Serum BCMA May Help Predict Outcomes, Monitor Disease in Multiple Myeloma

James R. Berenson, MD

Institute for Myeloma and Bone Cancer Research

Serum BCMA may be the way forward not only as a disease-monitoring tool in patients with multiple myeloma but as a way to predict outcomes in select populations, explained James R. Berenson, MD.

“Not only is it a marker of prognosis and predictability; it is also an excellent way to monitor the disease. It has several advantages over the conventional markers, which are the monoclonal immunoglobulin and the so-called M protein that's spewed out of the myeloma cell, which can be in a full form—what we call light chains,” Berenson said. “Those markers are traditionally how we follow myeloma.”

Using serum BCMA to get these answers for individual patients could also help determine if breaks in therapy or treatment holidays are possible for them, he added.

In an interview with CancerNetwork^®, Berenson, founder, medical and scientific director, and president and chief executive officer of the Institute for Myeloma and Bone Cancer Research, and private practitioner in West Hollywood, California, discussed serum BCMA and markers for predicting outcomes and monitoring disease in patients with multiple myeloma.

CancerNetwork: How common is BCMA? Is it expressed on all myeloma cells?

Berenson: BCMA is a tumor necrosis factor receptor that's on the surface of normal plasma cells, a late cell in the B-lymphocyte differentiation pathway. It's present on both normal and malignant cells that are in the late B-cell lineage, and that includes multiple myeloma. Pretty much all [patients with] myeloma express BCMA on their tumor cells. There are rare exceptions with either mutations or deletions of the gene, which sometimes occur because of therapy targeting BCMA, which has now become commonplace with new immune-based therapies.

How is BCMA currently used in practice?

BCMA is the target of several new immune-based therapies involving what are called bispecific antibodies targeting BCMA and the immune T cells that are the type of cells that kill myeloma. There are also T-cell therapies in which specific vectors are put into the T cells to allow them to target BCMA. They also activate to kill BCMA-containing cells, which are the plasma cells—not only the malignant cells but the normal plasma cells. There's a fair bit going on [over] the last several years, and it's growing in stature, as we see how effective it is in terms of soluble serum BCMA.

Diving into serum BCMA, what is the story there?

It turns out that BCMA is shed off the myeloma cells, like scissors cutting a string. The string sticking out of the cell then goes into the blood; you can measure it.The protein that specifically does that is γ-Secretase. When that's shed in the blood, you can measure it quite easily. The amount of BCMA blood correlates with the amount of plasma cells in the patient, and that includes, in myeloma, mostly malignant plasma cells.

How is serum BCMA going to be best used in the clinic?

For more than the past decade, BCMA is much higher in patients with myeloma than in normal individuals or healthy [patients]. It is also much higher in patients with active myeloma than smoldering myeloma, and in fact, the levels that occur in a smoldering myeloma predict the risk of a patient with smoldering [disease]. [This means] in a patient who isn't starting therapy, it predicts their risk of getting active myeloma and requiring treatment. The higher the level, the more likely they are going to need therapy over the next several years from the diagnosis. Similarly, in monoclonal gammopathy of undetermined significance [MGUS], the baseline test predicts the risk. It's a very nice, predictive, and easy test to predict your chances of moving from either MGUS or smoldering myeloma to requiring treatment for active myeloma.

In addition, we know that the levels of BCMA do predict your chances of responding and how long you're going to respond for. We also are embarking now in a large trial involving one of the drugs that we have been studying over the last several years of the JAK inhibitor ruxolitinib [Jakafi]. It appears that BCMA is quite good at predicting who is going to respond to that drug. We don't have the final data on that [yet], but it looks pretty much that way, and soon should be sending that in for publication.

Now, in addition, BCMA from our recent work also is predictive for those patients with Waldenström’s macroglobulinemia, a type of B-cell lymphoma of a late B-cell limit, [where] the levels are higher, and the amount at baseline predicts whether people are going to need treatment or not.

The problem is that over time, several patients at baseline have no marker, so you can't track them with these conventional markers. However, we now have a marker we know we can do that with, and that's a huge advantage. Formerly, these patients have had to have frequent bone marrow [assessments], and they must have PET scans, which are expensive and have some radioactivity to them. Now, they can avoid that and have a simple blood test to track their disease. We know in patients with conventional markers, there is a parallel tracking of the serum BCMA level to the M protein in those who have an M protein to track, and serum-free light chain for those who have that marker to track them.

The additional advantage, however, with BCMA is that it is a much more rapid way to assess changes in clinical status. If you follow the patient's M protein...BCMA is kind of like getting a message by email; it's much more rapid. We know why that's true now; it's because it shed off the cell much more rapidly than the traditional M protein. We also know that the turnover of the protein is very quick; it's 10 to 20 times quicker than the turnover of the conventional M protein. Therefore, you have a quicker turnover and faster shed, which means you can get a quicker read on whether the disease is getting worse or better.

What is that good for? If you can find the patient's disease is worsening more rapidly, that's big because that means you can take the patient off ineffective therapy more rapidly and get them onto something that would hopefully be better. It also avoids the toxicity that they might be getting from therapy that's not working. The big advantage in the future is that it's going to allow us to maybe tap down some of the therapies, give less drugs, and/or maybe lower doses, because you're going to know very quickly whether these things are working or whether the patient's disease is worsening.

It also may allow us to take patients off therapy more confidently and give them a drug holiday, which they would love. Certainly, the payers would love it as well [due to the] cost of these drugs. Then, you can jump back in [with treatment at] the first sign rises in BCMA. For the first time, we just enrolled our first patient on the first trial in the world to use BCMA to make a clinical decision. We are using ruxolitinib; we know it's active, but we know its activity is boosted with a drug called lenalidomide [Revlimid], but that's an expensive drug with adverse effects, so we'd rather start with a single agent. We know if you add in lenalidomide, you can overcome the resistance to the ruxolitinib. In other words, you pour another drug in, but we wait too long [to see if there is resistance]; we're too slow and patients are deteriorating. Now, with BCMA, we can do this more rapidly, and we think that will then certainly optimize the ability to boost the response by adding lenalidomide to somebody who may be [progressing on] ruxolitinib. It's going to be a big advantage for patient care.

Switching to BCMA-directed therapies, what are the safety or quality-of-life issues with these agents?

In terms of patients who are getting BCMA-directed immune therapies, it was thought that perhaps higher levels of BCMA may mean you're more likely to respond. Turns out, that is not the case. Consistent with all of our other data, it seems that higher levels, whether it's a BCMA-directed therapy or non–BCMA-directed therapy, make it less likely that you're going to respond to that treatment. That's probably a result of the amount of tumor that you have on board. If you have worse myeloma as well, you may have a larger tumor burden in your body than the patient who doesn't have that much myeloma. Therefore, you have more BCMA on cells, and more BCMA shed in the blood.

BCMA-directed therapies are highly effective but can be highly toxic early on. Patients can experience an immune overripe kind of reaction, similar to what happens with COVID-19 infections for example, where the immune system comes out unregulated. We call that cytokine release syndrome. It can be fierce, fatal, and it often will have fevers. Patients don't feel well, they can have aches, and they can have all sorts of problems, but that usually only occurs the first few days. If it's bad, it can be mitigated with steroids and antibody targeting. For one of the factors that is thought to be the culprit—interleukin-6—there's a drug called tocilizumab (Actemra) that can help with that. It doesn't occur that often, but you certainly must be aware of it. Patients are supposed to be hospitalized the first few days so that in case they get into trouble, they can be acted upon immediately.

The other major problem early on is called immune effector cell-associated neurotoxicity syndrome, which can [entail] seizures, Guillain-Barré syndrome, headaches, numbness, and/or weakness. These symptoms can be severe, but they are uncommon and usually occur in the first few days before going away.

As the patient traverses further, BCMA is not only present on the myeloma cells but on normal immune cells. This is a thorough take out of your immune cells, whether they're malignant or benign plasma cells, and thus you're like the emperor with no clothes; you don't have an immune system. You have to be very careful and vigilant to take care of these patients.

Because of this infectious risk, there's been an attempt to ameliorate or reduce that risk using normal, healthy antibodies called gamma globulin or intravenous immunoglobulin shots. Whether they're effective has not been demonstrated in any good randomized trials today, but they're used in people with low levels.

The other way you can prevent the infections is by stopping the drug. We're learning that these patients don't necessarily need to continue by adding a weekly dose. They may, in fact, be able to have drug holidays once they respond, and then their life is rekindled, because they don't have a fun life when they're having continuous infections, which can end up leading to chronic problems.

A more serious complication has occurred in those receiving the CAR T cells, and that is secondary cancers. We are putting a genetically manipulated vector in the patient, and it stays in there, and there are patients now that are cropping up with T-cell lymphoma. We're going to see more of this. We are also seeing some other problems that are rising and occurring late in these patients—quality-of-life issues related to aches and pains. We must be careful when we're taking care of these patients and choosing who will undergo these procedures because they're clearly not curative procedures, and they can lead to long, chronic problems.

Are there other markers worth mentioning that are being used for predicting outcomes or monitoring multiple myeloma?

We know there are specific genetic changes in myeloma that can predict response to a specific drug. The first example is the translocation of chromosome 11;14. This means that some of the chromosomal material in 11 moves to 14. When these [activate] together, they turn on a set of reactions that leads to overexpression. This one is called BCL-2 and is associated with an ability for the 20% of patients with multiple myeloma who happen to respond to a drug that blocks BCL-2 called venetoclax (Venclexta). It's very active, and it's not very active if you don't have that marker; it's kind of like winning the lottery [if you do]. We've shown that this drug is extremely active with another immune therapy that targets a protein on the surface of myeloma called CD38, and that's either daratumumab (Darzalex) or isatuximab (Sarclisa). When you put those together, they're great, active, well tolerated, and the responses last.

We have now embarked on a clinical trial combining isatuximab with venetoclax at low doses. We're very excited about that.

There is a series of genetic markers involving other chromosome translocations, which are called t(4;14), or t(14;16), or t(14;20). Those genetic movements also generally predict a poor outcome. Then, there's the big gun called p53, which is the controller on preventing things from going awry. These genetic markers are providing the basis for determining outcomes. We are now doing more work using a very sensitive technique called mass spectrometry to track myeloma, and that can more sensitively find the M protein. We know that when the M protein disappears, people [believe their disease is gone]. Well, it's not really gone, it's just the sensitivity of the assay is not able to detect it with the conventional machines we use. Now, we have this mass spectrometry test, and we can detect it with 100 to 1000 times better sensitivity.

That has a lot of implications for treatment and approaches to myeloma. Perhaps with these more sensitive markers, we can get people off therapy and then, like "Whack a Mole" at the county fair, we can whack them [with treatment] when it just starts to come up again. Rather than continuously treat folks, we give patients a drug holiday when their [disease] gets to a low, stable level. In addition, there are [minimal residual disease] tests done to look at the myeloma cells in the bone marrow. Those tests can also predict outcomes.

The problem with those types of tests is that myeloma is not the same throughout the bone marrow. You can put a needle one place and go, "Wow, look at all that myeloma," and then 2 inches away, there's nothing. The other problems with those tests are that there's a lot of variability in the sensitivity assay for individual patients, and we don't know what to do with the data right now. [If someone tests negative], what am I supposed to do with my treatment based on that? Do I stop it, or is a patient more likely to do better if I continue it? We just don't know the answers yet. There are other techniques and markers that are being used to either predict outcomes or, in the case of venetoclax and BCL-2, to say, "Hey, that's the drug you really should get."

Reference

Costa BA, Ortiz RJ, Lesokhin AM, Richter J. Soluble B-cell maturation antigen in multiple myeloma. Am J Hematol. 2024;99(4):727-738. doi:10.1002/ajh.27225