Optimizing Treatment Intensity and Dosing in Older and Frail Patients With Multiple Myeloma

Clinical Summary: 

• Joseph Mikhael, MD, examines treatment optimization for older and frail patients with multiple myeloma, emphasizing comprehensive frailty assessment, individualized dosing, and strategies to balance treatment efficacy with tolerability.
• Frailty assessment should extend beyond chronological age to incorporate functional status and comorbidities, while dose modifications involving lenalidomide, bortezomib, and dexamethasone may help reduce treatment-related toxicity without unnecessarily limiting access to effective regimens. 
• These strategies support a more individualized approach to multiple myeloma treatment, emphasizing optimal rather than maximum tolerated dosing to preserve quality of life and improve treatment in older and frail patients. 

Joseph Mikhael, MD, Translational Genomics Research Institute, Pheonix, Arizona, discusses strategies for optimizing treatment in older and frail patients with multiple myeloma, focusing on frailty assessment, individualized dosing, and reducing treatment-related toxicity. 

Dr Mikhael reviews the importance of assessing functional status and comorbidities rather than relying on chronological age when selecting treatment intensity. He also discusses practical dose optimization strategies for lenalidomide, bortezomib, and dexamethasone, including reduced dosing frequency and earlier steroid discontinuation, highlighting how these approaches may improve tolerability and quality of life while maintaining access to effective multiple myeloma therapies. 

Transcript: 

Hello, my name is Joseph Mikhael. I'm a professor at the Translational Genomics Research Institute in Phoenix, Arizona.

I have the privilege of being here at LL&M. My topic is, "How Much Is Too Much? How Do We Treat Older and More Frail Patients With Multiple Myeloma?"

Well, I'm sorry that you missed the whole talk, but let me give you the Reader's Digest version so we can press it into how it helps you care for your patients.

First of all, just to set the tone, we know that myeloma is a disease primarily of older individuals. The average age of diagnosis is approximately 69, albeit younger in African Americans and Latino Americans. We know that many of our patients are older, they're more frail, they've acquired other comorbidities. It's more common for our myeloma patients to have cardiac disease, renal disease, diabetes, hypertension, other things that we know may affect treatment.

When we go to conferences like these or when we see the data from big clinical trials, we always wonder, can I apply this to my patient?

The focus of my talk is really twofold. One, to talk about the whole notion of frailty so that we can better understand it. Unfortunately, there are all sorts of different scales that have been used, and there are none that are absolutely perfect. But the take-home message for us is for us to think a little bit about frailty. Don't just look at the age of your patient.

We know we have patients in their 70s and 80s running marathons. We have patients in their 50s and 60s who are unfortunately very ill with other comorbidities. Age itself should not be the definition of frailty. There should be other things that we can use. There are some validated models, grip strength, ability to walk, six-meter tests. Various things like this help us assess our patients more carefully.

If you have access to it, it would be great if you could more formally assess your patients with regards to frailty.

The second part and favorite part of the talk for me is when we say, "Okay, what does this actually mean for our patients?"

I start by saying there is literally no treatment we use in myeloma today that was the exact same way as it was first approved. Most of our drugs are approved based on maximum tolerated dose. As we get to use them, we start to realize that often less is more.

We've gone from twice-weekly to once-weekly bortezomib and carfilzomib, from high-dose to low-dose selinexor, from higher-dose IMiDs to lower-dose IMiDs. There's always been this evolution that we want to give the optimal dose to our patient, not just the biggest dose possible.

This is particularly important in older and more frail patients. For example, if we look at frontline therapy when we give quadruplets, quadruplets sometimes seem to be intimidating because they mean four different classes of drugs. But when we use these drugs carefully, there is a massive difference in quadruplets between the dosing of these different agents.

Let me drill down for my last couple of minutes on that so that you can have a take-home message to really help you in the clinic tomorrow.

As for the CD38 antibody, we typically don't make changes to that. Although now that we have isatuximab available subcutaneously and specifically through the on-body injector, I encourage its use, or subcutaneous daratumumab.

Let's talk about lenalidomide or the immunomodulatory drug. Almost all of these clinical trials start at 25 mg. I rarely start at that. In fact, when we look at real-world data, this is reproduced in the community. Most of our patients can start at 10 or 15 mg when they're older and more frail, and that prevents the challenges of the neutropenias, the fatigue, the other side effects we see from it.

Next is bortezomib. This is the one that I really think we have the strongest evidence for really giving weekly and not twice weekly like in the registration trials.

Furthermore, I'll share that when I give bortezomib, I typically give it weekly for up to six months if there's no neuropathy and then drop it to every other week and stop it at one year. Using it less frequently, we still get the benefit of that extra mechanism of action, reduce the risk of neuropathy.

Lastly, and the one I'm most passionate about, is dexamethasone. Let me suggest there is no more toxic drug in multiple myeloma than dexamethasone. We use way too much of it.

Most of our older and frail patients can start at 20 or even 12 mg. I would suggest they really only need it for the first two months, and then you can either discontinue it or rapidly taper.

Join the Down with Dex movement. The nurse practitioner I work with, who is amazing, she and I wrote a paper called "Down with Dex," and we've now seen more and more clinical trials being designed this way and real-world evidence that using less dex reduces all of those terrible side effects we see: the insomnia, the hypertension, the high blood sugar, the impact on cataracts, on the skin. It affects almost every organ system.

Taking all of the evidence we have, as myeloma continues to be a disease as we move closer and closer to a cure, we want to ensure that those great therapies can be applicable to our older and more frail patients.

Being able to apply these principles in dose reduction, in dose delay, in dose optimization is going to allow our older patients to not only live longer, but to live better.

I hope this is helpful to you as you take care of your patients.