Are there special factors you consider when selecting induction therapy for individuals diagnosed with high risk multiple myeloma (HRMM)?

Starting treatment for multiple myeloma can feel overwhelming, but it's important to know that you're not alone. Treatment is a personalized journey, often involving a combination of medications, and your care team will tailor your plan to fit your unique needs and the specifics of your disease. You'll have thoughtful conversations with your doctor about treatment options, possible side effects, and how this might affect your day to day life.

In this health three university lesson, you'll learn what myeloma specialists consider to be an appropriate treatment path. If you are diagnosed with high risk multiple myeloma.

Are there special factors you consider when selecting induction therapy for individuals diagnosed with high risk multiple myeloma?

for high risk patients that are newly diagnosed. And what we mean with high risk is mainly the cytogenetics

In June 2025, the International Myeloma Working Group updated the definition of high risk multiple myeloma.

Under the new definition, patients with certain genetic abnormalities or elevated beta 2 micro globulin levels are considered high risk.

If we see one or more of these, high risk features in the myeloma cells in the bone marrow,

For these patients, we want to give a very powerful treatment upfront. And we want to certainly discuss transplant and then discuss the type of maintenance that we give as well.

So right now for those that are transplant eligible, also for those that are transplant ineligible, we're getting more and more information that we should use the four drug regimens. For those that are on the younger side, the ones that we used to call transplant eligible, these are now kind of, going into these each other, these transplant eligible and transplant ineligible because we're using very similar treatments for the transplant, ineligible as well.

So four drug treatment an anti-CD38 antibody; daratumumab or isatuximab. One option is then to combine with bortezomib lenalidomide dexamethasone. The other option is to combine with carfilzomib lenalidomide dexamethasone.

So for the patients that is high risk. That is on the younger side. And we don't really see age as a number more biological age.

But somewhere around 70 below that in a high risk patients we would favor combination with carfilzomib.

So Daratumumab, isatuximab with carflizomib, lenalidomide, dexamethasone. And then this is based on the, iskia trial, Manhattan trial master trial. We're seeing very high response rates also in patients that have, one or more high risk cytogenetic features.

One thing to think about with carfilzomib is that, it can have somecardiac or heart side effects. So it is important to do a cardiac assessment before. For every patient where we consider carfilzomib we do an EKG and an echo. So an ultrasound of the heart, we do a history to see is there any underlying heart disease.

If there is not we would favor cafilzomib in this patient population.

And here is where we would do around four cycles of induction. And it's important when we do four drug combinations that we try to collect stem cells early. So for four cycles collect stem cells go to transplant and then consider even consolidation with a similar four drug combinations of two or more cycles depending on which trials you look at or have as your evidence for the maintenance, we do have several options. The one standard option is lenalidomide single agent. But for the high risk patient, we would consider either daratumumab, isatuximab with lenalidomide or even carfilzomib lenalidomide based on the forte trial where we're seeing long progression free survival.

So we see that the disease stays away for a long time with that doublet. With carfilzomib.

So that's something that I would recommend for a patient that has, one or more high risk cytogenetics.

So if a patient is found to have high risk genetic features in their tumor, I would certainly consider a quadruplets meaning four drugs during the induction therapy.

These four drugs are a combination of a Cd38 monoclonal antibody, such as daratumumab, a proteasome inhibitor such as velcade or Bortezomib, or carfilzomib, as well as an immunomodulatory drug such as lenalidomide, as well as a steroid.

Dexamethasone. So this quadruple combination has been shown to be really effective in myeloma.

And I would certainly encourage a patient with high risk disease to receive this in induction therapy. After induction therapy, they should, be evaluated for an autologous stem cell transplant.

This is a, more intensive therapy that involves very high dose chemotherapy.

What we do is we collect stem cells from the patient's body, and we preserve them in the freezer while we give the high dose chemotherapy, and then we rescue the patient of the toxicity from that chemotherapy by returning those cells.

This has been shown for many, many years to be one of our most effective therapies for myeloma.

However, I will say in the era of quadrupling therapies, it's not been compared head to head. So there is some uncertainty as to whether or not a Stem cell transplant is still needed after quadruplet therapy. Until that data becomes available, I strongly encourage patients to have a consultation to discuss the benefit of autologous stem cell transplant after a transplant, or in place of.

I strongly recommend patients receive maintenance therapy. So maintenance therapy is, not as much therapy as was given in the original induction. And it's continued, until the patient achieves, at least a minimal residual disease negativity, maintenance therapy can be a single drug like lenalidomide or revlimid, or it can be a combination like daratumumab, injections and, lenalidomide pills.

Would you be more inclined to use a two drug maintenance protocol in the high risk population?

I think I would assess the patient's minimal residual disease status at the completion of their induction therapy. If they achieve MRD negativity, I might lean towards, doing a simpler maintenance strategy rather than, doing a two drug combination if we know there's still residual disease at the end, let's say the monoclonal protein is still elevated. I would probably favor, doing a doublet.

Would you encourage people with high risk cytogenetics to go down the transplant path?

with the transplant there has there is a lot of discussion and there has been a lot of discussion for many years.

And for the high risk patient we would favor a transplant. So there are a few things that we consider when we decide and or discuss transplant with the patient.

So, decide first of all is is at all possible.

The transplant eligibility ineligibility based on biological age and probabilities. Second is look at the risk profile. So for the high risk patient we would favor a transplant early or upfront transplant. Then we look at the treatment response. We look at the MRD here at MSK we usually do a bone marrow before the transplant.

So we look at the disease response in the blood but also in the bone marrow.

And with imaging. the last thing that we look at is also in terms of age, if we have time to wait or not. So someone who is a little bit on the older side is probably better to do sooner rather than later to not lose that option of doing a transplant. So, if we summarize this for a patient who has high risk cytogenetics, that would favor a transplant, for those that are MRD positive, are, a little bit on the older side, but still eligible, those are the patients, we would certainly recommend transplant.

What are your thoughts on high risk patients stopping maintenance therapy if they maintain sustained MRD negativity?

There's a lot of, trials and discussion going on with maintenance, which I think is very exciting that in each and every step of the myeloma therapy, things are being reevaluated and we are updating and optimizing our therapies. if we look at the first trials, maintenance does increase or prolong the progression free survival, meaning that the disease stays away longer if we do maintenance in general, the standard recommendation is to do maintenance as long as it works.

So until progression. so in general not only high risk patients there is the question how do we tailor maintenance for each and every patient? Should we have two or more drugs for those that are high risk?

MRD positive can we de-escalate or stop maintenance for those that are on the other end of the spectrum that are MRD negative or not high risk? So we here at MSK, have an ongoing trial, and this is somewhat based on one of the trials from the UK myeloma group, where they saw that after three years, those that were MRD positive, there's still a benefit to continue maintenance for those that are more negative, It's questionable how much how much benefit we get with maintenance after the three years.

So based on this evidence or based on this data, we here at MSK, Doctor Korde, she's leading a trial for maintenance discontinuation. So for those that have sustained MRD negativity for three years, there is an option to stop maintenance. Early data from this trial, and also from the trial that Ben Derman is leading in in Chicago that was published.

We see that the majority of patients after 1 or 2 years are still MRD negative. There are a few that have turned from MRD negative to positive. However, not all of them have started maintenance again, so some of them can still be monitored because it can still take a long time until we actually see disease that we need to treat.

So we take that group that are probably not the high risk group, more of the standard risk with sustained mid negativity for three years. the standard recommendation is still to continue maintenance. But that's the patient group where we can consider and talk to each and every patient. We do this of course we want to see the the data from the trials.

But that's the patient group where we can de-escalate for those after three years that are positive, there is a benefit of continuing maintenance.

For the high risk group I would still recommend keeping maintenance. And here is also the group where we would discuss all the way from the beginning, doing more than than just one drug maintenance or probably two drugs maintenance for those that have one or more, and particularly those that have, two or more high risk cytogenetic features.

I have to caution by saying we do not yet have the data finalized to make the determination that everyone should go off therapy if they're MRD negative. We know that many patients who are MRD negative will eventually relapse. And patients who sustain that MRD negativity will be less likely.

So at this point in time, I think it needs to be an individualized decision between the doctor and the patient, discussing the potential risks and benefits without having all of the the data and evidence to make a final recommendation for everyone.

To learn more about sustained MRD negativity, watch the Health Tree University lesson on this topic in our MRD course.

If you found this lesson helpful, consider giving us a like and be sure to watch the other lessons in Health Tree University's starting myeloma treatment course.