Fonseca Leads Debate on the Use of Minimal Residual Disease in Multiple Myeloma

Throughout a digital Focused Oncology Case-Primarily based Roundtable occasion, Rafael Fonseca, MD, lead a dialogue on how MRD standing can information remedy of a number of myeloma.

RAFAEL FONSECA, MD: How would you describe prognosis for sufferers with a number of myeloma?

QUILLAN HUANG, MD: That’s a troublesome query to reply. The way in which I like to debate prognosis is I strive to not volunteer precisely what the Revised Worldwide Staging System [R-ISS score] is likely to be….Normally, what I prefer to [say is], “Let’s see the way you reply to frontline remedy.” Typically, in the event that they’re going to reply nicely to frontline remedy, they’re extra prone to have a greater long-term final result.

FONSECA: A number of sufferers are fascinated with what’s anticipated, however what are a number of the ranges of what you may see for outcomes?

MURTAZA N. BHURIWALA, MD: There was a Nationwide Public Radio podcast a few years in the past that described myeloma remedy as one thing long run, like diabetes. I inform my sufferers it’s a long-term [situation] like diabetes and that there are a number of drugs on the market to regulate the myeloma. [There are] some aggressive sorts, like aggressive diabetes, and also you handle them a bit extra aggressively. There’s a milder kind, [for which] you may have a mix of pictures versus capsules. Normally [for a patient with] stage II and no high-risk options, we’ll do induction. If they’re youthful than [age] 65, we are going to contemplate transplant. However that is determined by what they need and the way they undergo remedy and the longer term traces of remedy that we’re going to do.

FONSECA: There’s a complete vary of conversations. It will be laborious as a result of a whole lot of that is determined by the remedy which you could give and the elements.

ROBERT Z. ORLOWSKI, MD, PHD: [I’ll discuss] a number of the gadgets that others have talked about, just like the R-ISS stage. We additionally attempt to do gene expression profiling. We discover that to be a useful adjunct to the fluorescence in situ hybridization. We additionally do a focused gene sequencing panel that generally will be useful down the street in choosing focused therapies if the affected person has a RAS or RAF mutation. All of these collectively put the prognosis into larger focus.

FONSECA: How do you clarify extremes of the dangerous and the nice? How do you current that to sufferers?

ORLOWSKI: The excellent news is that most individuals statis-tically are going to have standard-risk illness they usually most likely have a 10-year, not less than, median general survival [OS] at this level from the time of analysis. I attempt to reassure them that most likely that quantity is not going to go down by a 12 months each time a 12 months goes by as a result of new therapies coming in are going to be superior to what we’ve now.

For the 15% to twenty% who’re excessive threat, that’s a harder dialog, and we attempt to get into all of the choices—[including] a number of the new immunotherapies—and emphasize the significance of hopefully reaching minimal residual illness [MRD] negativity. I’m extra aggressive with transplant in high-risk sufferers than I’m with standard-risk sufferers.

FONSECA: That is sensible. I like that: You don’t lose a 12 months for yearly that goes by. It’s not essentially a ticking bomb. That’s what we all know in 2021.

Within the second line, how are you serious about transplant eligibility and desirability for transplant? I do know that’s a continuously evolving matter, and we see some research that also ask the query “How a lot do we’d like transplants?”

URMEEL PATEL, MD: I’ve to agree with the remainder of my colleagues right here. If they’ve an incredible efficiency standing, I’d positively contemplate it. For sufferers who’ve high-risk cytogenetics, poor prognostic elements, an ISS rating of three or 2, I might positively contemplate transplant. I nonetheless contemplate that as an possibility for these sufferers.

FONSECA: For many sufferers who’re younger, do you continue to steer them towards stem cell transplant?

PATEL: Yeah. In the intervening time, I nonetheless do.

FONSECA: I do as nicely. I do know that issues may change, however I’m nonetheless a believer on the affect of stem cell transplant. Maybe that may change as we get extra data.

DILIP L. SOLANKI, MD: It has change into clearer that maybe autologous stem cell transplant produces deeper remissions than customary remedy, so the two full responses [CRs] usually are not the identical. We began with some data that got here out of the Myeloma XI trial [ISRCTN49407852], the place they didn’t have all of the medicine [we have now], aside from thalidomide [Thalomid], they usually discovered that once they did get CR, the CRs had been higher following a transplant than in the event that they received a CR simply with chemotherapy.¹ Over time, it has change into clear that that’s the case. The autologous transplant has come again as a superb factor to do if the affected person is appropriate.

FONSECA: We all know now {that a} response will not be [another] response and {that a} CR will not be [the same as another] CR. The query is “Is MRD [negative status] the identical as one other MRD [negative status]?” Maybe not. Maybe the depth of response retains mattering fairly a bit.

ORLOWSKI: I’m going to present a contrarian opinion. When you’ve got a younger standard-risk affected person, particularly in the event that they obtain CR and MRD negativity, the possibilities that they’re going to have the ability to get a salvage transplant are very excessive. We now have sufficient knowledge that present {that a} second-line transplant has virtually as a lot, if not an equivalent, profit as frontline transplant. I paradoxically suppose that for a standard-risk younger affected person, it’s positive to delay transplant in the event that they obtain CR and MRD negativity. Now, if they’re 70 years or older, then you definitely [should] do the transplant since you by no means know what’s going to occur. Folks’s well being doesn’t have a tendency to enhance, however that’s simply the best way that I do issues.

FONSECA: I can sympathize with that argument, however I might need to know that I’m measuring very deep. If you happen to say I’m going to go together with MRD-driven [treatment], I need to be sure that [the sensitivity is] 10-6 and that we’ve a really deep stage of response….This idea goes to proceed to evolve.

SOLANKI: The Myeloma XI trial didn’t have the multi-planar move cytometry, but it had simply been launched, they usually went again and checked out a few of these sufferers and located that those that had the autologous transplant had a deeper MRD or tended to have MRD extra typically than those that simply received chemotherapy. It is determined by the sensitivity at which you might be testing for MRD. All MRD [statuses] usually are not the identical.

FONSECA: How do you suppose you’re going to start out remedy? We talked about prognosis. What are your targets in that affected person inhabitants?

DAI CHU N. LUU, MD: All of it is determined by the targets of care. Normally I attempt to enhance their signs, get their M-spike protein down a lot as potential in preparation for a transplant in the event that they’re eligible….All of it is determined by the objective. I’ve a transplant-ineligible affected person in his late 70s. The objective for him was to ensure he has a greater high quality of life, minimal signs from his most cancers, and never too many adversarial results from chemotherapy.

FONSECA: That’s a great way to consider it. I’m considering with the identical mentality. I could also be an outlier, however [with] the perfect obtainable remedy proper now and the depth of the responses, we’re going to start out seeing cures. A few of these sufferers are 7 to 10 years out, [have] a CR, and are doing very nicely. Nonetheless, relapses are going to happen. However we’re seeing that increasingly more.

FONSECA: To your targets of remedy up entrance, how are you approaching remedy?

NADEEM QURASHI, MD: I nonetheless do RVd [lenalidomide (Revlimid), bortezomib (Velcade), dexamethasone] as a primary line…[and] it has a superb response. Some sufferers don’t have a response both manner, after which I exploit daratumumab [Darzalex]. However I do get each affected person evaluated by a transplant physician, simply to ensure they’re eligible for transplant or not.

FONSECA: In a extra summary manner, do you all the time go for the deepest response potential when you concentrate on remedy for sufferers?

QURASHI: Relying on what it’s; if they’re older, sure. However my impression earlier than transplant is the higher the response you get, the higher the end result of transplant is.

FONSECA: You might make that agnostic to any remedy: the higher the response, the higher the outcomes, it doesn’t matter what. A number of of us imagine that transplant nonetheless provides to that. But it surely’s most likely agnostic to no matter remedy, if that’s CAR [chimeric antigen receptor] T cells or bispecifics sooner or later, then who is aware of?

FONSECA: What are your ideas about MRD, and what function ought to it’s enjoying within the remedy of myeloma?

BHURIWALA: I work in a neighborhood [setting], so I don’t actually get the MRD assessments. I requested my pathologists the place we do the next-generation sequencing, and he stated it’s tough to get an MRD….In observe, it is rather tough to do. I might reasonably ship a affected person for transplant after which do the MRD evaluation.

FONSECA: It’s tough, and it’s being applied. However do you suppose—as you learn the literature—MRD dictates what you’re serious about these regimens or not but?

BHURIWALA: Sure, I do, however it’s extra in tutorial settings than in neighborhood settings. It’s good to see…[but] it’s not applied in neighborhood observe but.

PATEL: I’ve to agree with Dr Bhuriwala. It’s tough to realize in the neighborhood setting. It has a task in understanding and treating our sufferers, however making an attempt to get MRD within the outpatient neighborhood setting is tough.

WILLIAM VELASQUEZ, MD: In some circumstances, we use [MRD]. We now have to ship it to a selected lab to get it achieved. Nevertheless, within the common labs, it’s too tough, and there’s not a transparent demonstration of compatibility between one lab and one other to ensure MRD [assessment is done]. It’s a good idea, and in these sufferers, who had been in a position to obtain MRD negativity, [response] can be achieved [more] than it could be in any other case.

FONSECA: What about that interpretation of the literature? How do you’re taking that into consideration?

VELASQUEZ: As with many hematologic issues, undoubtedly, the less malignant cells left after your remedy, the higher survival or disease-free survival can be. A number of myeloma is a selected case, and up to date MRD [assessment] continues to be a comparatively new idea and never very nicely capitalized—like we used to do in continual myeloid leukemia [CML]. These days, the CML knowledge are clear, and all of the labs are mainly adhering to the identical protocol. It’s not [the case] for MRD in myeloma.

SOLANKI: MRD, conceptually, is a good suggestion as a result of that means that you can assess the depth of response. Now, how a lot depth of a response may equate with treatment? We don’t know. Plus, how far we will push the know-how to assist us in that? It’s tough to take the MRD knowledge and begin altering all practices wholesale with out good proof. The second factor is the logistical problem of doing MRD [assessment] on the bone marrow.

Until you’ll be able to give you one thing that’s simpler to do in a medical setting, not in a analysis setting, it’s going to be laborious to use it. That is not like CML, the place we’ve a definitive marker, which we will check in a peripheral blood; that has made it straightforward. Now we’re in a position to discontinue remedy in a proportion of sufferers primarily based on that. However that may be laborious to do in a number of myeloma and continual lymphocytic leukemia, for instance, as a result of we don’t have a superb marker—as a result of MRD will not be a marker. It’s a quantitative evaluation.

VELASQUEZ: I keep in mind in CML, the preliminary trials tried to reveal MRD. They weren’t standardized, they usually had been in all places. It’s solely when all of the labs change into standardized about what we measure and the way we measure—that is turning into essential too.

ORLOWSKI: [We are using MRD in]most likely 2 methods. [One way:] In standard-risk sufferers, determine whether or not to supply them the choice to delay a transplant. That’s 1 option to do it. Additionally, from time to time, there are individuals who need to cease remedy. Most of what we do now’s steady remedy, and relying on the state of affairs, in the event that they actually need to contemplate stopping, I supply them the choice of doing MRD testing in the event that they’re in CR. In the event that they’re MRD unfavourable, I’m a bit much less against stopping remedy. But when they’re MRD optimistic, I normally inform them that I nonetheless strongly suggest persevering with remedy. Apart from these 2 pretty small indications, I don’t use it routinely off the examine but.

FONSECA: What about prognostication and dialogue with sufferers? How do you cope with that?

ORLOWSKI: I try this within the up-front setting to attempt to gauge how nicely the induction remedy has labored and in addition to contemplate whether or not extra induction could also be wanted. MRD negativity does assist from a prognostic perspective. However as a result of individuals can nonetheless obtain MRD negativity down the street, it’s nonetheless not a unfavourable issue essentially in the event that they’re MRD optimistic.

FONSECA: Peripheral blood is fascinating and may need a spot [in terms of MRD testing], however from all we will inform, not less than by the [next-generation] sequencing, it doesn’t have the identical vary of sensitivity that we see with direct bone marrow. Biology will trump know-how there. Nevertheless, the mass spectrometry is coming in robust instead methodology to measure MRD. It nonetheless requires some laborious work, however it may come to be changing one thing like immunofixation and the whole lot else. We’re excited with that. One of many points with mass spectrometry, although, is that the half-life of the proteins will be so lengthy that we’ve to interpret how these play out into timing whenever you’re going to be measuring MRD. But it surely’s a extra exact evaluation of the proteins for positive.