The Evolution of Treatment Regimens, From Newly Diagnosed to First Relapse and Beyond

Beth Faiman

In our discussion today, Melanie, I'm curious to get your thoughts on patients, whether they’re transplant-eligible or ineligible, with newly diagnosed myeloma.

What are some of the considerations? Is it fitness and/or frailty or is it the geography? I try to think of what their social situation is. Does the individual work full-time, which presents a challenge in frequent visits? Do they have older people that they have to care for, younger people they have to care for? So, treating them is not just about controlling the disease, but educating on the diagnosis too. From a treatment standpoint, what are some of your thoughts?

Melanie Douglas

There are a lot of factors to consider, and especially in those with medical comorbidities. Consider whether or not they have a history of COPD, heart failure, or coronary artery disease. And then we need to apprise their performance status. I think especially later on in the disease, it's very relevant to think about logistics, how far away they are from the hospital. There’s a lot to educate the patients on, especially with transplant. With protocols and transplants, how willing are they to be stuck multiple times a day with labs? How long can they stay in the hospital? Do they have family or caregivers around to help out with their children or affairs or even just to help support them mentally through this whole thing?

Beth Faiman

Absolutely. I was just at the 2023 European Hematology Association (EHA) meeting in Frankfurt, Germany, which took place in June. And while we do have a larger meeting on myeloma in September and also the American Society of Hematology Meeting in December, there were some really interesting papers that came out with regard to the treatment of newly diagnosed patients with multiple myeloma.

I have to say, in the over 20 years that I've been managing patients with myeloma, I have seen an evolution in the standard of care. Starting in the mid- 2000s, the standard induction treatment was to administer two drugs, such as an immunomodulatory drug and dexamethasone, or bortezomib and dexamethasone. Currently, the standard treatment is 3 or 4 drugs with evidence that shows even frail people can benefit from four drugs, often with  low doses.

Regarding daratumumab (dara), there are several studies which have looked at combining  daratumumab with bortezomib, lenalidomide and dexamethasone (dara+VRd) or carfilzomib, lenalidomide and dexamethasone (dara + KRd). A few papers evaluated dara with a newer drug, called iberdomide, and even older regimens. This is such an exciting time for myeloma patients, and for providers too in that we are not only using the best drugs we have and combining them in new ways, but we’re starting them earlier on in therapy.

Melanie Douglas

Speaking of standard of care, Beth, what do you consider when you’re deciding which course of action to take with a patient?

Beth Faiman

So right now, the standard of care for myeloma patients is you pick treatment A, B, C, or D, taking into consideration those factors you mentioned such as fitness, frailty, and the social and financial aspects; and then we sit together in that shared decision-making space and we recommend the right therapy for the patient based on their disease status and all those other factors. It’s funny because when we're having these conversations, a lot of the practitioners still want to say that daratumumab is the best drug for later, and I was talking to a friend and they said, "I don't know of any cancer you save your best drugs for last." So, it made me kind of laugh because dara is an effective medicine.

The standard of care is you give three or four drugs induction, and then transplant if they can, and then a maintenance, right? And lenalidomide maintenance is the gold standard of care based on so many studies. Randomized studies have not yet been finalized; it was mostly retrospective studies.

I want to talk about treatment a little bit more so we’ll come back to that, but what about some supportive care things like bone health, Melanie? What are some of the things you think of with protecting bones in myeloma and some of the drugs you might use?

Melanie Douglas

Of course, multiple myeloma patients are at a higher risk for lytic lesions, non-pathologic fractures, so you want to give them supportive treatment to protect those bones. Those phosphonates like zoledronic acid and pamidronate are really the first line, and an alternative is denosumab. We even give it to patients with severe hypercalcemia to help that as well. It's a monoclonal antibody, and especially in patients with significant renal dysfunction, it's a consideration as well. You just have to keep in mind that it could have rebound osteoclastic activity if you discontinue it, so at some point you have to get the patient transitioned to a bisphosphonate. Also, we have to remember that osteonecrosis of the jaw, while rare, is a very severe side effect of bisphosphonates, so ideally, we like to get patients evaluated with the dentist before starting one.

Beth Faiman

Absolutely, those are excellent points. The International Myeloma Working Group has guidelines from 2021 that recommend, based on cost, efficacy, and 20 years of data, using zoledronic acid upfront. Then, if a patient has CKD or a GFR less than 30, you should give the denosumab, just like you mentioned. Even on dialysis, this is safe in other conditions.

And I think what you brought up, Melanie, was an excellent point about that rebound bone loss. Giving one dose of zoledronic acid after you decide to stop the denosumab is what's recommended by the International Myeloma Working Group, and that was extrapolated from osteoporosis guidelines in patients without cancer, and this is something that I do in my practice. If for some reason we want to stop the denosumab, I'll give them a dose of zoledronic acid because we know the bisphosphonates stay in that bone microenvironment for several years and they could continue to be effective even when one is no longer receiving the drug. So again, making sure that you're remembering to image your patients with whole body low dose CT scan is the new gold standard for imaging. We have a bone health center on the JADPRO website that you can refer to, as well, if you wanted some more recommendations for bone health.

Let's go back and talk about the three versus the four-drug regimen and the maintenance as recommended to suppress the malignant clones because myeloma's a clonal disorder of the plasma cells, and these cells will regenerate and regrow if we stop suppressing them. Lenalidomide is the current gold standard. We had data at EHA 2023 that suggests that daratumumab might be another emerging option, especially for patients with high-risk myeloma. Let’s talk about first relapse, Melanie. What is the choice of treatment regimen? How does that differ for you from newly diagnosed? What do you think about with that?

Melanie Douglas

With the first relapse, we have to take into consideration how long it took them to get to this relapse? How aggressive is their disease? Even the first relapse can help portray, aside from their cytogenetics, how aggressive their disease is. Based on that, you can try to decide the next steps. And then you can still keep in mind the patient's fitness level, comorbidities, and social situation.

Beth Faiman

Right. And we think about what did they have before and did it work? What didn’t work?

Melanie Douglas

Yes.

Beth Faiman

So, let's say somebody started treatment with daratumumab, lenalidomide, bortezomib, and dexamethasone. So that's dara-VRd. It's a very standard treatment we're giving these days based on some randomized Phase 3 trials. We saw updated data at ASH 2022 on that. We'll update that in 2023 as well. Let's say they had those four drugs, what do you do when they relapse? What we try to do is get them to transplant and then maintenance with just lenalidomide. So if they're relapsing on lenalidomide, you can give them back dara or bortezomib. Do you use KPD (carfilzomib, pomalidomide, dexamethasone) in your practice or KRd, Melanie?

Melanie Douglas

Yes, definitely. Sometimes you can use carfilzomib as an alternative to bortezomib. It's also a proteasome inhibitor. I think there's some data to show that especially for the high-risk patients, it could be useful. It’s not very common, but you how have to watch for cardiotoxicity with that. So, you always have to do an echocardiogram upfront before starting that. And that's a great drug also for first relapse. I have even seen it used once in a while for frontline in a high-risk patient.

Beth Faiman

That's an excellent point. We use a lot of dara-KRd upfront in the newly diagnosed high-risk patients.

Melanie Douglas

Definitely.

Beth Faiman

Regarding KRd data, the FORTE study by Francesca Gay in the Italian myeloma group, was a really well-done study with KRd induction, then transplant, and then patients were randomized to different maintenance arms. Patients with high-risk myeloma did very, very well in this study by achieving minimal residual disease (MRD) negative rates.¹ That’s the ability to eradicate the bone marrow plasma cells with effective treatment. The technique to determine MRD-negative status is  through next generation sequencing, which is the most sensitive sequencing we have to detect aberrations. Currently, we have FDA cleared tests in which you can detect one in a million plasma cells or 10^-6.

And MRD-negative status is one of those features that we look at for prognosis and long-term progression-free survival, which hopefully 10 years down the road will be overall survival. There is currently a lot of controversy as to whether you continue treatment in a patient who is MRD negative, or stop therapy, and after which time frame. So MRD is nice to know but outside of well-designed clinical trials, I wouldn’t make treatment decisions based on results.

Getting back to the combination KRd, if a patient didn't receive this combination at diagnosis, this is an excellent choice for an early-relapsed person with myeloma. As far as the cardiotoxicity, there are not any standard ways to evaluate for cardiotoxicity, but just like you said, Melanie, I like to make sure I have a baseline echo within six months before starting the drug.

Melanie Douglas

Right.

Beth Faiman

We want to also make sure our patients don't have concurrent cardiac amyloidosis. Amyloidosis is this folding of the light chain protein tends to be lambda, but can be kappa. That can latch onto tissue such as the heart muscle, and it'll make a thickened myocardium. So, if you get an echo, you look at the posterior wall thickness, and if that's over 1.1 or 1.2, and they're not a 75-year-old with long-standing hypertension, you think, why does this 40-year-old have a thick heart wall? And you want to really make sure to do a cardiac MRI and check activity.

Melanie Douglas

Exactly. You should have a session because it's very hard to diagnose cardiac amyloidosis. You may need a cardiac MRI, even refer them to a cardiologist.

Beth Faiman

Yes, for sure. But it still can be safely given. If I'm working up somebody in aggressive relapse with first-relapse myeloma and I want to give them carfilzomib, I'll do a lower 20/27 schedule because there are lots of different doses, 20/27, 20/56, and 20/70. And we do that step-up dosing because in 2007 in the early trials, there were some cases of tumor lysis syndrome in myeloma patients. The prescribing information and the recommendation say to start at 20mg/m2 carfilzomib, and then the next week (if you give it weekly) you escalate to the 27 or 56 or 70, whatever your dose is if it's combined with something else. But that's an interesting point; I like to remind people to tell the patients that you're going to plan the escalation because I've had situations where the treatment nurse calls me and the patient's upset that they think that the treatment's not working because they're getting a higher dose this week.

The pre-med for the carfilzomib is usually 4mg, but if you're giving it with daratumumab or other agents because it is approved, dara-KRd, dexamethasone first relapse, they'll oftentimes be getting dexamethasone and anti-hypersensitivity meds too.

There’s another thing one must consider, and that is blood clot risk. When I get a newly diagnosed patient, I’m concerned about the increased risk of venous thromboembolic events especially in patients who are prescribed carfilzomib and IMiDs such as lenalidomide. What do you do for your patients when they're on those two drugs? Do you fully anticoagulate them? Piedra et al had a paper that evaluated the use of  direct oral anticoagulants  (DOACs), compared to aspirin in a retrospective chart review study  of 305 patients who received KRd or VRd as induction therapy. While the incidence of venous thromboembolic events (VTE) was low in patients who received VRd and aspirin as VTE prophylaxis, the incidence of clots increased to 16%. When patients were given a DOAC, they didn't have any major bleeds with the DOAC, and decreased the risk to 2.2% in both groups.² Melanie, are you aggressive with anticoagulation in your myeloma patients?

Melanie Douglas

Absolutely. A lot of times I see a DOAC, it’s usually not a full treatment dose. It's not the same dose as a patient you're treating for a stroke or atrial fibrillation or DVT, so we call it a prophylactic dose. One that I see a lot is 10 milligrams of rivaroxaban instead of 20 milligrams. There are patients on other agents though, such as apixaban. I sometimes see baby aspirin as well. Naturally, we must watch for development of thromboembolic events while patients are on these agents and have a high index of suspicion for them when they present with a relevant clinical picture. There was a patient of mine who developed a stoke while on lenalidomide. Her rivaroxaban was increased to full dose and she was referred to a benign hematologist who deemed that she could continue with the lenalidomide as long as she remained on the treatment DOAC dose.

Beth Faiman

Kristen Sanfilippo was the investigator on the paper about predicting venous thromboembolism and the use of IMPEDE VTE score.³ We used this IMPEDE VTE score in myeloma and we use this tool to risk-stratify each of our patients. We recently validated the IMPEDE VTE score at our institution, as it's been done in other institutions. We published our paper about it in the British Journal of Haematology in 2021.⁴ It gives you a score based on things like immobility, increased body mass index, if they’re undergoing major surgeries. If they have a high score, we give them the rivaroxaban or apixaban, whatever their insurance covers. And if they have a low score, then everybody just gets baby aspirin if it's a regimen that we worry about thrombotic risk.

Melanie Douglas

That’s great information to have. Was there anything else you wanted to talk about?

Beth Faiman

Yes, the last thing I want to talk about is super important in myeloma and it is infections. They’re a big deal with some of our new bispecific antibodies, CAR T-cell therapies. But it's also a big deal to our patients with newly diagnosed myeloma. There's a high incidence of patients with early death in the first three months of therapy, so much so that they've done studies in Europe, which turned out unfortunately, to be negative. We found out that levofloxacin prophylaxis was recommended by the TEAMM study.⁵ We thought that that was going to protect people from early death, from infection during the induction phase. And unfortunately, at one year it didn't meet its primary endpoint. So, we don't do that, but we do other things, like antiviral prophylaxis with proteasome inhibitors and other regimens.

Melanie Douglas

Out of all antimicrobials that I see, almost everybody on is acyclovir. Even for patients who aren't the most immunocompromised, never gotten infections before, we're always worried about shingles or herpes.

Beth Faiman

Absolutely. With regard to shingles prevention, I think back to the early days of bortezomib with studies that dated back to before the 2003 approval. One study by Kim et al showed a 22% increase in shingles reactivation among patients who did not take acyclovir prophylaxis. Swaika et al. (2012) evaluated 100 patients who received acyclovir prophylaxis. None of the 100 patients experienced reactivation.⁶ And because the Shingrix vaccine has not been tested in immunocompromised individuals, even if they've been vaccinated for shingles, we still recommend the acyclovir or valacyclovir. So the take-home point is that if patients are on treatment and receiving proteasome inhibitors, monoclonal antibodies like daratumumab or elotuzumab, or if they've undergone stem cell transplant, acyclovir prophylaxis is recommended.

In 2022, Noopur Raje was the lead author on a paper about infection prevention guidelines and recommendations based on the International Myeloma Working Group.⁷ The thing I like about this paper is from newly diagnosed to heavily pretreated, they give you different levels of what is recommended for infection prevention, such as the CDC guidelines of pneumococcal vaccination. I follow the CDC Guidelines, and most institutions now are going to the conjugate vaccine, PCV20. So, if your patient has a myeloma diagnosis, regardless of age, they should all be vaccinated against the pneumococcal. And that's still about every five years. It’s hard these days because people go to their primary care provider and then they are admitted inpatient, and then they'll go to a different hospital. It’s helpful for the patients to know what they're getting when they get it and then write it down so you have that immunization record and they don't keep getting immunized. There’s also the seasonal inactivated influenza vaccine. The COVID vaccination continues to change and evolve. We need to make sure the patients are aware of signs and symptoms and red flags and know to go to the ER or call the office.

What do you tell your patients about infection with myeloma?

Melanie Douglas

As you were alluding to earlier, once you have a diagnosis of multiple myeloma, even you haven’t been treated yet, or you’re on your first line if treatment, you're still at risk for infection just because you're more immunocompromised and the pathophysiology of it. So we tell patients when we send them home after they're done with chemotherapy to call their doctor or even report to the hospital if they have a fever because it could be a neutropenic fever.

Beth Faiman

What are some other protection things that you do for your patients with myeloma, Melanie?

Melanie Douglas

Both a prophylactic antibiotic and antifungal are recommended in patients with prolonged neutropenia and in patients on aggressive regimens like VD PACE or DCEP which tend to knock out counts. In heavily pretreated patients receiving a bispecific antibody that works by attacking multiple cell surface antigens, PJP prophylaxis should be considered. Patients on steroids with dosing equivalent to dexamethasone of at least 40 mg per day for four days per week should be on PJP prophylaxis. Bactrim is often well tolerated, but one must keep in mind that this is often not the agent of choice in patients with hyperkalemia, renal failure, or severe pancytopenia as it could suppress counts; of course there are quite many myeloma patients that would fall into at least one of these categories. So an alternative agent such as atovaquone or pentamidine may need to be considered, with careful consideration of the patient’s individual medical profile. Additionally, it is imperative to screen for HIV and Hepatitis B before starting treatment, as well as Hepatitis C depending on the patient’s profile.

Beth Faiman

One must not forget about practical things right? Wash your hands, avoid people with colds, that kind of stuff.

Melanie Douglas

Especially when COVID started, we were telling patients, I'm sorry, we don't advise that you go to anywhere, don’t go to the wedding for example. It’d be so hard. This was in the beginning, before we could administer vaccinations.

Beth Faiman

Great. Well, Melanie, I wanted to thank you for taking time today.

Melanie Douglas

This has been a great conversation. I’m going to review these trials that you talked about, review the data that backs up what I see that we do.

Beth Faiman

There’s always something new to learn.