Next-Generation Regimens for Multiple Myeloma - Episode 9

Using MRD to Determine Cure in Multiple Myeloma


A. Keith Stewart, MB, ChB: Can we cure myeloma, Sagar?

Sagar Lonial, MD, FACP: We already are.

A. Keith Stewart, MB, ChB: Ed?

Edward A. Stadtmauer, MD: I still think there’s a bit of a ways to go to get most of the patients cured.

A. Keith Stewart, MB, ChB: Amrita?

Amrita Krishnan, MD, FACP: I’d say yes with immunotherapy.

A. Keith Stewart, MB, ChB: In who, all patients?

Amrita Krishnan, MD, FACP: I think in all patients because I think immunotherapy is risk agnostic.

A. Keith Stewart, MB, ChB: Can we cure myeloma, Tom?

Thomas Martin, MD: I think in frontline, we cure maybe 10% to 15% of patients with a transplant. Whether we can cure them at relapse is still yet to be seen.

A. Keith Stewart, MB, ChB: Ajai?

Ajai Chari, MD: I think, yes, 10% of patients have not relapsed, as published in Blood, without any treatment in 10 years, so that’s a functional cure.

A. Keith Stewart, MB, ChB: High-risk as well or just low-risk patients?

Sagar Lonial, MD, FACP: Well, I think right now it’s the hyperdiploid standard-risk patients who are getting benefit from an autotransplant. I think with our new strategy. So, we looked at 1000 patients at our center who got RVd, transplant, and maintenance. Seventy percent are in remission and are alive at 10 years.

A. Keith Stewart, MB, ChB: Do you tell your patients, “I may be able to cure you,” or are you more, “We’ll do the best we can and we’ll see what happens”?

Sagar Lonial, MD, FACP: I tell them that there is a fraction, 10% to 15%, and I’m doing my best to put them in that fraction.

A. Keith Stewart, MB, ChB: What do you tell a high-risk patient?

Edward A. Stadtmauer, MD: I tell them that I don’t use the C word, but that I have patients who are decades out doing well.

A. Keith Stewart, MB, ChB: We all have them but they’re hard to identify in the beginning, aren’t they?

Sagar Lonial, MD, FACP: You’re right.

A. Keith Stewart, MB, ChB: OK. Do we need MRD negativity to cure people?

Thomas Martin, MD: I would say MRD is here to stay. We’re going to be testing it in myeloma more and more, and we’re going to have more data to do risk-adapted changes in treatment. But, yes, to be cured of myeloma, I think you have to be MRD-negative for a certain period of time, whether it’s 1 year or 3 years or 5 years. That will be ascertained.

A. Keith Stewart, MB, ChB: You don’t subscribe to the hypothesis you can turn people back to MGUS…?

Thomas Martin, MD: I do, actually. So, there is a small percentage of patients, maybe that’s 5% of patients, who have that residual MGUS clone that’s going to still be there 10 years later with an M protein of 0.5 or 0.7, and that isn’t going to change. And we all have those patients who never got maintenance and their M protein is still 0.7 like 10 or 15 years down the line.

A. Keith Stewart, MB, ChB: Do you think to cure we should be treated earlier, Ajai?

Ajai Chari, MD: Well, I think to integrate those 2 questions, the limitations of MRD is you really need to not just know the MRD status but what’s the bone status in terms of imaging. And also, what is comprising that MRD positivity? When we looked at our patients who had known smoldering prodrome, they didn’t necessarily get into CR states, but they had a longer overall survival. So, I think that speaks to your question.

But treating smoldering, my problem with this is we need to, at the end of the day, have a randomized phase III study. And if we don’t pick the right model, we’re going to underpower these studies, because not everybody with smoldering is going to progress. So, if you start treating everybody, you’re not going to be able to identify. And I personally believe that, in particular, the free light chain ratio and the bone marrow criteria are not perfect. And I think those patients who are currently being classified as myeloma are the very ones we should be studying in terms of treating early and not moving them into early treatment without the studies.

A. Keith Stewart, MB, ChB: Anybody disagree with this? Anybody think we should be treating all our smoldering myelomas to cure them?

Sagar Lonial, MD, FACP: And if you look at the mutation burden of a smoldering patient compared with a newly diagnosed myeloma patient, it’s identical. So, what I worry about is interventions early may be suppressing the immune regulation that’s keeping it in smoldering and not allowing it to progress to myeloma. And so, outside of clinical trials, I don’t advocate for treating smoldering early.

A. Keith Stewart, MB, ChB: So, there are clinical trials underway with active very aggressive treatment of smoldering myeloma—KRd, transplant, more KRd. What do you think of those, Ed?

Edward A. Stadtmauer, MD: Well, just like I have patients who are decades out from aggressive therapy and transplant, I have patients who are decades out with smoldering myeloma who I’ve just been monitoring and keeping our neurosis level low. So, I think we really need better prognosticators to really differentiate. What I always tell the patients is I don’t want to treat you 3 years before you need treatment, but I don’t want to treat you 3 months after you needed treatment. I want to treat you about like 6 months before you need treatment.

Ajai Chari, MD: To echo your sentiments, I think this baseline risk stratification is really misleading because, first of all, we don’t really know how long that patient has had the smoldering myeloma and we just picked the time point as their first marrow. But what’s really more important is the kinetics of the disease. In our hands, when you compare the baseline criteria to the kinetics, which is evolving hemoglobin, evolving M-spike, evolving light chain, those are what really matter. And it’s just like in CLL, the doubling time. And so, I don’t know why we’ve gotten lazy and just take the baseline and totally blind ourselves to what happens…

A. Keith Stewart, MB, ChB: So, it sounds like the consensus is smoldering myeloma treatment still belongs in trials and don’t do it at home.

Amrita Krishnan, MD, FACP: And I think the other misconception that has sort of been propagated is looking at early breast cancer, DCIS (ductal carcinoma in situ). This is not DCIS because the burden of therapy you’re going to put on someone with smoldering myeloma is tremendous if you start.

Ajai Chari, MD: Not to mention, we don’t treat early, MDS, CLL, or follicular. So, we have a lot more in common with the hematologic malignancies than early stage breast, prostate, and colon cancers.

Transcript Edited for Clarity