CAR T-Cell Therapy Continues Forward in Multiple Myeloma Development

Nina Shah, MD

CAR T-cell therapy is poised to have a significant impact on the treatment of patients with relapsed/refractory multiple myeloma, said Nina Shah, MD, a hematologist/oncologist at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center.

"There is a lot of interest as to whether CAR T-cell therapy is ready for prime time in multiple myeloma," said Shah. "I'd say not just yet. However, the reason we even ask that question is because we have a therapy that is eliciting high response rates in heavily pretreated patients, demonstrating that patients who are very sick can be rescued with CAR T-cell therapy."

In March 2020, a biologics license application was submitted to the FDA for idecabtagene vicleucel (ide-cel; bb2121) for the treatment of adult patients with multiple myeloma who have received ≥3 prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.¹

The application is based on data from the phase II KarMMA trial,² in which the BCMA-directed CAR T-cell product produced an overall response rate (ORR) of 73.4% in patients with relapsed/refractory multiple myeloma.

Topline results demonstrated a 31.3% complete response rate, a 10.6-month median duration of response, and an 8.6-month median progression-free survival (PFS) across the target dose levels of 150 to 450 x 10⁶ CAR T cells.

Moving this therapeutic modality earlier in treatment may significantly enhance responses for patients, explained Shah.

"There isn't a plateau on the curve yet," said Shah. "In order to make that plateau better, we have to move CAR T [into earlier lines of treatment] rather than waiting until the last minute. I am happy that a lot of cooperative groups, myeloma thought leaders, and pharmaceutical companies are considering doing this."

In an interview with OncLive, Shah, who is also an associate professor of clinical medicine at UCSF, highlighted some of the recent advances that have been made with CAR T-cell therapy in multiple myeloma, as well as other exciting updates in the space.

OncLive: What data have we seen regarding the investigational CAR T-cell therapy ide-cel?

Shah: There are several CAR T products that are being investigated. The 1 with the most long-term follow-up in the United States is [ide-cel]; data with that agent showed a median PFS of 11.8 months in the phase I trial.

Additionally, there was a press release on the KarMMA data, which is the phase II clinical trial [with ide-cel in] over 120 patients. The ORR was in the 70% range at a dose of 450 x 10⁶ CAR T cells.

The numbers in the phase II study were a bit less than what we saw in the phase I study. The reason for that is because the 450 x 10⁶ dose did better. If you only look at that dose, patients are doing just as well [as those in the phase I trial]; in fact, the PFS was nearly the same.

It is important to remember that the patients who were enrolled in the KarMMA trial were surprisingly sicker [compared with those enrolled in the phase I trial. Patients on KarMMA had to] be actively progressing [to be eligible for enrollment]. That is a high bar to set, patients with relapsed/refractory multiple myeloma, exposed to all the novel agents, and actively progressing. Therefore, I was happy to see that data.

What it means to me is that we have to move CAR T-cell therapy earlier in treatment. We need to plan in advance.

What other CAR T-cell products are under investigation in multiple myeloma?

Other products that are being investigated include bb21217, which uses a PI3K inhibitor in the culture to increase the number of stem cell—like memory T cells or central memory cells in order to get more longevity and increased persistence out of the product.

Also being investigated is JCARH125, which uses an optimized ratio of CD4 and CD8 when patients start their culture in order to increase persistence.

There is also the CAR T-cell product from Poseida that uses a non-viral transduction. It also has an interesting extracellular protein. In theory, all of this would increase the persistence [of the product].

We also have data with Legend’s product which was initially presented in China a couple of years ago. We now have longer follow-up data; the original PFS was approximately 15 months [in all-comers] and 24 months in patients with minimal residual disease (MRD) negativity. Those data are very impressive and look better than the original data from bluebird bio. We have to remember, however, that those patients were not as heavily pretreated [than those in the LEGEND-2 trial].

At the 2019 ASH Annual Meeting, preliminary data from the US version of [LEGEND-2] were presented and showed at least a 91% ORR with [JNJ-4528] in the CARTITUDE-1 trial. In the US study, patients had to have had at least 3 prior lines of therapy. We know that these patients are likely sicker than those who were included in the Chinese study, because they had more [treatment] exposure.

How does safety impact the utility of CAR T-cell therapy in myeloma?

Some think it is difficult to implement CAR T-cell therapy because of safety. There are 3 main potential [treatment-related adverse events]. One is cytokine release syndrome (CRS), which essentially feels like a really bad flu. The second is neurotoxicity, and the third is low blood counts. All of these can be severe, but in general, they can be well controlled in the multiple myeloma population.

The reason for that is because we have been able to gain insight from our experience with CD19[-directed CAR T-cell therapy]. We learned how to manage CRS. We now know that giving tocilizumab (Actemra) isn't a bad thing, and it is not going to cause the cells to become less effective.

We also know that it is probably best to start dexamethasone at the first sign of neurotoxicity because you want to err on the side of patient safety and not worry about the cells.

In addition, we know that some patients have low blood counts [with CAR T-cell therapy]. As such, we have to ensure that we monitor them closely, even 1 or 2 months out. When patients are sent back to the community, we have to inform those doctors that this toxicity could persist, have a plan to address it, and make sure there is good infection prophylaxis.

What are some exciting updates regarding triplet or quadruplet regimens in myeloma?

We know that 3 drugs are better than 2, but we are still figuring out whether 4 drugs are better than 3. We know that with the daratumumab (Darzalex) experience in CASSIOPEIA, and now the GRIFFIN trial, that patients may achieve deeper responses with 4 drugs versus 3. Adding another novel agent such as daratumumab plus carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd), [or] daratumumab plus bortezomib (Velcade), lenalidomide, and dexamethasone (VRd) is really novel.

What are your thoughts on the data that compared lenalidomide with ixazomib (Ninlaro) as maintenance therapy?

The MMRC060 trial looked at ixazomib versus lenalidomide maintenance. I am happy this trial was done because a lot of us [wanted to know which drug is superior in this setting]. The trial was designed for newly diagnosed patients who got dealer's choice of induction therapy and then went on to transplant. After transplant, they received 4 cycles of ixazomib, lenalidomide, and dexamethasone consolidation. That evened the playing field for all patients.

Afterward, patients were randomized to receive lenalidomide versus ixazomib. The abstract that was published had some preliminary numbers, but I would like to know what to do for my patients if I have an option. We know that lenalidomide and ixazomib are both superior to doing nothing, but understanding how they compare to one another is a new question.

What are the updates with selinexor (Xpovio)?

We saw an abstract with selinexor, pomalidomide (Pomalyst), and dexamethasone in patients with relapsed/refractory multiple myeloma. Those patients had a nice ORR and we were able to limit the nausea to mainly grade 1/2. Investigators settled on a dose of 60 mg of weekly selinexor with pomalidomide at 4 mg in order to optimize patients’ blood counts. We have to use all the drugs available to us. Selinexor gives us another option.

As we get more data with selinexor, we may want to consider not waiting until the end [of a patient’s treatment course] to give the agent. Instead, perhaps we use it more upfront to achieve a better outcome. We know how to manage the nausea a bit better, so with time we will have more experience with this drug.

Venetoclax (Venclexta) could also have a role in multiple myeloma. Could you speak to the data we have seen with the agent and what its potential utility may be in this space?

At the 2019 ASH Annual Meeting, we saw the subset analysis of patients with translocation(11;14) or BCL-2—high multiple myeloma and their experience with venetoclax. This is a subset analysis of the BELLINI trial, which was stopped before completion due to a [negative] overall survival (OS) signal.

The BELLINI trial randomized patients to receive venetoclax, bortezomib, and dexamethasone versus bortezomib and dexamethasone. Although the original trial was stopped due to safety concerns, the subgroup of patients with t(11;14) or BCL-2—high disease did much better with venetoclax. They did not have a worse OS and their PFS was strikingly better.

Understanding this is a subgroup analysis, we don't have the power to detect these differences. However, we have to take information from these trials and use it. If a patient with t(11;14) has relapsed disease, [venetoclax] would be a viable option.

References

1. Bristol Myers Squibb and bluebird bio announce submission of biologics license application (BLA) for anti-BCMA CAR T cell therapy idecabtagene vicleucel (Ide-cel, bb2121) to FDA. Bristol Myers Squibb. Published March 31, 2020. https://bit.ly/2UtAxm6. Accessed April 22, 2020.
2. Bristol Myers Squibb and bluebird bio announce positive top-line results from the pivotal phase 2 KarMMa study of ide-cel in relapsed and refractory multiple myeloma. Bristol Myers Squibb. Published December 6, 2019. https://bit.ly/3btPIlt. Accessed April 22, 2020.