Treating and Educating the Newly Diagnosed Patient

Melanie Douglas

Thanks for taking the time today to discuss treating early-stage multiple myeloma, Beth. Let's focus today's conversation on the newly diagnosed patient.

Beth Faiman

Thanks Melanie. I'm so excited to be discussing this very important topic today. So let's start off with setting the scene: What does a newly diagnosed patient with multiple myeloma look like in your practice? How do they present to you at MSKCC?

Melanie Douglas

We see patients who present in a variety of ways. Many newly diagnosed patients are admitted to the inpatient service, which I’ll discuss more because that’s where I practice. They come through to us with pathologic fractures, associated pain, and difficulty with activities of daily living, which would be difficult to manage as an outpatient. There are some patients who come through with lab abnormalities, including cytopenias, even to the point of requiring transfusions, and symptomatic hypercalcemia, which I’ve seen occur often with an acute kidney injury (AKI). These patients require urgent front-line treatment.

We recently had a newly diagnosed patient with anemia and high protein on labs that were drawn at his annual primary care office visit. Subsequently, he developed blurry vision in the setting of hyperviscosity requiring hospital admission for plasmapheresis. In the hospital setting, we give four doses of dexamethasone often followed by cyclophosphamide, bortezomib, and dexamethasone (CyBorD). This is easy to do in the hospital and as a temporizing measure for the disease, especially if the patient has an AKI. Once they’re discharged from the hospital, cycles can be adjusted to any three- or four-drug regimen that’s being considered.

Beth Faiman

I totally agree that that's a classic presentation. I was hoping we wouldn't be seeing as many acute hypercalcemias of malignancy in people going through the ER, but unfortunately with the pandemic, I think a lot of people lost their jobs and consequently lost their insurance. Or they weren't working as much. And then the hospitals were kind of on shutdown for non-COVID or non-emergency patients. It was hard to get in to seek routine care. So now that things are quieting down, I'm hopeful we don't see this as much, but we do.

We do the same thing at Cleveland Clinic as you do in your practice. If a patient presents with hypercalcemia of malignancy, we'll give a bisphosphonate, then administer IV fluids to prevent or treat AKI. We'll also attempt to correct the underlying disease pathology by starting a 3-drug regimen like CyBorD. We’ll do the bone marrow biopsy, get as much of the initial workup as we can, and then when they get out of the hospital we might adjust the treatment plan when pathology has been resulted.

In my mind, one of the most important tests is fluorescent in situ hybridization (FISH) testing up front. Sometimes when patients present to the hospital they have anemia, and you don't know that they have multiple myeloma yet. You're thinking it’s just anemia, so you do a bone marrow biopsy.

Melanie Douglas

Right. I see this frequently. 

Beth Faiman

We can’t always do FISH before starting chemo, so what we’ll do is get the bone marrow. We're not always going to go back and do another bone marrow biopsy because if we have a tissue diagnosis and 60% plasma cells, then we'll just start treatment with the CyBorD, as mentioned previously. Melanie, do you always do FISH at diagnosis? Or if you missed it, do you go back and do another bone marrow biopsy to FISH abnormal clones in multiple myeloma?

Melanie Douglas

I've had patients come in with debilitating fractures, and we just get all the workup that we can get. If they definitely have the CRAB criteria, we’ll get a peripheral flow and then decide if that’s good enough.

Beth Faiman

What are some of the FISH abnormalities that you see in your practice?

Melanie Douglas

High-risk chromosomal abnormalities that we see include p53 mutation and translocations including like t(4;14), t(14;16), and t(14;20), and other attributes showcasing high-risk or extramedullary disease such as circulating plasma cells or plasma cells escaping the bone marrow. Reviewing FISH abnormalities and other aspects of the patient's disease, as well as the patient's frailty and lab values such as LDH and beta-2 microglobulin and albumin, can all be put together in assessing the patient's risk factors. Then we know if they're high risk, low risk, or somewhere in the middle, and where we should start with them.

Beth Faiman

I think you make some great points. I also like to take into account the patient's frailty and fitness status. I use the International Myeloma Working Group recommendations.¹ Fortunately, we have new and ongoing studies to learn from. For many years, we used three drugs, bortezomib, lenalidomide, dexamethasone, and now clinical trial results show that the addition of daratumumab followed by autologous stem cell transplant can help keep patients in remission for an extended period of time. There was a trial, the MANHATTAN study at Sloan Kettering, that you had had patients on as well.²

Melanie Douglas

Right, we did. It looked at the addition of daratumumab, specifically to carfilzomib, lenalidomide-dex, as front-line therapy in both transplant-eligible and transplant-ineligible patients. It showed improved clinical outcomes. This study was unique in that it looked at patients who are both transplant eligible and transplant ineligible up front to see how it would help their disease.²

Beth Faiman

Frailty and fitness are really important. Think about a typical patient who presents in the hospital with back pain and compression fractures. We mentioned that a common practice is to administer dexamethasone pulses and then treat them with CyBorD in the hospital.

The question is, is this a 75-year-old who has COPD and smokes? Should we alter the drug doses or regimen? Or if the patient is 55 years old and works full time, how would you treat them differently? I take into account the frailty by using a myeloma frailty calculator http://www.myelomafrailtyscorecalculator.net/, which takes into account the Charlson Comorbidity Index, Katz basic activities of daily living, and instrumental activities of daily living, to compile a total additive score.

We know that patients who are more frail at diagnosis should be given less dexamethasone, and that certain drug doses should be dose-reduced, such as lenalidomide. We’ll also recommend different types of treatment and delay transplant. Of course, it’s a possibility that they're frail from the disease, and that it’s the disease that’s debilitating them.

Melanie Douglas

That's a really important point.

Beth Faiman

Just getting the treatment under control can help a transplant candidate. I like modeling two studies. The first study is called the Forte trial for high-risk myeloma.³ Francesca Gay is the lead investigator, and her group did KRd (carflizmob/lenalidomide/dexamethasone) vs. autologous, and then autologous stem cell transplant, and then maintenance. There was some randomization of maintenance afterwards. For high-risk patients with myeloma it’s inducing MRD-negative status. We know that with MRD (minimal residual disease), trying to find one in a million plasma cells is an important endpoint in clinical trials now. It's more prognostic up front. We see MRD-negative after CAR-T and bispecifics and later lines of therapy, but we're still learning how to use it. Do you decide a patient’s therapy based on whether they’re fit or frail?

Melanie Douglas

Yes, it's very important to consider fit vs. frail patients and evaluate the therapies. It plays a role in determining induction therapy and determining transplant eligibility. I had a 74-year-old patient with high-risk chromosomal abnormalities who didn't have very good performance status, so they were on a three-drug regimen and still made it to MRD-negative.

Beth Faiman

That's great! How many drugs are better? Three drugs vs. two drugs? That's always a big debate. There was a trial of transplant-ineligible patients called the MAIA study. One group of patients in this study were given lenalidomide and dexamethasone pills, and the other group was randomized to daratumumab, lenalidomide, and dexamethasone. What was seen in that study is that the frail patients who were able to take the three drugs did much better than those taking the two-drug regimen. Their quality-of-life scores seem to improve.⁴

Melanie Douglas

That's really interesting. You wouldn't necessarily expect that.

Beth Faiman

No, you wouldn’t. Even if the lenalidomide pills were stopped, people still continued to respond. Daratumumab was given weekly for 8 weeks, then every other week for 3 months, and then monthly. What's cool about this is that there's very little treatment; once a month they come in, they see their provider, they get their cookies, and it's a shot in the belly. We're checking their status and the quality of life tends to be pretty good.

One of the problems as people get older or are on therapy for a while is adherence. Do you run into any problems with adherence in any of your patients? And what are some of the strategies you use to keep people on therapy long term?

Melanie Douglas

Absolutely, and of course it's not easy. We have to tell these patients that we don't know how long they're going to be on this therapy. It could be indefinitely. The treatment side effects can make it very hard for patients to remain adherent, so we have different strategies.

Our pharmacists are very involved. They spend a lot of time with the patients, make phone calls, and follow up with them. They talk about treatment calendars, smart pill boxes, leaving pills on their bedside table for evening dosing, like with lenalidomide for instance.

We tell patients to call the office if they develop side effects. We can treat them symptomatically or, if we have to, we'll lower the dose. Of course, there are always some instances where you have to come up with an alternative or take them off the medication, but that's pretty rare.

Beth Faiman

Those strategies sound great. One of the barriers I see, especially in the patients who are non-transplant candidates, is the copay. For some, even a low copay can lead to financial toxicity. Many people qualify for some copay assistance. This year we're having a bigger challenge with the copay assistance, so we have to apply to more places. Fortunately, we're in the United States, a county where we have access to a lot of different drugs that even Canada and other parts of the world do not.

We might have to be a little bit crafty about getting the medications working with side effects. But I set the expectations up front. Since multiple myeloma is a cancer of the bone marrow plasma cells that are programmed to survive forever, they're part of our humoral immunity, the plasma cells are really hard to kill and they can come back.

I tell patients that it's like your garden in the wintertime when things freeze over, and you think all of the weeds are gone. But then in the summertime they all emerge. And that’s like the myeloma. If we aren't able to suppress the malignant clones, then the clones will evolve and become harder to treat in some cases. So we have that discussion with the patients and the family that this is an ongoing thing: We need to suppress the cancer cells and keep things sleeping. A need for ongoing treatment for multiple myeloma is like with other incurable medical conditions.

Another analogy I use is that with a patient with type 1 diabetes who is on a lot of insulin, you would never have them just stop their insulin because their condition would get worse. With high blood pressure, you can rarely stop that medication. There are a lot of medical conditions that are incurable, but they can be very manageable with medications.

Are there any analogies you use with your patients?

Melanie Douglas

I think those are amazing analogies. I'm going to save them in my mental toolbox and use them with my patients tomorrow.

Beth Faiman

There you go! You absolutely can. 

Melanie Douglas

Multiple myeloma is a chronic disease. As you said, unfortunately it’s not curable. But on the other hand, there are so many therapies out there and more are coming. You touched on CAR-T cells and bispecifics. At MSK, we just started giving teclistamab. The physicians at our institution are very excited about that.

It's amazing to read some patients' charts, see that they've been on nine lines of therapy, and see that they're doing okay. They have good quality of life and good performance status. That’s really quite remarkable.

Beth Faiman

I know. When I started managing myeloma patients in the 1990s as a nurse in the hospital, I could never have imagined all the changes, all the CAR T-cell therapies, or engineering the T cells to become fighters. I never would've thought that all these treatments were possible, but we're living it, right?

Wow, we sure have covered a lot of ground in this conversation!

Melanie Douglas

We really have, but there’s so much more! I look forward to really diving into our future conversations.