High-Risk Smoldering Multiple Myeloma Highlights from ASH 2022

What Newly Diagnosed Patients and Caregivers Need to Know

Multiple myeloma patient advocate Jack Aiello has been living with myeloma for 28 years.

In this conversation, he speaks with Dr. Shaji Kumar, a hematologist at the Mayo Clinic whose research focuses on the development of novel drugs for the treatment of myeloma.

They discuss the difference between smoldering myeloma and active myeloma, the determining factors of high-risk patients, and what high-risk smoldering patients can do to delay or possibly avoid progression to active myeloma.

This interview has been edited for clarity. This is not medical advice. Please consult with your healthcare provider for treatment decisions.

Introduction

Jack Aiello: I’m with The Patient Story. I’m a myeloma patient and have been for 28 years. I have followed this field very closely and always know that there’s more to learn.

Dr. Shaji Kumar: I’m a hematologist at Mayo Clinic in Rochester, Minnesota.

What is smoldering multiple myeloma?

Jack: Around 30,000 oncologists, researchers, physicians, pharma reps, and more from around the world attend the annual American Society for Hematology conference, also known as ASH, to hear the latest myeloma research from clinical trial investigators, like Dr. Kumar.

We’re going to primarily focus on a topic of myeloma called smoldering myeloma and that’s important because it’s a precursor to myeloma, although you may have never been diagnosed as smoldering.

Dr. Kumar, can you explain the differences between smoldering myeloma and multiple myeloma? And what determines high risk for smoldering vs. high risk for myeloma?

Dr. Kumar: With myeloma, we have precursor stages that clearly exist before patients actually get active multiple myeloma.

What we have learned is that the process that eventually leads to [the] development of active myeloma probably happens sometime in the 30s for many patients. We think it takes an average of about 15 years for that initial seed, so to speak, to grow into a stage where it is actually creating problems like active multiple myeloma does.

There are two distinct stages within this precursor phase. One of which is called monoclonal gammopathy of undetermined significance, essentially saying that you can find that initial condition. We can find some abnormal plasma cells, but they’re quietly sitting in the bone marrow, making protein that we can detect in the blood, which allows us to identify and diagnose this condition, but not really doing any major damage that we are aware of. We know that in some people, it can lead to some symptoms other than what we see in myeloma.

It’s important to note that this monoclonal gammopathy of undetermined significance is not something that is uncommon and certainly increases with age. In fact, if you take 100 people who are 70 years or older, you’re probably going to find that eight to ten of those people will have a monoclonal protein in their blood, suggesting that they do have this early condition that is sitting there.

We also know from long-term studies that [for] the vast majority of the people, eight out of ten people with that monoclonal gammopathy, it will amount to nothing. People will just live their normal life, a normal length, without it ever becoming a problem. But for the other two out of the ten, it can evolve into something that needs something to be done to it and that is often multiple myeloma.

When patients develop multiple myeloma, clearly they have damage to their body because of this abnormal group or collection of plasma cells or myeloma cells which have become cancerous. They can destroy the bone, produce high amounts of protein that get deposited in the kidneys and cause renal failure or kidney malfunction, can cause high levels of calcium, [and] can cause people to be anemic.

In some people, we can certainly identify them before these things happen or identify them at a stage where these things are very imminent and we can start treating them. But those definitions overall together [are] what you would call active myeloma or symptomatic myeloma that clearly needs treatment.

Wedged in between active myeloma and monoclonal gammopathy of undetermined significance or MGUS are people with what we call smoldering multiple myeloma. These are patients or individuals where the amount of plasma cells or proteins [has] progressed to a point where there is [a] considerable amount of those cells in the bone marrow, typically defined as more than 10% or an M protein in the blood that’s more than 3 grams.

Over time, what we have learned is these people are in between the markers and myeloma; [it] is not a distinct diagnosis, so to speak. It’s more of a collection of people who truly has more MGUS or more myeloma. We just can’t do one test and say you are more myeloma-like or you are more MGUS-like. We just have to depend on time for things to declare itself.

For at least half or two-thirds of people with smoldering myeloma, it is okay to sit and wait, but the other third may be at a higher risk of progressing. Those are the individuals [whom] we really think we could do something with the treatments we have and actually make a difference.

When we say make a difference, we mean [delaying] the time they actually get active myeloma, maybe [preventing] them from ever getting active myeloma, or maybe [curing] some of those people and we can just forget that they will ever get myeloma and not even worry about it again.

How do we identify those people? We need to be able to get to them in as precise a fashion as we can. We want to limit the number of people who might get exposed to these treatments, which may not have the same benefit [to] others.

One of the ways we do that is to use the International Myeloma Working Group criteria. Laboratory markers tell us the risk of that individual getting active myeloma in the next two years. If you think it’s more than [a] 50% chance, we feel like we need to do something about it.

There have been large phase 3 trials that have been done, which clearly show that there is a rationale for intervening in those people.

The difference between smoldering myeloma & multiple myeloma

Jack: You’re saying there is a method to determine high-risk smoldering. What’s the difference between them?

Dr. Kumar: We are talking about a stage that you may or may not have gone through. Not everybody has to be in a smoldering stage before they go from markers to myeloma, but many would have gone through the stage.

What we are trying to do here is to see [if] we can do something different for future patients, a course that is different than what you all went through.

The most critical thing that is different is, of course, whether it’s doing damage to your body — bone lesions, kidney problems, anemia, high calcium — or not. There are some individuals who may not have those characteristics, but the risk of getting that is very high: 80% plus in the next two years. Those people, we already consider as active myeloma and not smoldering anymore.

Jack: High-risk myeloma patients are more determined by mutations of certain chromosomes and things like that, right?

Dr. Kumar: That is right. When you talk about high-risk multiple myeloma or active myeloma, we’re talking about people with chromosomal abnormalities (translocations or 17p deletion), high LDH levels, or if they have stage 3 [based on] the International Staging System.

What is the ASCENT trial?

Jack: At ASH, you presented abstract 757 on the ASCENT trial for high-risk smoldering myeloma patients. What was this trial about?

Dr. Kumar: When you think about doing something different with people with high-risk smoldering, what’s our ultimate goal? We want to make sure they never get myeloma and they never have to get myeloma-type treatment that is often given continuously for long periods of time.

There are two approaches. One is obviously to give less intense treatment than what we do in myeloma and try to kind of kick the can down the road, so to speak. The other option is since we caught it so early, to see [if] we actually just get rid of it completely and maybe never even worry about it.

The former approach is what has been taken in the large phase 3 trials that the Spanish group did [and] the cooperative group in the US did. Both trials showed that people with high-risk smoldering myeloma, if you treat them with lenalidomide or lenalidomide and dexamethasone — far less intense than the three- and the four-drug combinations we use for patients with active myeloma — those interventions actually delay the progression to myeloma and, in fact, make people live longer.

What we’re really trying to do with the second approach is trying to cure the disease. There have been some trials looking: can we use more intense treatments and give it for [a] short duration to try and get rid of those myeloma cells?

The Spanish group did a trial called the CESAR trial, which was also updated at ASH [2022]. They treated people with the combination of carfilzomib, lenalidomide, and dexamethasone (myeloma-type treatment), did [a] transplant (this trial only included transplant-eligible patients), and then get them on maintenance treatments like what we would do for myeloma but give it over a defined period of three years instead of giving it continuously until [the] disease comes back.

With a longer-term follow-up [of] four-plus years, what they have seen is only five of the 81 or so patients that they enrolled have progressed to active myeloma. [For] many of those people who have progressed, the progressions have been predominantly just biochemical, meaning the M spike goes up [but] they don’t actually get myeloma.

What the ASCENT trial did was take a slightly different tact. Knowing that a significant number of people cannot go do a stem cell transplant, instead, we will do a monoclonal antibody, like daratumumab added to carfilzomib-len-dex. We use carfilzomib, lenalidomide, daratumumab, and dexamethasone for 12 cycles and then gave them maintenance for 12 cycles for daratumumab and lenalidomide. Basically, two years defined duration of treatment in patients with high-risk smoldering myeloma.

What we found was these results are quite similar to what we have seen in [a] myeloma setting. We get deep responses. Almost two-thirds of the people actually get what we call a stringent, complete response, meaning we can’t really see any protein. We can’t really see any myeloma cells under the microscope.

More importantly, nearly two-thirds of the people who got there also were minimal residual disease negative. We cannot even detect myeloma cells in the bone marrow by using highly sensitive approaches. It seems like this approach does manage to eradicate at least a significant proportion of the myeloma cells in the bone marrow.

The question that’s going to be really critical for us is: does this eradication mean that these cells will not grow back like what it does in myeloma? Only time will tell. I think both studies will continue to follow these patients over a long period of time to see if this emerging activity that we have seen is something that can be sustained over a long period of time without continued treatment.

How long until SMM patients are cured?

Jack: How long do you think you need to follow these patients before you can say these patients are cured?

Dr. Kumar: That is a good question and I don’t know if we all know the right answer to that. But the longer we can go without the disease coming back, I think the higher the probability that we may have actually eradicated this.

I’m just going to put a number out there. If in 10 years from the start of the treatment — that means eight years without any treatment — the myeloma hasn’t reared its head back up, I think I would call it successful. Obviously, each passing year is more and more of a success.

Jack: I guess we hope to see some plateau of the curve where people are no longer relapsing if you will.

Dr. Kumar: I think that is going to be the key because, in myeloma, we know that even if they get to be MRD negative, that curve never becomes flat. People continue to kind of fall off because of myeloma coming back. We’re hoping that it would be a different picture here, like what we see with some other hematological cancers like lymphoma and so forth.

Are there still trials open for high-risk smoldering patients?

Jack: At the IMF ASH symposium, Dr. Vincent Rajkumar said that treatment for all high-risk smoldering patients should either be Revlimid with or without dexamethasone or a clinical trial. Do you agree? Are there still trials open for high-risk smoldering patients?

Dr. Kumar: Yeah, I completely agree. We have to always build upon what we have learned and what we have learned in smoldering from two large trials that doing something is better than not doing anything. Giving them at least lenalidomide or lenalidomide with dexamethasone [not only] prevents the myeloma [from] coming back, [but] the Spanish trial has actually made people live longer. We owe it to our patients to have that discussion about the choices.

Ideally, if I had the option, I would definitely put everybody on clinical trials rather than using that treatment because there’s so much more to be learned. We don’t know if lenalidomide-dexamethasone is the right approach. Should we treat them like myeloma with three drugs, which is the focus of the ECOG trial?

The SMM trial is currently enrolling so that is a trial that can be considered. There’s [an] isatuximab trial that is currently accruing looking at isatuximab-len-dex versus len-dex. There [are] also multiple smaller trials in different institutions that are looking to try and see: are there specific combinations or specific drugs that might actually provide a meaningful benefit for patients with high-risk smoldering? It remains an area of active investigation so I would strongly encourage everyone to consider enrolling in clinical trials.

Asking your doctors about clinical trials (high-risk smoldering patients)

Jack: The important thing for smoldering patients is to ask their doctors: are they considered high-risk smoldering or not high-risk smoldering? If they are high-risk smoldering, they should be asking their doctor about trials. Most of these trials that you just mentioned can actually be done locally. They don’t necessarily, I think, have to be done at major cancer centers. Is that correct?

Dr. Kumar: That is right. That’s especially true for the cooperative group trial like the one we have in ECOG. It should be open in pretty much all the community cancer centers across the country.

Conclusion

Jack: Thank you so much. I’ve learned more about smoldering as well. As I said, you can always learn more about myeloma and different avenues of myeloma treatment. Any final takeaway from ASH that you want to mention?

Dr. Kumar: There’s a lot of data presented at ASH. Spanning all the way from simple questions like, “Should we be doing a bone marrow in patients with MGUS?” to obviously, “How do we treat those people or new drugs that would be potentially effective in people who have seen it all?” It’ll probably take hours to go through all that important data.

There are so many new therapies that are coming through that are so effective, especially immune therapies. We started seeing some of those being employed in the first-line treatment and the first relapse. In five years, the treatment of myeloma is going to look very different than what we are doing today.

Jack: Dr. Kumar, it’s always a pleasure talking with you and I want to thank you so much for providing your insights to The Patient Story.

Dr. Kumar: Thank you, Jack.

Multiple Myeloma Patient Stories

Clay D., Relapsed/Refractory Multiple Myeloma



Symptoms: Persistent kidney issues, nausea

Treatments: Chemotherapy (CyBorD, KRd, VDPace), radiation, stem cell transplant (autologous & allogeneic), targeted therapy (daratumumab), immunotherapy (elotuzumab)
...

Melissa V., Multiple Myeloma, Stage 3



Symptoms: Frequent infections

Treatments: IVF treatment & chemotherapy (RVD) for 7 rounds
...

Elise D., Refractory Multiple Myeloma



Symptoms: Lower back pain, fractured sacrum

Treatments: CyBorD, Clinical trial of Xpovio (selinexor)+ Kyprolis (carfilzomib) + dexamethasone
...

Marti P., Multiple Myeloma, Stage 3



Symptoms: Dizziness, confusion, fatigue, vomiting, hives



Treatments: Chemotherapy (bortezomib & velcade), daratumumab/Darzalex, lenalidomide, revlimid, & stem cell transplant
...

Ray H., Multiple Myeloma, Stage 3



Symptoms: Hemorrhoids, low red blood cell count

Treatments: Immunotherapy, chemotherapy, stem cell transplant
...

Newly Diagnosed Multiple Myeloma Highlights from ASH 2022

What Newly Diagnosed Patients and Caregivers Need to Know

Multiple myeloma patient advocate Cindy Chmielewski has been living with myeloma for nearly 15 years. After experiencing excruciating back pain for two years, she was diagnosed with IgG Kappa stage 3 multiple myeloma.

In this conversation, she speaks with Dr. Caitlin Costello a hematologist-oncologist at the University of California, San Diego and Dr. Sagar Lonial, the chief medical officer at the Winship Cancer Institute at Emory University.

They discuss cutting-edge treatments and therapies for both transplant-eligible and transplant-ineligible patients, combination therapies and the necessity of stem cell transplants.

Thank you to Janssen for its support of our patient education program! The Patient Story retains full editorial control over all content.

This interview has been edited for clarity and length. This is not medical advice. Please consult with your healthcare provider for treatment decisions.

Introduction

Cindy Chmielewski, Myeloma Patient: I’ve been living with multiple myeloma since 2008. I was a fifth-grade teacher and I simply loved my job.

Around 2006, it became very difficult to teach. I was experiencing excruciating back pain. Standing was very hard, recess duty was almost impossible, and I couldn’t even take my class on a field trip. The tears would come down my cheeks. That’s how much pain I was in.

For the next two years, I was prescribed pain medication and physical therapy. I was a very different person than I am now. I grew up in [the] age of doctor knows best so I really didn’t question what my doctor was doing, although I thought that maybe we should be taking an X-ray of my back.

I was diagnosed with IgG kappa stage 3 multiple myeloma. The multiple myeloma was in over 99% of my bone marrow.

I started treatment immediately. The treatments back in 2008 were very different than now. In the beginning, I had a tough time. The treatments were not touching my myeloma. I had initial success, but then it stopped working. I had a stem cell transplant and that didn’t work. I was devastated. I really didn’t think I was going to live much longer.

A treatment that my doctor suggested began working for me. It worked so well that it put my disease into remission.

Since about 2010, I’ve been on maintenance therapy and able to live my life. In the meantime, I retired from teaching because I didn’t know what I was going to be doing.

I’m a different person now. I don’t teach fifth graders; I teach myeloma patients about myeloma and how important it is to be actively involved in your care, not to be that person like I was back in 2008 just blindly following doctor’s orders

It’s important to learn all you can about your myeloma, to ask questions, and to make decisions. It’s so exciting because now, there are so many treatments to choose from that if one thing stops working, there are so many other choices.

[In this conversation] I talk with two myeloma specialists about the latest happenings for the newly diagnosed population coming out [of] a meeting called ASH [American Society of Hematology].

Dr. Caitlin Costello is the hematologist-oncologist at the University of California, San Diego who specializes in treating multiple myeloma and participates in many of the myeloma clinical trials.

Dr. Sagar Lonial is the chief medical officer at the Winship Cancer Institute at Emory University, the chair of the hematology and medical oncology department, and a lead voice in the myeloma research community.

Transplant-eligible and transplant-ineligible patients

Cindy, TPS: Usually, newly diagnosed [patients] are broken up into two groups: transplant eligible and transplant ineligible. Before we even start talking about what’s happening in that area, how are those defined? How do you know if I’m transplant-eligible or ineligible?

Dr. Caitlin Costello: Good question and, actually, a bit of a moving target. [Transplant eligibility] is usually assigned at the time of diagnosis. A patient first gets diagnosed with multiple myeloma.

Historically, oncologists got kind of a gut instinct to say, “This patient is younger, older, healthier, less healthy, [have] a good performance status.” They’re independent [in] their activities of daily living. They can bathe themselves. They live alone. They do their own grocery shopping. Whatever it is. We’d look at a patient and say, “Healthy, not healthy, old, young,” and make generic assignments to people.

That’s really challenging to do when someone’s first diagnosed with myeloma because when you’re first diagnosed, you’re sick. You don’t feel good. You’ve spent months trying to figure out what’s going on. It may have taken a while to get the diagnosis at that point. Many bones have been affected by myeloma. It can be very painful. A lot of people just aren’t what we think normal health is.

Traditionally, we have made assignments when patients were first diagnosed to say, “You are healthy enough, strong enough, or well enough that you can get an intensive regimen called a bone marrow transplant or not.”

There’s been a bit of an evolution to the concept of transplant eligibility as some more data has emerged to say, “Does everyone have to get a transplant?” Maybe we don’t need to use those same kinds of assignments to make that determination. 

I think the better way to distinguish between patients who may be able to get a transplant and patients who may not is frailty. Frailty is a little bit more of an objective, as opposed to a subjective, means of evaluating someone’s health and independence. 

[It can] really help identify those patients who may be candidates for more intensive therapy throughout their myeloma diagnosis and their treatment. That is kind of where we’ve landed on transplant eligibility and ineligibility. Do we think people are well enough to undergo a bone marrow transplant?

Improving frailty in patients

Cindy, TPS: Frailty is dynamic now. It can’t be just measured at one point because, throughout the course of treatment, you may improve because the treatment is helping you out.

Dr. Costello: That’s our goal. So many patients are not well when they’re first diagnosed but can turn around pretty quickly where they perk up. Their bone pain is under control [as well as] their anemia, their kidney disease, or whatever way the disease manifested. 

Treatments now are so good that patients are responding so quickly. They get better quickly. The way that your doctor first met you when you were diagnosed is unlikely the same person that they will meet two months down the road after you’ve started treatment.

Our job is to continually reassess your health and your general wellness to make that decision because what you were yesterday may not be what you are tomorrow.

Treatment for transplant-ineligible patients

Cindy, TPS: Let’s talk about that group, transplant-ineligible patients, people who may be not strong enough for their body to endure this treatment. What’s the most common type of treatment that this group of people usually get?

Dr. Costello: A bit of an evolution as well. We’ve had so many new drugs developed in multiple myeloma. When drugs get developed, they are first approved for patients who have had many prior treatments. They’re looking for the next newest and greatest. 

That’s usually how the FDA approves these drugs. They approve it and say, “Let’s just start with this group of patients.” Over the years, it gets tested with more and more patients earlier on in their diagnosis. 

One of the things that patients with newly diagnosed myeloma, who are not planning or not eligible or too frail to go to transplant, have enjoyed is the addition of daratumumab to the first treatment you receive when you’re diagnosed. 

Daratumumab, [as] I like to describe [it], is a bit of a magnet. It’s technically called a monoclonal antibody, but it is a medicine that predominantly is given as a shot. It is particularly looking for a sign on the myeloma cells that says, “Hey, this is me.” When it finds it, like a magnet, it sticks to it. 

That helps pop it open and it pops it open with many different approaches. It’s a real kind of targeted treatment and uses your immune system to help kill as well. I have seen daratumumab evolve into the gift that keeps on giving because it really has helped so many patients [at] various time points in their disease. 

Now, being so effective, why wait? Why can’t we use it when patients are first diagnosed? That has really now turned into the optimal treatment as a basis for when older, frail, weak, or less healthy people are diagnosed with myeloma. 

But remember, we like to use multiple drugs. I think of it as like the old game of Clue. Instead of just using a candlestick, a revolver, or a lead pipe, we want to use all the tools we have together as a cocktail so that we can approach the myeloma, sneak up on it, and kill it [in] different ways. 

Daratumumab is great in combination with many different treatments. I’d say the frontrunner right now is the combination of daratumumab with lenalidomide, also known as Revlimid, plus or minus dexamethasone, which is something that we’ll get into.

What is maintenance therapy?

Cindy, TPS: Since this is a program for newly diagnosed patients, sometimes all these terms are hard to understand. Can we talk about what maintenance therapy is? Why is it important?

Dr. Sagar Lonial: That’s an important question and it gets into another important data set that was presented at ASH [2022], really focusing on [the] duration of maintenance therapy. What we know is that if you give highly effective therapy, you will get a deep response. 

Many of the measures we use to evaluate how much myeloma remains are not perfect. Even MRD, which is minimal residual disease testing at one in a million or fewer, is still not necessarily a surrogate for [the] cure or elimination of the disease. 

What we’ve learned is that a little bit of low-dose, non-intensive therapy can maintain that remission for a longer period of time. In randomized trials [where] patients that got no maintenance therapy versus patients that got Revlimid alone as maintenance therapy, the remission duration was at least double for the patients that got maintenance therapy.

The goals of maintenance therapy are to be low intensity and not necessarily impact [the] quality of life. While I’m aggressive about continuing maintenance as long as I can, I usually say we continue until progression or toxicity. Obviously, toxicity is an important variable in that discussion. 

What we now know is that high-risk myeloma patients need more than just Revlimid as maintenance therapy. Our group, and now several other groups, have shown that a drug like Velcade added to Revlimid, or carfilzomib added to Revlimid, is able to induce deeper and more durable responses, particularly in high-risk patients. Maintenance means lower intensity, but the goal is to ultimately improve outcomes.

3 vs 2 drugs (MAIA trial)

Cindy, TPS: There were some updates in the MAIA trial at ASH [2022]. Can you tell us the latest and greatest from the MAIA trial?

Dr. Costello: The MAIA trial was designed for [the] patients that we’re talking about. They got the combination of three medicines — daratumumab, lenalidomide, and dexamethasone — and compared it to patients in that same group and only gave them two of the medicines — lenalidomide and dexamethasone. 

The whole point was to understand: is three better than two? If so, how can daratumumab help improve above and beyond just the two? It was designed for patients when they were first diagnosed, not going to transplant. [They] use these treatments for as long as they are effective and as long as it’s tolerated by the patient. 

It’s been a good number of years now since this trial started [and] ended. [They] are still following these patients for many years to try and see over time not only how successful it is but how durable it is.

The greatest thing and probably the most important thing we can do is [to] get people into remission the first go around. We like to say the first cut is the deepest. How can we have the most success when the myeloma is in its most kind of naive state? It doesn’t know any better. It’s not going to become resistant. We want to throw our best kind of weapons at it first.

[In] the MAIA trial, over the last many years, we’ve seen updates that come out that tell us time and time again that the three medicines combined are [an] extremely successful combination to get people into remission [and] keep them there. 

The durability is because we are killing so much myeloma. The myeloma you can see above the surface [and] under the surface that’s very hard to detect. We’re just killing it all.

By making the myeloma stay away, people are living longer. We’re seeing all these outcomes and results from the MAIA trial year after year, showing that the success of these three medicines together is great because it works and it lasts.

Using 4 vs. 3 drugs for treating transplant-eligible patients

Cindy, TPS: The MAIA trial was trying to see for the ineligible patients if three is better than two. For the transplant-eligible patients, I know the question is, “Is four better than three? Should we be adding daratumumab to RVd (Revlimid, Velcade, dexamethasone)?” One thing that keeps coming up is quality of life. Can we talk about 4 vs. 3 in the newly diagnosed transplant-eligible population?

Dr. Costello: If we’ve proved three is better than two medicines together, it brings up the next natural question: is four better? That question is trying to answer if [they should be] adding daratumumab to another group of patients who have just been diagnosed with myeloma.

Let’s say that this is a younger, stronger, healthier group of people, who we have historically treated with three medicines called lenalidomide, bortezomib, and dexamethasone. For the last many years, that combination has been the mainstay. It’s been the most widely accepted, most successful treatment that we’ve been able to achieve ever. But we need to always do better.

The GRIFFIN study looked at patients who were younger, healthier, stronger, going to go to transplant, divided it in half, and said, “I’m going to give you three medicines like we always do. This is the current standard of care,” or, “I’m going to give this other half four medicines.” The same treatments that the first three got — Revlimid, Velcade, dex — and add the daratumumab to it for a group of four. 

All patients got the treatment that they were assigned. All patients subsequently had a bone marrow transplant. After the transplant, all patients got consolidation and maintenance, which just means a little extra therapy after your transplant, followed by some amount of maintenance therapy, which is usually either fewer drugs or lower doses as a means of maintaining the successes you’ve had from all the treatments prior.

By comparing four drugs to three drugs for this group, again, daratumumab keeps winning. We see that daratumumab is effective at deepening response, killing more myeloma, making it get into remission more likely, [and] allowing patients to get back to themselves, to get stronger, and to continue on some amount of medicine that’s going to allow the myeloma to stay in remission in very deep ways. 

Again, seeing the same outcomes we saw in MAIA, the addition of daratumumab to our standard of care allows for great successes that last.

Do you think the 4-drug combination will be the new standard of care?

Cindy, TPS: Do you think the four-drug combination is going to be the new standard of care for newly diagnosed myeloma patients?

Dr. Costello: I don’t think “will.” I’m already doing it. It’s hard to ignore the data when it’s that good. Granted, the reason I think why you’re asking is because the trial that was done was technically a phase 2 trial, where [there is] a lot of drug development and new combinations.

The people that are the most critical of statistics and evaluating successes are the ones that really want to see what we call big studies, phase 3 trials, randomized data, or you’re comparing the standard to something new and novel. Those are happening. The same drugs, the same study, more patients — it’s happening. We’ll get that information. 

But on the same token, if I already have some information that shows me just how effective it is with a good number of people, I don’t want to wait. I want to do good and do well [for] these patients with these early successes that we’re seeing now. I think it’s here.

Who is eligible for quad-based therapy?

Cindy, TPS: When you’re talking about quads upfront, are we talking about all patients? How about frail, transplant-ineligible patients? 

Dr. Lonial: I think it typically tends to be the transplant-eligible [patients]. If somebody is frail enough that transplant is not really an option for them, I’m a little concerned about whether you can really give them a quad. 

There are some trials that are testing that right now and I’d like to see some of that data. In general, for the truly frail patient, the dara-len-dex (daratumumab, lenalidomide, and dexamethasone) combination is so good. Median remission is five years. It works regardless of age. That was evaluated in the MAIA trial.

I think that that’s a pretty good regimen and I’d like to see whether adding in bortezomib to make it four drugs really does improve not just death but [the] duration of response or lets us discontinue therapy at a certain point, which would be a huge step forward for that patient population.

Cindy, TPS: We’re talking about dara-len-dex upfront for the frail as opposed to RVd upfront. Is there a role for RVd now? Should it be a quad or dara-len-dex?

Dr. Lonial: I think there is a role for RVd in the frail patient, with weekly bortezomib in a patient that may have [a] high-risk disease. I still do believe that the proteasome inhibitor adds benefit there.

I don’t think carfilzomib is necessarily the right drug [for] a frail patient. I am still using RVd, in the beginning likely without dara, but certainly willing to add it in if I need to, if we don’t get where we want to go.

What does it mean to be high-risk?

Cindy, TPS: What do you mean by high risk?

Dr. Lonial: There are both clinical and laboratory features of high-risk myeloma that I think people should be aware of. 

An elevated LDH, lactate dehydrogenase, is one evidence of that. Circulating plasma cells [are] another laboratory evidence of extramedullary disease. Genetics, meaning FISH (fluorescence in situ hybridization) testing, looking for certain high-risk genetics on the myeloma cells. Things like 17p deletion, where you’re missing p53, 4;14 translocation, 14;16 translocation. In general, those are considered high-risk features. 

On the clinical side, patients that present with a lot of myeloma outside of the bone marrow, extramedullary disease if you will, tends to be high-risk disease as well. Some of these characteristics you can identify on lab tests. Some of them you can identify on exams or imaging. Those are the general rules that we use to try and evaluate risk at the time of diagnosis.

Side effects for different drug combinations

Cindy, TPS: The other thing that patients always are concerned about are side effects. Are there more side effects with the four drugs than [with] the three? What about quality of life? What are you seeing in your clinic?

Dr. Costello: The addition of daratumumab to any of these regimens, fortunately, is a reasonably well-tolerated medication. It is initially a little bit more inconvenient because of the frequency of the dosing. 

This drug is given once a week for eight weeks then every two weeks for another eight times. After those first six months, it goes down to once a month, which is a very attractive option for patients. They can just come in once a month, get their blood drawn, get a shot, and get out of there. From a perspective on [the] quality of life from inconvenience, I think it’s a really nice option. 

The greater side effect we think about — there’s probably two, I would say — that we’ve learned a lot in the midst of a COVID era.

One is [a] very small risk: 1 out of 10 patients with the first injection may have what we call an injection-related reaction, where patients may, kind of like a bee sting, have a variety of reactions.

Like a bee sting, you may get a little red spot, but some other people may need to have an EpiPen. With your first dose, we have to kind of stare at you a little bit [to] make sure that you’re not having those reactions. After that first administration, the likelihood of having a reaction is somewhere about 1 to 2% thereafter, so very low. The reaction risk is small but important.

The second one — and I think it’s a little bit more relevant these COVID-era days — is that multiple myeloma patients inherently have a weakened immune system. Their immune system is so busy making myeloma that it’s not making adequate amounts of your normal immunity. 

If you take a drug that’s designed to kill the immune system problem, you’re going to take some innocent bystanders with it. The daratumumab is going to try and kill all those myeloma cells, but those myeloma cells are plasma cells. Plasma cells are designed to make the weapons you need to kill the bad guys, whatever it is — flu, COVID, pneumonia, whatever. 

If we are taking patients who already have a somewhat weakened immune system or [are] trying to get their immune system to build back up, there is going to be some effect on the immune system that puts patients more at risk for getting infections. 

It’s important to make sure we are prepared for that. Vaccinating against the handful of different things we know are important for myeloma patients, whether it’s COVID, flu, or pneumonia, and sometimes using preventative antibiotics when patients are first diagnosed. 

I’m glad to say that unlike other medications that we use with myeloma that cause neuropathy where you have numbness, diarrhea, or severe fatigue — things that really can affect your day-to-day lifestyle — I don’t think daratumumab affects it as much.

The necessity of stem cell transplant (DETERMINATION trial)

Cindy, TPS: We have all these wonderful drugs that you’ve been talking about now. In the era of these novel therapies, is stem cell transplant still needed initially?

Dr. Costello: The million-dollar question. It’s ironic because it keeps getting asked. I think everyone is so hopeful that we can get rid of auto transplants because we have all these new medicines. Every time a new medicine comes out, the question is posed. A trial is done to say, “Do we still need [a] transplant or is this better?” 

That’s what this trial was designed to do. It took patients who were eligible for transplant, divided them in half, and gave everybody the same medicine: our triplet combination of Revlimid, Velcade, and dex.

[Then they] said, “You get this and you go to transplant. You get this and you don’t go to transplant. Let’s see what happens between those two,” with the idea of looking at [if] one group [is] going to have their myeloma come back sooner than the other group. 

The DETERMINATION study was the U.S. version of it. The French had their own version and they’re always ahead of the game with us with clinical trials. They were able to complete enrollment, get the results, [and] publish it well before we did. 

They showed that patients who got [a] transplant stayed in remission longer than those who didn’t. But after looking at the data for a handful of years, what they saw was that there was no difference in how long people lived. 

[There are] lots of arguments about whether that is important — and one would argue yes — [and] whether enough time had passed by to say, “Here we are. We keep applauding and patting ourselves on the back for how well these treatments are working. Maybe we haven’t had the full time pass by, enough to say that there’s going to be a great difference in survival or not.” 

When the Americans did theirs, the only subtle minor difference was that after [the] transplant, patients stayed on Revlimid maintenance indefinitely, as long as the maintenance was working. 

If they did not go [for a] transplant, they stayed on Revlimid as long as it was working, which was different from the French. They only took it for 12 months and then stopped. 

There were a good number of people who stopped therapy and often never had progression for 6 [to] 7 years. What the American side of the trial showed was similar. The transplant group stayed in remission longer. 

The survival was no different, but there did seem to be improved time to staying in remission because, we think, of the longer-lasting use of the maintenance Revlimid. 

I think it begs the question: is it that we need to get rid of transplant or is it that transplant is complementary? They parsed through that data left, right, up, and down to try and understand: was it the blondes who did better, was it the African Americans who did better, or [did] someone who had different kidney function do better? 

[They] tried really to see: is it a general statement we can make across the board? I think the thing that was the most helpful for me to try and parse through whether or not transplant was important or still has a role… While I would love to know that it saves lives, let me hearken back to my “the first cut is the deepest” comment. 

If we are really trying to make a deep impact in myeloma when it’s first diagnosed with the presumption that that’s going to allow for the longest periods of remission until the next newest and greatest comes out, then it’s pretty clear the way they parse the data to say that those who had transplant are more likely to get to what we call MRD negativity, minimal residual disease, which is [myeloma] way under the surface. 

We have lots of tricks to count myeloma. I can do a bone marrow biopsy instead of my pathologists. They look under the microscope and say, “Yep, I see it. Nope, I don’t.” But in 2023, shouldn’t we have super high-tech technology that can look for myeloma in the smallest little micron of DNA?

Dr. Costello: We want to try and get rid of every last bit of myeloma because those patients, we can tell time and time again now, are the ones who are staying in remission the longest.

The DETERMINATION study was helpful for me to say we’re not saving lives. We’re not letting people, as far as we know, live longer because of doing a transplant, but we are having patients stay in remission by doing it. 

Maybe we need more time to pass by, maybe we don’t. I think for the meantime, transplant really seems to me — disclaimer, I’m a transplant-er — that it’s complementary. I think it works with our novel agents, not better or worse than our novel agents.

Dr. Costello: Maybe we can try and figure out if our initial treatments didn’t do the job, maybe that’s the group of people who should proceed. So stay tuned. Lots to come.

Dr. Lonial: I think that with the results of the DETERMINATION study, it’s pretty clear to me that even with good drugs, transplant continues to offer [a] benefit. 

There are a lot of folks that say, “Well, if you’re already MRD-negative [and] it’s cycle 4, maybe you don’t need the transplant.” We actually don’t have any data that says that. My goal is to maximize the duration of that first remission because the myeloma is never more sensitive than it is at the time of the first presentation. 

By the time it relapses once or twice, you may lose the ability to gain the benefit from high-dose therapy, really high-dose melphalan. Certainly, at our center, we encourage patients to go into transplant in the first remission.

IVIG and daratumumab

Cindy, TPS: What about the use of IVIG with dara? Is that being used at all?

Dr. Costello: It is. I call [IVIG] a magic trick to try and build your immunity up a bit. Whether your myeloma is not making enough of an immune system or the treatments have compromised your immune system, your IgG, which is one of your weapons to kill the bad guys, can be decreased, can be accidentally killed, [or] can [be] whatever to suppress your immune system. 

If your immune system is weak because your IgG levels are low, why don’t I just give you some IgG? That’s what IVIG is: intravenous immunoglobulin. If I can give you some booster to your immune system, perhaps that will prevent some of these infections from happening. 

Historically, the way IVIG has been approached is to say if someone has severe, recurrent, life-threatening infections, those patients should receive IVIG. As we’re getting more and more aware of some of these infections that can happen with a variety of different medications that are out there for multiple myeloma, I know I have become much more liberal with my IVIG use because I think it could only potentially help.

Dexamethasone

Cindy, TPS: Let’s talk about this other drug that’s been around forever. As a matter of fact, I think in ancient times it was the only drug used to treat myeloma: dexamethasone. It’s always part of every combination.

Some studies being presented show that in the frail population, after a couple [of] rounds of therapy, we can maybe start lowering or dropping dex. Can you talk a little bit about that, too?

Dr. Lonial: In my experience and those of many of my colleagues, when we use dex, particularly in older, frailer patients, we tend to use a lower dose and for a shorter duration of time.

In my mind, the maximum benefit of dexamethasone is the first four to six months. I will often start to taper after the first or second cycle to try and get to lower doses and then hope to be off between month 6 and month 12.

That approach is something that many of us are doing in general. [For] patients getting daratumumab, for instance, the label says dex before and after the dose. We only have to do that for the first two cycles at the most then you can get away with dex around daratumumab.

The same with Tylenol and Benadryl that is often used as pre-med. I know a lot of people say, “Benadryl knocks me out for the next 6 to 12 hours.” After the first few doses of dara, you don’t really need that anymore.

Some of that is just experience, knowing that that’s what we did in the early trials, and that it’s okay to do it now. If you’re not seeing somebody that sees a lot of myeloma, you may just be on a plug-and-play where everything just gets recycled from cycle to cycle without necessarily reducing or taking them off to make life easier for the patient.

Dr. Costello: Dex is clearly the drug that everyone loves to hate. I think it’s important to say that dex is an oldie but a goodie. It’s been around for a long time. It is not a chemo, but it is designed inherently to kill myeloma. 

That’s an important part because patients oftentimes ask, “Well, can I just stop it?” I want to say, “Yes, but remember, consider this part of your treatment regimen also.”

It is hard. I’ve heard people say, “It’s a dex day,” and I look at the spouse or the caregiver and say, “How’s it going?” Because that can affect your quality of life more than any of the other treatments do. People plan out their lives around the days they’re taking dex or the days after their dex.

It behooves us to really understand the importance of dex for all of these regimens because if it is playing a huge role in killing myeloma, then sometimes, it’s worth it. 

If we are using it for an initial period of time to make a dent in the myeloma, for example, if we can get people off dex and continue the rest of the treatment, sometimes that makes it much more manageable for everyone across the board, let alone older, frailer patients.

At ASH, we heard about a trial [that] was one of the first, if not the first, randomized trial that was done specifically for frail myeloma patients. This trial took frailer patients, divided them in half, and said, “One half, you’re going to get Revlimid and dexamethasone. The other half, we’re going to do Revlimid, but instead of the dexamethasone, we’re going to do daratumumab.”

It’s similar to the MAIA study we’ve talked about when combining daratumumab and Rev, but this time with the hope of using as little dexamethasone as possible to see if these two groups, both receiving two medicines, can have good outcomes still without using the steroid in the study arm.

Now, I’ll say that these patients did get dex for the first two cycles, I think it was. That’s important. I think dex plays a role in helping to mitigate reactions to the daratumumab. Beyond that, maybe we can get rid of it.

They compared these two groups and said, “Dara-Rev, Rev-dex, how does it go?” Again, the dara-Rev group won. It is possible, we’ve learned, to get rid of the dex on our older, frailer patients. 

[It] is [likely] going to be practice changing to say if we can drop the dex as soon as possible, patients may not have the same side effects: emotional lability, water retention, feeling swollen, appetite, [and] not sleeping at night.

If it’s not going to play a huge role, it’s in the best interest of everyone to get rid of it. This was the first time we’ve seen not only for a frail group but how we can successfully get rid of dex. I think it’s practice-changing.

Cindy, TPS: My house was always the cleanest on dex stays and most organized.

Dr. Costello: It just really affects everybody in different ways, but it’s life-changing.

FasTCAR T cell therapy

Cindy, TPS: Is there anything that we did not touch upon that you think we need to share about the newly diagnosed multiple myeloma patients from ASH?

Dr. Costello: One thing I really liked from ASH [is] super exciting. I don’t know if this is here to stay. It was only 17 patients, but the FasTCAR study in the newly diagnosed myeloma.

This was a Chinese group that developed a CAR T-cell. Right now, there [are] two different CAR T-cells that are approved by the FDA for refractory myeloma for patients who’ve had more than four prior lines of therapy. Again, these are patients who had myeloma [for] a long time. They’ve had lots of treatments. 

Right now, it’s not available in the U.S. for patients who are just diagnosed. The Chinese designed a CAR T-cell and have started doing clinical trials, evaluating it for someone who’s just diagnosed with multiple myeloma. 

In the U.S., the CAR T-cells that we have take five [or] six weeks, sometimes longer, to manufacture. [The Chinese study] figured out how to manufacture it in one to two days. The initial results they presented at ASH showed that it worked for 100% of the people they treated and 100% of those patients were MRD negative, meaning that they cleared out every last myeloma cell. 

One of the things that we are very excited about is CAR T in general, but how can we use it earlier in the disease course? This is one of the first trials we’ve seen where somebody is trying exactly that with what seems like good success. Disclaimer: it’s a very small group of people. To be determined, but exciting.

Cindy, TPS: It was exciting. I like the idea of the FasTCAR because even the FasTCAR in the relapsed/refractory setting would be helpful because too many people are waiting too long or they don’t have [the] ability to wait.

Seeing a myeloma specialist

Cynthia, TPS: This is something that patients should be asking their doctors if their doctor didn’t tell them. You’re always giving us this little pep talk that all patients at some point should go see a myeloma specialist. Can you explain that again?

Dr. Lonial: The field is moving really fast. Things [change] once, twice, three times, or 10 times a year.

We’ve had multiple drugs approved in the last four years. Even through COVID, we still saw drug approvals. I think that the field is moving fast enough that if you have a really good general oncologist, they may be able to keep up to date, but they may not know the latest and greatest.

For that reason, I think having a myeloma center of record, if you will — a place that’s close to you, a team you feel comfortable with — that can partner with your local oncologist really guarantees that you’re getting access to the latest and greatest agents or combinations [and] that your team knows what approaches are going to be the most forward-thinking approaches to keep you going for the longest period of time.

Conclusion

Cindy, TPS: We talked to Doctors Lonial and Costello about newly diagnosed myeloma patients and treatment options for them. We learned about transplant-ineligible patients and the MAIA trial. We’ve talked about transplant-eligible patients, the GRIFFIN trial, and different ways to modify treatment. We also talked about stem cell transplant and if it’s really necessary. 

It’s really important to be actively involved in your care. Take some of these points of information and have discussions with your doctor to see what may be the best treatment options for you.

Special thanks again to Janssen for its support of our independent patient education content. The Patient Story retains full editorial control.

Multiple Myeloma Patient Stories

Clay D., Relapsed/Refractory Multiple Myeloma



Symptoms: Persistent kidney issues, nausea

Treatments: Chemotherapy (CyBorD, KRd, VDPace), radiation, stem cell transplant (autologous & allogeneic), targeted therapy (daratumumab), immunotherapy (elotuzumab)
...

Melissa V., Multiple Myeloma, Stage 3



Symptoms: Frequent infections

Treatments: IVF treatment & chemotherapy (RVD) for 7 rounds
...

Elise D., Refractory Multiple Myeloma



Symptoms: Lower back pain, fractured sacrum

Treatments: CyBorD, Clinical trial of Xpovio (selinexor)+ Kyprolis (carfilzomib) + dexamethasone
...

Marti P., Multiple Myeloma, Stage 3



Symptoms: Dizziness, confusion, fatigue, vomiting, hives



Treatments: Chemotherapy (bortezomib & velcade), daratumumab/Darzalex, lenalidomide, revlimid, & stem cell transplant
...

Ray H., Multiple Myeloma, Stage 3



Symptoms: Hemorrhoids, low red blood cell count

Treatments: Immunotherapy, chemotherapy, stem cell transplant
...

Relapsed/Refractory Multiple Myeloma Highlights from ASH 2022

The Role of Bispecifics in the Treatment of Relapsed/Refractory Multiple Myeloma

Patient advocate Jack Aiello is a 28-year survivor of multiple myeloma. When he was diagnosed, he was told he would only have two to three years to live and only two treatment options were available.

Jack underwent two transplants and then went onto a clinical trial for thalidomide but nothing worked until a third transplant.

In this conversation, he speaks with Dr. Ajai Chari, the Director of Clinical Research at the Multiple Myeloma Program at Mount Sinai in New York and Dr. Sandy Wong, a blood disease specialist at University of California, San Francisco, with a special interest in multiple myeloma.

They discuss game-changing treatments for relapsed/refractory patients, bispecific antibodies, treatment side effects, and emerging clinical trials.

Thank you to Janssen Oncology & AbbVie for their support of our patient education program! The Patient Story retains full editorial control over all content.

This interview has been edited for clarity. This is not medical advice. Please consult with your healthcare provider for treatment decisions.

For today’s newly diagnosed patient, you can be more optimistic about your diagnosis than [at] any time in history. We don’t have a cure [but] we have treatments available to manage this disease.

Jack Aiello

Introduction

Jack Aiello: I’m a 28-year survivor of multiple myeloma. When I was diagnosed in 1995, the doctor told me I had two to three years to live and [that] there were only two treatment options available. I remember going home to my wife, [telling] her the little bit I understood about this disease, and, suffice it to say, we shared a good cry. 

I had kids who were 16, 14, and 10 years old at the time. I knew I was going to have to go to the hospital so I just told them that there was something wrong with my blood and I was going to have to have it treated. But I wondered, would I be seeing the kids graduate from high school? Who was going to teach my son to hit a curveball in Little League? Who was going to pay for them [to go] to college? It was a difficult time.

Since then, we’ve had 13 or 14 new drugs approved by the FDA, more combinations of these drugs, and even more are in clinical trials today.

I really believe that for today’s newly diagnosed patient, you can be more optimistic about your diagnosis than [at] any time in history. We don’t have a cure [but] we have treatments available to manage this disease.

For relapse/refractory patients, you’ll hear some great results from the recent ASH meeting. Many abstract presentations were on the topic of drugs and a category of drugs called bispecific antibodies.

To help us understand more are Drs. Ajai Chari and Dr. Sandy Wong. 

Dr. Ajai Chari is the Director of Clinical Research at the Multiple Myeloma Program at Mount Sinai in New York.

Dr. Sandy Wong is a blood disease specialist at [the] University of California San Francisco, with a special interest in multiple myeloma.

Let’s kick off the conversation with what was the big buzz this year: bispecific antibodies. We’ve heard of monoclonal antibodies like daratumumab. Most recently, the FDA approved a bispecific antibody called teclistamab or Tecvayli. What exactly is a bispecific?

Bispecific antibodies

Dr. Ajai Chari: It’s a really exciting time. I’ll start with one of my favorite stories about the development of immunologic treatments in all humans. In [the] 1980s, the Nobel Prize was actually given for creating a standard antibody that was taken by fusing a myeloma cell with a spleen cell.

Every human antibody that we use — whether it’s for COVID, autoimmune diseases, [or] cancers — owes its legacy to myeloma. The first naked antibody, which is this Y-shaped structure, was not approved [for] myeloma until about 30 years after that Nobel Prize was given even though antibodies were helping everybody else. 

The first naked antibodies were daratumumab and elotuzumab. The ends of the Y-shape bind to one target and typically that’s the myeloma cell or whatever cancer cell.

It’s either a handcuff or double-sided tape. Basically, what it does is it takes one side of the Y, binds to a T-cell through a target known as CD3, and the other side can bind to a myeloma cell. You can change that up based on the protein.

The one that’s commercially available now that’s called teclistamab binds CD3 and the T-cells to BCMA or B-cell maturation antigen.

It’s remarkable how well these agents are working.

Dr. Ajai Chari

Jack: So the difference between that and a monoclonal antibody is the monoclonal antibody doesn’t have that second arm connecting to the T cell, is that correct?

Dr. Sandy Wong: That’s correct. Monoclonal antibodies activate the immune system in a different way.

For example, drugs like daratumumab or isatuximab activate the immune system [in] several ways. One is they act almost like Post-It Notes, if you will, where they flag cells [that] are not supposed to be there, i.e. the myeloma cells, and that leaves the immune system to know, “Hey, this is not supposed to be there. Let’s get rid of this myeloma cell.” That’s how a monoclonal antibody works.

Bispecific T-cell engagers physically attach to T cells and bring the T cells in physical proximity with the myeloma cells. The T cells get rid of myeloma cells that [are] not supposed to be there so they secrete their toxins, etc., and get rid of the myeloma cells. They work very differently.

Dr. Chari: It’s remarkable how well these agents are working. Basically, it’s an off-the-shelf product so that’s important.

A lot of people may have heard about CAR Ts that also target BCMA, but the difference is this is ready to go. It doesn’t have to be manufactured for each patient.

You don’t need to go through the T cell collection, manufacturing, and waiting. This is an off-the-shelf product. That’s the same for every patient with myeloma. 

What the drugs do is basically traffic the T cells in our bodies to whatever you’re trying to bring them to. In this case, the T cells in a patient are preexisting or trafficked to wherever the myeloma is, and when the T-cells are brought right up against the cancer, they recognize the cancer. 

They release certain chemicals or cytokines that poke holes in the cancer cell and that lead to cell death. I say it’s like bringing your army straight to the enemy, as opposed to hoping and praying that they find the right place to go.

It’s a mind-changing, game-changing era that we’re in with this immunotherapy treatment.

Dr. Chari

Treatment for relapsed/refractory patients

Jack: The teclistamab that was just approved and the other bispecifics, just to let the [readers] know, are so far for relapsed/refractory patients. Those [are] patients who have gone through several lines of previous treatments before getting to these bispecifics. Is that right?

Dr. Chari: Yeah, that’s exactly right. Just to put this whole space into context, about five [or] six years ago, the way drugs get approved is that they’re first tested in heavily treated patients — as you mentioned, relapsed/refractory myeloma.

The benchmark to get a new drug approved was about [a] 20-30% response rate, lasting about three to four months. Those numbers sound modest, but we have to keep in mind those are in patients who had exhausted all available therapies. 

When I started in myeloma 17 years ago, thalidomide was just coming on the scene. At that point, [to treat] relapsed/refractory, you had thalidomide and maybe a transplant. Now, typically, we’re talking about the big five drugs:

• lenalidomide (Revlimid)
• pomalidomide (Pomalyst)
• bortezomib (Velcade)
• carfilzomib (Kyprolis) 
• CD38 antibodies, such as daratumumab or isatuximab

That is a very different patient than somebody who just had had thalidomide. As we keep approving drugs, this unmet need, which is patients who have exhausted their currently available therapies, keeps changing. 

In spite of that, what’s remarkable about the entire T cell redirection, whether it’s bispecific or CAR T, is we’re saying 70-100% [response rate] is the new 20-30%. That’s how many patients are responding to these drugs. Even though these are much, much sicker patients and have had more treatments [and] more drugs, we’re getting better responses. 

That’s what’s really exciting. I literally have patients [with] whom we had discussed hospice a few years ago and now they’re in their deepest, longest remission they’ve had in years. It’s a mind-changing, game-changing era that we’re in with this immunotherapy treatment.

How is talquetamab is different from other bispecifics?

Jack: For one who’s been watching new treatments being developed and now seeing [a] 60% or 70% response rate, it’s pretty incredible.

Dr. Chari, you presented a different bispecific called talquetamab, also from Janssen, the same manufacturer of teclistamab. Can you share the results of this trial and what might make talquetamab different from other bispecifics?

Dr. Chari: First of all, this work takes [a] tremendous team, starting with the patients and their caregivers and then the entire study team, Janssen, the pharmaceutical, the FDA, and other regulatory agencies. 

With the phase 1 portion of the study, we’re looking to just find the safety and what’s the right dose and schedule. The phase 1 study just got published in [the] New England Journal so that was very exciting. It was also a large phase 1 study with over 200 patients. 

Efficacy and safety (how well it works in the safety profile) were then validated in this phase 2 study and that’s what we presented at ASH [2022]. The phase 2 study had 3 major cohorts of patients:

• One got a dose of what we call 0.4 mg per kg subcutaneously every week
• A second cohort got 0.8 mg per kg every two weeks 
• The third cohort could have gotten either one of those doses, but [in] a very important subgroup of patients who already had prior T cell redirection therapy, meaning patients who had had other CAR Ts and bispecifics

Even though these are 60-100% response rates, we’re still seeing relapses so you still need new agents. The goal of this study was to really look at these three subgroups. I would start with who these patients were. These were patients with heavily-treated disease.

About 60% were high-risk in some way, which is a very high number. That could be defined either by what we call high-risk genetics, so cytogenetics and FISH; high risk because they had myeloma coming out of the marrow, what we call extramedullary disease; or high risk because they had so-called ISS stage 3 disease at the time of study entry. 

In this population, with the typical five to six lines of therapy over six to seven years where almost 95% of patients were refractory to daratumumab, 75% were what we call triple-class refractory (proteasome inhibitor, IMiD, and CD38) and 95% of patients were progressing on their last therapy.

In this heavily, heavily treated group, as a single agent drug, we saw [a] 73-74% response rate in both of those schedules that we mentioned. That response rate was maintained in high-risk patients, ISS 3 patients, and patients regardless of lines of therapy, regardless of the number of drugs they were refractory [to]. 

One group who had [a] slightly lower response rate was those with extramedullary disease and even those had a 50% response rate, which I think is outstanding. I think safety is also equally important and distinguishes this from some of the other drugs.

What makes alnuctamab different from other bispecifics?

Jack: Dr. Wong, you presented on a bispecific called alnuctamab from Bristol Myers Squibb. Can you share the results of this trial and what might make alnuctamab different from other bispecifics?

Dr. Wong: We presented both the updated follow-up on the intravenous alnuctamab cohort as well as the subcutaneous alnuctamab cohort. The intravenous cohort was actually presented initially in ASH 2019 so there’s been quite some time that’s elapsed.

Basically, the take-home message with the IV alnuctamab was that even though the response rates initially looked exciting, when we got to target doses of 10 mg, there was a lot of high-grade cytokine release syndrome. People got really sick from CRS and one person actually died from it so it was not really optimal in terms of the side effects. Obviously, we don’t want people to get sick from these treatments.

Patients that were on the intravenous alnuctamab responded for a really long time so we’re really, really excited about that. However, we had to pivot to the subcutaneous alnuctamab because of those safety concerns. With the subcutaneous alnuctamab, the overall response rate was at 65%, which is very much in line with other T-cell engagers.

In terms of safety, all the CRS events were very low-grade. They were short-lived. They’re what we call grades 1 to 2 and, in terms of safety profile, it was a lot more manageable compared to intravenous alnuctamab.

That was what was really exciting about our presentation. Not only is subcutaneous obviously more convenient for patients, but the CRS events were much easier to handle and the overall response rate was 65%.

How does this stand out from the other T cell engagers? Several things. This is not the only subcutaneous BCMA-directed T cell engager, but there are some that are intravenous. For example, ABBV-383 is intravenous. So this is great that this is subcutaneous.

It’s hard to compare apples to oranges because all these different BCMA-directed T cell engagers have different follow-up time frames. For this one, the follow-up was very, very short. The median [was] only around four months.

In terms of infectious events, in terms of opportunistic infections, we really haven’t seen much of that for this particular drug so maybe that eventually will pan out longer follow-up studies but unclear because follow-up is pretty short.

What is really exciting is that the MRD negativity was 80% despite these patients [not being] followed for that long. That is actually really exciting. We don’t have a signal for these high-grade infections or opportunistic infections though. Again, follow-up is pretty short with this drug.

What are common side effects for bispecifics?

Jack: Speaking of infections, what are the common side effects we’re seeing with bispecifics altogether? I understand some research is unearthing data about how myeloma patients on certain drugs do with COVID and the vaccine.

Dr. Chari: I’ll start with what’s the most severe toxicity and then we’ll go to what’s common because I think they’re different and they’re both equally important to address. From a patient perspective, if it’s severe but rare, you may not be as concerned, but if it’s common and frequent, that’s different. 

The most severe side effect is low blood counts. We see that in about a third of patients with this drug. Typically, it happens in the first few cycles.

My personal hypothesis, I think what’s happening is when the army is going to the marrow where a lot of myeloma lives, you kill the myeloma but you may temporarily also affect the rest of the marrow. Then once the myeloma clears, you see that [improvement].

Jack: Patients may hear that called cytopenia. Is that correct?

Dr. Chari: Correct. That’s exactly right. It could be the white cells, the red cells, or the platelets. Those are important. This is already a little bit less than some of the other drugs, which can have as high as 60%. This is about half of that. 

The second huge thing, which you alluded to and it’s very important, is the infection. I can tell you, being in New York City [during] the pandemic, this was really a difficult situation. We had patients on experimental therapies and we were facing these life-threatening COVID decisions every day. We didn’t know what to do with this setting.

I think the infection profile of talquetamab is very unique. I’ll give you three ways why I think it differs from some of the other products.

First, the rate of severe infections was about 10-15%. We want it to be zero, but to put that into context, some of the other drugs are 45%.

We’re not just talking [about] minor infections, which can be seen with any myeloma patient because of the nature of the disease. [These are] severe, life-threatening infections, what we call grade 3-4. That was relatively modest. 

Second, the COVID signal is very different with this agent. Talquetamab as well as a lot of the other bispecifics are all accruing during the era of COVID. Yet in the phase 1 study that was published in [the] New England Journal with about 250 patients, there were zero COVID-related deaths.

In this study, there were two COVID-related deaths despite 10% of the patients having COVID. That’s a unique signal. In fact, in our laboratory at Mount Sinai, when we’ve tested people getting talquetamab [and] their response to the COVID vaccine, they do very well. They’re able to generate antibodies, which we don’t see with some of the other bispecifics because of the nature, I believe, of the target.

The third and final difference between this drug and some of the other bispecifics is the need for infection-prevention treatments. Is there anything we can do to reduce infection? There is IVIG, which is intravenous immunoglobulin, that’s an intravenous infusion given once a month to boost IgG levels. Here, only about 10% of patients needed IVIG.

All of those features of this drug are very unique. Some of the other products are having as high [a] rate [as] 40% of patients needing IVIG. I think this bodes well because these are probably the two most important features, which [are] cytopenia, blood count, and infections in terms of how these drugs are used in the future.

The ability to combine drugs depends on each agent’s side effect profile. Because infections and blood count issues are quite common, that can make some of these bispecifics difficult to combine. I think, in contrast, that bodes well for talquetamab.

There are some issues with talquetamab that are common but typically low-grade. One you’ve alluded to is cytokine release.

I would say as a class, all the bispecifics have cytokine release syndrome on the order of 70% or so, typically low-grade. In contrast, some of the CAR Ts have a little bit higher, more severe cytokine release.

What is cytokine release? It’s when the army recognizes the cancer. The T cells release their chemicals and those chemicals can cause symptoms such as fever, low blood pressure, low oxygen, confusion, lethargy, seizures, and even death, in rare cases. With bispecifics, it’s generally very low-grade. Most of the patients are getting a fever.

Everybody eventually would love to be able to use these drugs [in] an outpatient setting… If we’re able to do this safely as an outpatient, that would be really a big game changer for patients and their quality of [life].

Dr. Sandy Wong

Lowering cytokine release syndrome with treatments

Jack: There’s a big focus on lowering cytokine release syndrome with treatments like bispecifics. In particular, I saw one trial which looked at trying to reduce CRS by giving tocilizumab ahead of time. I’ve seen things like step-up dosing to reduce side effects. I know doctors have asked for possible pre-treatments for reducing infections. Can you share more about this?

Dr. Wong: Everybody eventually would love to be able to use these drugs [in] an outpatient setting. Nobody wants to be admitted to the hospital for a week just to get started on these drugs. If we’re able to do this safely as an outpatient, that would be really a big game changer for patients and their quality of [life].

Dr. Chari: We have to keep in mind one of the very things that’s going to make bispecifics different than CAR T.

CAR Ts are done at transplant centers and specialized large academic centers. These are off-the-shelf products that we hope eventually can get to the community because we recognize that most myeloma patients are not being treated in the global setting and academic centers. They’re being treated by community doctors.

If we want to get these drugs out to the community, we have to make them as safe as possible. How do we reduce that 70% cytokine release? One is by giving tocilizumab. In one of the studies with a bispecific known as cevostamab, [the] rate of cytokine release dropped from 70-80% to about 30%. That’s very encouraging. 

The other way to do that, which you mentioned, is don’t throw the whole army at the disease at once. Gradually increase the doses so that if there is some chemical release, it’s not all at once. That creates a lot of drama. You start with a low dose and you gradually work your way up. 

Both strategies are being done. With talquetamab, we did do preventative tocilizumab, which is the anti-IL-6 antibody, which blocks the fever. We were allowed to give it when patients had cytokine release, but we didn’t give it preventatively, which is what was presented at ASH [2022] in that one study. 

The other side effects [of] this drug are three things. One could ask, “Why is this one different than other drugs in terms of why potentially the infection was better? Why were the blood count issues perhaps not as bad?” We think it has to do with the target.

The target is GPRC5D, which is basically a protein that is expressed on myeloma cells primarily. We think [it’s expressed] less so [in] normal plasma cells and even less so in the normal hematopoietic compartment, which is the precursor cells that give rise to our blood counts. 

Perhaps the specificity of this protein is what underlies the favorable blood count and cytopenia issues, as well as the infection profile. There are a few tissues that do express GPRC5D and, fortunately, it’s not the major organs. We didn’t see [the] heart, lung, liver, [and] kidney. Those organs were not affected. 

The main thing we did see is GPRCs expressed on heavily keratinized tissue. Keratin [is] in the skin, nails, hair, etc. We didn’t see a lot of hair loss, but we did see some rashes in the early part of the treatment, which [is] typically managed with either oral or topical steroids. 

We did see some nail changes and taste changes. We saw dryness, difficulty swallowing, [and] change of taste. That, I think, is the most difficult to manage. We’ve tried artificial saliva and other things.

In spite of everything, the one signal that you can look at to see the tolerability of a drug is how many people came off for non-progression. This was 5%, which means that we were able to manage the side effects to keep people on the drug. I still think we need to do better. 

We have to keep in mind that the side effect profile that a heavily treated population might accept is going to be different than the side effect profile of maybe somebody who’s only had one line of therapy. 

The good news is that we do think these side effects are responsive to modulating the dose and intensity, so either dropping the dose or skipping a dose, giving it less frequently. Those seem to help. I think that’s why the rate of discontinuation was relatively low. 

Again, a huge shout-out to the nurses because they’re really on the front lines and helping patients deal with these side effects. I never take my entire outstanding, talented nursing colleagues for granted. They’re really doing an amazing job. Those are basically, I think, the main side effects to cover with talquetamab as well as most bispecifics, I would say.

We have to keep in mind that the side effect profile that a heavily treated population might accept is going to be different than the side effect profile of maybe somebody who’s only had one line of therapy.

Dr. Chari

Managing side effects for bispecifics

Jack: Let’s summarize the side effect profiles for these bispecifics. I would stay on bispecifics typically until they stop working. I take them every two or three weeks, depending on how they’re dosed. Do these side effects change? Are they worse at the beginning? Whatever side effect I get at the beginning, [does it] continue as I’m taking the drug?

Dr. Chari: There [are] three major bispecific targets that are being explored. We’ve talked about GPRC5D with talquetamab. There’s actually a second company also pursuing that. That was also presented at ASH [2022] from Roche, targeting GPRC5D.

The BCMA is a very busy space. I think it’s like the statins of myeloma, like Crestor [and] Lipitor. It’s great for patients because more competition means more choice [and a] better cost profile. I think it’s great for the market.

I would say the BCMAs seem to keep having a rate of infection that we don’t see a plateau in. That’s what’s concerning to a lot of us. How do we find the right dose, schedule, and duration?

It’s one thing to have an infection in somebody whose myeloma is uncontrolled because that we’ve seen before. Myeloma patients whose myeloma is uncontrolled will get infections because that’s part of the cancer. 

What can be sometimes difficult to tease apart in these single-arm studies is you can’t isolate what’s coming from the patients (like if the patient is a very sick patient), what’s coming from the disease of the myeloma itself, and what’s coming from the treatment because you don’t have a control arm in which to compare it to. 

One of the things, as your question astutely asked, is there any change? With the infections, we’re not seeing that level off with the BCMA. With talquetamab, we’re not seeing it as much. 

I would say with the cevostamab, it’s probably somewhere in between. That’s targeting another protein called FcRH5. I would say [with] infections, we haven’t found the right magic sauce yet. Perhaps IVIG.

One other interesting paper that I think speaks to this topic is Genentech/Roche, the same company that did the prophylactic or preventative toci (tocilizumab) also happens to have the only bispecific that is a fixed duration. They don’t treat the progression. They treat for about a year.

What we saw is there’s a small number, but about 17 patients that had come off the therapy and were in longer follow-up on that study. What we know so far is of the patients that had a deep remission, they’ve been doing pretty well off therapy. Again, [that’s] amazing for patients to have a treatment-free interval. 

With talquetamab, we’re not seeing that relentless increase in infection — and to the opposite, the side effects [with] skin, nails, and taste actually seem to get better with time. There may not be as much of a need to do the fixed duration there. Maybe it’s once-a-month dosing or something. 

We’re pursuing all of these different strategies, but I would say that we’ve got to look at everything. We’ve got to look at the dose, the frequency, [and] the duration of treatment and figure [it] out for a given patient, based on a given target and on their response.

That cevostamab data, which [was] discontinued for those patients that were not in a complete response, did have [an] earlier relapse.

I think you can’t have a blanket statement. You just got to look at each patient as an individual. It’s nice to have these options that are giving such outstanding responses.

Bispecifics are here. It’s a dawn of a new era… We have multiple drugs against multiple targets that are showing impressive response rates.

Dr. Wong

Next steps for research

Jack: Thank you so much. I’ve learned a lot about bispecifics. I can also tell there’s still a lot of work to do to understand the dosing, to understand if there will be prophylactics that go along with them to minimize those side effects, to see if fixed duration or use till progression will be the right treatment, or just to reduce the dosing going forward.

I still go back to what you said earlier that we’re seeing response rates so high for just this drug, not even combined with something else, and for patients that have already gone through lots of prior treatment lines. It’s certainly an exciting field.

Dr. Chari: Not only are we seeing these responses, [but] the median time to response is one month and the median time to best response is two months. I mentioned those points because it gives us, as physicians, a lot more comfort in backing off on the dose and schedule.

You’re seeing the response early and it’s deep. If somebody has side effects, you’re not as worried about backing off. That’s what’s really nice about these drugs. Even if somebody does have side effects, it’s very gratifying to them to have this myeloma that was shooting off and suddenly it’s completely flattened out. That’s why I think the side effect profile we’ve got to do more work on. 

What are the next steps? All the phase 1 and phase 2 single-arm studies have confirmatory randomized studies where the drug’s being combined with different backbone agents.

Also, because of the unique side effect profile, talquetamab in particular is also being combined with all those standard myeloma drugs in single-arm studies as well as with the other bispecific, which is really cool. Completely chemo-free teclistamab with talquetamab is being studied. 

Lastly, we’re trying to also improve the T cell function because we think one of the reasons the drugs may peter out is because of T cell health. There [are] approaches using things like checkpoint inhibitors, which boost your T-cell function, in combination with these agents.

Bispecifics are going to be a fabulous treatment option for myeloma patients… I’m excited to see what comes next in myeloma.

Jack

Final takeaways

Jack: Doctors, as we wrap up this discussion on the latest in myeloma, specifically bispecifics, what are your thoughts on where we are in myeloma treatment and research? What’s your message to myeloma patients and families in 2023?

Dr. Wong: Bispecifics are here. It’s a dawn of a new era because finally, we have [an] off-the-shelf drug, which means that you can just take it right off the shelf and just give it to a patient. And for an off-the-shelf drug to have a response rate of 60 to 70%? That is absolutely amazing.

Previous to this, dara (daratumumab) was our darling drug. We use it so common nowadays in the front-line setting and the relapse setting. When dara was FDA-approved, the single-agent response rate in patients who are relapsed/refractory was only around 30%. Right now, we’re hitting 60 to 70% so this is extraordinary.

And it’s not just one drug. We have multiple drugs against multiple targets that are showing impressive response rates. I think really good news this ASH. I’m really excited to see all that amazing data being presented.

Dr. Chari: I think it’s a really exciting future. We’re just in the beginning and, of course, in less heavily treated patients, it’s also a big area of investigation in addition to combination. Stay tuned for all of those exciting new studies, hopefully soon.

Jack: Bispecifics are going to be a fabulous treatment option for myeloma patients. Thank you so much, Dr. Chari and Dr. Wong, for your presentations, [for] helping us better understand bispecifics, and [for] being part of this conversation.

I hope you took away something helpful and hopeful from this conversation. I’m excited to see what comes next in myeloma.

Special thanks again to Janssen Oncology & AbbVie for their support of our independent patient education content. The Patient Story retains full editorial control.

Relapsed/Refractory Multiple Myeloma Patient Stories

Theresa T.



Diagnosis: Multiple myeloma, relapsed/refractory

Subtype: IgG kappa Light Chain

Initial Symptom: Extreme pain in right hip

Treatment: Chemotherapy, CAR T-cell therapy, stem cell transplant, radiation

Laura E.



Symptom: Increasing back pain
Treatments: Chemotherapy, stem cell transplant, bispecific antibodies

Donna K.



Diagnosis: Multiple myeloma, refractory
1st Symptoms: None, found by blood tests
Treatment: Total Therapy Four, carfilzomib + pomalidomide, daratumumab + lenalidomide, CAR T, selinexor-carfilzomib

Connie H.



Diagnosis: Multiple myeloma, relapsed refractory
1st Symptoms: Chronic bone pain
Treatment: IV Chemotherapy, CAR T cell therapy

Elise D., Refractory Multiple Myeloma



Symptoms: Lower back pain, fractured sacrum

Treatments: CyBorD, Clinical trial of Xpovio (selinexor)+ Kyprolis (carfilzomib) + dexamethasone