multiple myeloma and occur in the majority of patients. And indeed, in some of our patients where we're giving them CAR-T or other therapies where the bone marrow may not be sufficiently involved, we may actually see circulating tumor cells that may be reflective of other sites or extramedullary disease. Next slide.

Adam?

Dr. Adam Sperling
Yes. And then so our third point has to do with the timing of NGS testing. Currently, the way this is written is that multiple claims within six months may be suspended for review because the LCD only allows for testing at the initial diagnosis or confirmed relapse. So we agree that we shouldn't be performing unnecessary repeat testing on short interval. But I'm not sure that six months should be an automatic delay because we certainly have patients that progress our relapse much sooner.

And so we'd like to sort of make that distinction.

And so, next slide, please.

And so I think this is just, you know, not just a theoretical concern. These are data from patient cohorts. On the left here is the CARTITUDE 4 data. This was data that led to approval of CAR T-cells in patients with multiple myeloma. And you can see that up to 35% of patients in this randomized phase three trial progressed in six months or less. And so it's very important that as patients progress, as you reevaluate them and reevaluate them for next line of therapy, that you be able to kind of fully restage them and assess the molecular status of their tumor.

And then this is even more of an important feature in patients that are sort of multi-refractory to therapy. So these are patients that are hepta-refractory going on to get cellular therapy. And you can see that the majority of patients who are multi-refractory are going to progress in less than six months, and so these are particularly patients in which we need NGS testing in order to identify mutations, you know, in cell therapy targets, for example, that might predict their response or refractoriness to subsequent lines of therapy. And so I think certainly many of our patients unfortunately progress in under six months, so we don't want to limit testing to, you know, six months or greater in patients that have a medical need.

Dr. Irene Ghobrial
And I just want to highlight that this is reality. Unfortunately, this is what we're seeing in the clinic all the time. And it is truly essential as we're cycling from one therapy to the other. When we're seeing those patients, they're rapidly progressing. We're trying to make a decision whether we put them on a BCMA or GPRC5Z therapy, CAR T and others, which are very expensive, but also toxic for our patients. So if we pick something because they do have a BCMA mutation or a deletion, that's critical for us to avoid unnecessary toxicity for our patients. So that need is actually very critical for the NGS testing for us to make a decision for our patients at that time. Next slide.

So we just want to, oh, go ahead, Adam. No, no, no. So, go ahead.

Dr. Adam Sperling
I was just going to say, yeah, we just want to summarize the request here. So I think request one, just summarizing the data that Dr. Ghobrial presented, we adding the ICD-10 code 47.2, which is for smoldering multiple myeloma, so that medically necessary NGS testing is covered for these patients. So we can define risk and define the population of patients that may need, may warrant early intervention with therapy.

The second thing is that we want to explicitly allow the clinically appropriate and validated testing on different tissue types, so bone marrow, peripheral blood, or extramedullary specimens that may be required for patients with different presentations of plasma cell neoplasms.

And third, just clarifying the testing interval, that while six months is reasonable for many patients, there are many patients with multiple myeloma who progress or relapse much faster than six months, and who will need repeat testing in shorter intervals of time in order to define their next line of therapy and provide them for the optimal therapy that minimizes, you know, unnecessary toxicity.

And so on the next slide, we've provided lists of peer-reviewed references, many of which we cited in our comments. And I think these will also be included in our written comments. And, you know, we're certainly thankful for the opportunity to comment on this really important proposed policy, and we welcome any questions or correspondence going forward. Irene, do you have any other additional comments?

Dr. Irene Ghobrial
No, absolutely agree. And we again want to thank you for giving us the opportunity to present some of the points that we wanted to highlight here.

Dr. Aparna Rajadhyaksha
Thank you, Dr. Ghobrial and Dr. Sperling for very valuable comments. We do appreciate and value all your comments which you've made. I mean, and this is a platform for it, right? Please let us know where we could improve. So we look forward to having your comments in writing so we can address them as such and either incorporate them or let them know a reason why we cannot.

But thank you again for coming on. We appreciate it.

Dr. Irene Ghobrial
Thank you.

Dr. Adam Sperling
Thank you.

Dr. Aparna Rajadhyaksha
Our next LCD is MolDX, Genome-Wide Molecular Methodologies for the Detection of Copy Number Alterations and Structural Variants in Hematologic Neoplasms DL40411.

Next slide, please.

Testing by non-next generation sequencing for the diagnosis of myeloproliferative neoplasms must also fulfill the criteria as outlined in L39923 MolDX: Non-Next Generation Sequencing Test for the Diagnosis of BCR-ABL Negative Myeloproliferative Neoplasms.

Must also fulfill the criteria outlined in L38123, sorry, MolDX: Next Generation Sequencing Lab Developed Tests for Myeloid Malignancies and Suspected Myeloid Malignancies. And testing for response to therapy or minimal residual disease is out of scope of this policy and must fulfill the criteria outlined.

L38814 MolDX Minimal Residual Disease Testing for Cancer. Next slide, please.

Genome-Wide Molecular Assays for the Detection of Copy Number Alterations and Structural Variance in Hematologic Malignancies are covered when all of the following criteria are met.

One, the patient is undergoing workup for hematopoietic neoplasm and the results of the testing will inform either A, diagnosis in accordance with current expert or professional guidelines, such as WHO, ICC, or myeloid and lymphoid myeloid disease, and other reasonable possible causes have been considered and excluded as documented in the medical record or clinical management in accordance with the current expert or professional guidelines such as the NCCN, at the time of initial neoplastic diagnosis made by non-molecular testing like flow cytometry or morphology upon non-molecularly confirmed progression or relapse. A. MRD testing is not considered within scope of the cell CD. Next slide, please.

Two, testing for CNAs and SVs or structural variants has not already been performed and is not in the process of being performed by another genome-wide molecular methodology or by multiple, more than one chromosomal and or molecular methodologies, example chromosome banding, or FISH, chromosomal microarray, NGS, et cetera, unless one of the following apply. A. A rapid targeted test was performed for PML-RARA to evaluate for acute promyelocytic leukemia or BCR-ABL to inform initiation of therapy in leukemia, and additional genomic information is necessary. B, the patient was confirmed to have a hematologic malignancy by flow cytometry histology and a complete genomic workup using standard chromosomal molecular assays as above showed a complete absence of abnormalities. C, the patient previously had an oncologic workup for the same indication utilizing standard chromosomal molecular assays, as above, that was negative and presents with further signs or symptoms, such as worsening blood counts, suggestive malignancy, or progression of malignancy, in accordance with expert or professional guidelines, (as above) and as documented in the medical record. Next slide, please.

Three, the test has satisfactorily completed a technical assessment or TA by the Molecular Diagnostic Services Program to ensure analytic validity, clinical validity, and clinical utility standards are met. This test demonstrates detection accuracy for targeted analysis compatible or superior to current gold standards of testing.

B. The test demonstrates detection accuracy for targeted and analytes, comparable or superior to other genome-wide tests that are met coverage criteria under this policy. C, the test has been validated in the intended use population and with the intended use sample types. Next slide, please.

We do not have any requests for comments for that policy, so I will go into the next one.

The final one, MolDX: Transcription Biomarkers for the Therapeutic Decision Making in Renal Cell Carcinoma, DL40435. Next slide, please.

Coverage indications, molecular and proteomic transcriptional biomarkers for therapeutic decision-making in renal carcinoma are currently not covered by this contractor. However, should evidence be further developed to meet reasonable and necessary standards, such tests may be considered for coverage when all of the following criteria are met.

One, the patient is being managed for a diagnosis of renal cell carcinoma according to national or international consensus guidelines such as the NCCN or the AUA.

Two, the patient is a candidate for multiple potential treatments and at least one of the following is true. A, the therapies under consideration have varied levels of intensity based on a consensus guideline, and the physician and the patient must decide among these treatments, or the test has shown that it predicts response to specific therapeutic intervention among accepted therapy options based on nationally recognized society guidelines, such as NCCN, AUE, ASCO, or Urologic Oncology Society guidelines. Next slide, please.

The patient has not been previously tested with the same test or other comparable tests for the same intended use.

Four, the test demonstrates significant improvement in accuracy for identifying risk of recurrence or metastasis or for predicting a therapeutic response compared to available information in the clinical medical record. Next slide, please.

Five, testing is performed according to the intended use of the test in the intended patient population for which the test was developed and validated.

Six, if the test relies on an algorithm, the algorithm must be validated in a cohort that is not a developmental cohort for the algorithm.

Seven, the analytes measured have demonstrated clinical validity and clinical utility in the peer-reviewed published literature, establishing a clear and significant biological basis for stratifying patients and subsequently selecting either positively or negatively their clinical management decisions within a clearly defined population. Eight, analytical validity, clinical validity, and clinical utility assessed as part of the successful technical assessment by the Molecular Diagnostic Services Program.

Nine, the test demonstrates equal or superior performance in risk stratification or therapy response prediction to any other biomarker test that has already met the criteria above. Note: diagnostic testing using NGS for tumor mutation profiling are not within the scope of this policy and are governed according to criteria LCD L38119 MolDX : NGS for solid tumors. Next slide, please.

All right, for closing and next steps, I'm going to hand it over to Jo Gilbertson. Thank you for attending.

Jo Gilbertson
Thank you, Dr. Rajadhyaksha. Next slide, please.

The comment period for the proposed LCDs will remain open until October 11th, 2026. All comments to be considered by our medical directors for the proposed LCD must be submitted in writing. To ensure all cited literature can be fully reviewed and considered during the LCD development process, commenters who will reference published studies, articles, or other supporting evidence should submit a complete copy of each cited document for their comments. References provided without an accompanied full text copy may not be considered if the full text copy cannot be obtained for review. Written comments can be emailed to PolicyDraft@noridian.com or mail to the address on your screen. Comment information for our proposed LCD is located on our website at noridianmedicare.com.

On review of the comments, our medical directors will either finalize or retire the proposed LCD. LCDs that go on to be finalized we'll have response to comments and will be viewable in the response to comment articles.

Please monitor our website or register for listserv notifications to be informed of actions taken on our proposed LCDs.

Dr. Rajadhyaksha, do you have anything else you would like to say before we end this meeting?

Dr. Aparna Rajadhyaksha
No, all except for all your comments are very valuable. We look forward to receiving them in writing. Thank you for listening to the session and attending it.

Jo Gilbertson
This concludes our meeting. Thank you for attending the Noridian Open Public Meeting.