Why a Two-Drug Combination Could Change Myeloma Treatment

Multiple myeloma treatment has moved quickly toward bispecific antibodies, which link a patient's own immune cells to a protein on the surface of myeloma cells. Two targets have driven most of that progress: BCMA and GPRC5D. Both have shown benefit in patients whose myeloma returned after several prior treatments. The next question was whether they work earlier, at first relapse.

The phase 3 MonumenTAL-6 trial includes top-line results comparing two Talvey (talquetamab) combinations against established standard-of-care regimens in relapsed or refractory multiple myeloma. In this Q&A with Dr. Ajay Nooka, director of the Myeloma Program at Emory Winship Cancer Institute and an investigator on the trial, he walks through the results for what they may mean for patients.

CURE: Can you tell us what MonumenTAL-6 was designed to test?

Nooka: Talvey belongs to a class of drugs called bispecific antibodies. They attach to the myeloma cell on one end and to the patient's own immune cells on the other, bringing the two together so the immune system can go after the cancer. Talvey attaches to a protein called GPRC5D.

Most of the recent progress in myeloma has come from drugs aimed at one of two proteins, GPRC5D or BCMA. Both have helped patients whose myeloma returned after many rounds of treatment. Once those drugs were approved, the next question was whether they would work earlier, at the point when myeloma comes back after a patient's first treatment.

Talvey was approved based on MonumenTAL-1. In that trial, close to 70% of patients whose myeloma had returned after many prior treatments responded to it, meaning the cancer shrank or stopped growing. MonumenTAL-2 tested Talvey with Pomalyst (pomalidomide), and the response rate went above 80%. The lab results pointed the same way, with more of the immune cells that go after cancer and more of the signal the immune system uses to switch those cells on.

MonumenTAL-6 divided patients into three groups. The first received Talvey with Tecvayli (teclistamab). The second received Talvey with Pomalyst. The third received one of the current standard treatments, either Empliciti (elotuzumab), Pomalyst and dexamethasone, or Darzalex (daratumumab), Pomalyst and dexamethasone. When you set up a comparison group, you need to make sure it is strong enough for the test to be fair. These are established regimens that give patients a benefit of anywhere between 12 to 15 months.

What did the top-line results show?

Compared with those standard-of-care therapies, Talvey plus Tecvayli had a hazard ratio of 0.11 for progression-free survival. Progression-free survival is the length of time a patient lives without the myeloma getting worse. A hazard ratio compares that risk between the two groups, so 0.11 means the risk of the myeloma getting worse, or of death, was 89% lower for patients on the combination.

We also looked at overall survival, which is how long patients lived, whether or not the myeloma got worse along the way. There, the risk of death dropped by close to 67% compared with Empliciti, Pomalyst and dexamethasone.

The second combination, Talvey plus Pomalyst, was measured against that same standard-of-care arm. It had a hazard ratio of 0.27, a 73% reduction in the risk of the myeloma getting worse.

The bottom line is that the traditional treatments we use every single day need to go to the back burner. These innovative therapies targeting GPRC5D and BCMA should be coming to the front line.

What does an 89% reduction in the risk of progression or death mean for how long a patient stays in remission?

It is too early to answer that with the follow-up we have from the top-line results. What I can say is that these drugs work well enough that some people may not need more treatment. Patients on the combination went a long stretch without their myeloma getting worse, and that is the only way you see a hazard ratio as low as 0.11.

That number compares the two groups against each other. It means patients on the combination were not progressing, while patients on the standard-of-care treatments kept getting worse. This is the best hazard ratio we have ever seen in multiple myeloma. If somebody is looking for a cure, this is likely the first step toward it.

Why target two different proteins on myeloma cells at once instead of one?

Myeloma cells carry different proteins on their surface, and each of these drugs is built to latch onto a different one. By going after two of those proteins at the same time, we expected the effects to add up. You're reaching the myeloma cell from two directions, so any cell that one drug can't attach to can still be picked up by the other. That is what we saw in the results, with responses that went deeper.

The biggest concern from a patient's perspective is always whether adding a second drug means more side effects. Based on what we have seen, it does not.

What does treatment look like day to day?

Patients don't start on the full dose. The first few doses are smaller and step up gradually, and the drug labels call for that step-up period to happen in the hospital.

Over the last two years, we have learned how to give those doses safely in the outpatient setting instead, where a patient comes in, gets the dose and goes home the same day. In the last two years, only a handful of our patients have started in the hospital rather than as an outpatient. I don't see a reason why it should be inpatient. I'm watching what the REMS program says about how that risk can be managed so more patients can start on the outpatient side.

Once the step-up period is done, Talvey is given at 0.8 mg/kg every other week, which works out to two doses in each 28-day cycle. If a patient responds well after the first five cycles, that can stretch to one dose every four weeks. Tecvayli is given every four weeks. After the first four or five months, many patients settle into coming in every other week and alternating between the two drugs.

What side effects should patients expect with Talvey and Tecvayli together?

Cytokine release syndrome and neurologic toxicities are not higher. It is a manageable safety profile.

Two or three years ago, when we had these agents individually, they came with a lot of side effects. We did not know what those side effects would be, and we have since learned to manage them better. We started to incorporate interventions as prophylaxis to prevent side effects, and then to treat them. Take infections with the BCMA bispecific antibodies, or the weight loss and taste-related side effects from the GPRC5D bispecific antibodies.

Those can all be managed as long as we can space these out. We emphasize following all the infection prophylaxis, which is much more adapted now than two to three years ago. We also have better supportive measures for taste-related side effects, hair-related side effects and rash. All of that allows patients to receive these treatments with a mitigated side effect profile.

Can patients maintain a normal routine on this combination?

Patients should be able to keep working, traveling and maintaining a normal routine because none of these drugs are chemotherapy agents. I have patients who work full time while using these bispecific antibodies. The caution around preventing infections and other side effects needs to be up front. There is no reason why patients should not be able to work full time if they want to.

What comes next?

This combination came from the relapsed and refractory space. When you look in the early relapse setting and see improvements like this, there's no reason not to evaluate it in the frontline setting.

I'm curious to see the data myself, in terms of how deep the responses are and how durable these remissions are. But preventing progression or death by 89% is huge. That one number tells us that at least a big portion of patients got those depths of response and are not progressing as expected.

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