Berdeja Looks Ahead in Multiple Myeloma Treatment

Jesus Berdeja, MD

Findings presented during the 2017 ASH Annual Meeting generated excitement in the field, says Jesus Berdeja, MD. Some of the most impactful data presented included the ALCYONE study and the dose-escalation study of the BCMA-directed CAR T-cell therapy bb2121.

Results from the phase III ALCYONE trial showed that the addition of daratumumab (Darzalex) to bortezomib (Velcade), melphalan, and prednisone (VMP) reduced the risk of progression or death by 50% compared with VMP alone for transplant-ineligible patients with newly diagnosed multiple myeloma. The progression-free survival (PFS) rate at 18 months with the daratumumab-containing regimen was 71.6% (95% CI, 65.5%-76.8%).¹ The FDA granted a priority review designation on this frontline regimen based on these findings in January 2018.

The updated findings from a dose-escalation trial of bb2121 were also presented at ASH. Treatment with the CAR T-cell therapy induced complete remissions for 56% of patients with relapsed/refractory multiple myeloma.²

OncLive: Can you share your insight on some of the recent advances in myeloma?

In an interview with OncLive^® during the 2018 State of the Science Summit™ on Hematologic Malignancies, Berdeja, director of Multiple Myeloma Research at Sarah Cannon Research Institute, reflected on these pivotal studies in multiple myeloma and discussed potential advancements in the upcoming year.Berdeja: The 2017 ASH Annual Meeting was very good for myeloma—we had a lot of exciting things happen. [Some] were simple things that may make a big splash in the treatment of myeloma in the field of supportive care. One of the things that we struggle with in myeloma are infections. There were 2 studies presented [at the meeting]; the first was with antibiotics in the first 3 months from diagnosis, which significantly decreased morbidity and mortality in myeloma. A simple intervention like an antibiotic can make a significant difference. The other study looked at the influenza vaccination in patients with myeloma. It looks like if you give the high-dose vaccination and a booster 30 days later, you get a significantly greater amount of protection than with just 1 dose. Again, this is another simple intervention that can make a big difference in our patients.

One of the biggest splashes was the ALCYONE study. That was daratumumab with bortezomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone. This was a large study that showed a significant improvement with the daratumumab arm both in PFS and depth of remission. That was an impressive result. Bortezomib, melphalan, and prednisone is not a very commonly used regimen anymore, but it was a proof-of-principle kind of study. We will start seeing more data forthcoming with combinations in the frontline setting that could potentially change the field quite a bit.

If bb2121 is approved, how would it fit into the treatment landscape?

In the relapse setting, the big splash has been CAR T cells for the last year or so. There were several presentations [at ASH] and we presented the data with the bb2121 cells. The responses seen in the relapsed/refractory population are incredible. There was a 94% overall response rate and a 56% complete remission rate in patients who had a median of 7 prior lines of therapy, reaching minimal residual disease—negative status.Right now, if it were to get approved, the indication would be in the relapsed/refractory setting. It would be patients who had at least 3 prior regimens and exhausted all other options. It is not clear if this is the most appropriate population. Obviously, being able to move it earlier in the course of disease before the patient has toxicities from all their prior therapies may yield better results. Those trials are actually already in the works.

It is still early. We just presented the dose-escalation trial, and the dose-expansion study has just completed. Some of that data will be presented at the 2018 ASCO Annual Meeting.

There are still a lot of unanswered questions. We don't know how long these remissions are going to last. At the 2017 ASH Annual Meeting, we did present that 4 patients had progressed, so progressions are still occurring. We don't know why the patients are still progressing; there did not seem to be 1 particular factor. There was a thought that there was a BCMA-negative escape, but that does not seem to be the case for all the patients. It was then thought that maybe cells were not lasting long enough, but that did not seem to be the case either. It wasn't based on cell dose either, so we don't know exactly why some patients relapse and some don't.

Considering what has occurred so far in the trials of immune checkpoint inhibitors in myeloma, do you believe there could still be a role for these agents?

What study results or regulatory decisions can we anticipate in 2018?

This trial allows retreatment, so it will be interesting to see whether a second dose once a patient progresses actually works. There are still some toxicity issues that are present. There will be some presentations at the 2018 ASCO Annual Meeting that will be looking at who may have toxicities and who may not. There is so much more to learn. Ideally, we could give these to all patients and they would respond without toxicity. Until that is achieved, there is a lot to do.PD-1 and other checkpoint inhibitors still have a role in myeloma. It was very sobering to see that not all combinations are benign. What we struggle with is that checkpoint inhibitors do not seem to have much activity by themselves. Part of that may be because the innate immune system of myeloma is not able to respond to a simple PD-1 inhibitor and requires the second agent to boost it. However, part of what we saw was based on the population that was tested. We were so excited that is was quickly moved to the frontline setting and, like I said before about infections, 20% of patients die from infections in the first few months. Targeting that population may have been a mistake; it hurt and set back the potential for PD-1 inhibitors. The holds right now are on immunomodulatory drug (IMiD) combinations, but there is still potential for combinations with other checkpoints or IMiDs. I don't think we have heard the last of PD-1 inhibitors. In 2018, there is a chance that bb2121 may be approved. There is a chance that daratumumab may be approved for frontline treatment in myeloma. Selinexor and some of the selective inhibitors may be approved in the relapsed/refractory setting. I am not sure if they will be approved quickly, but there will be a lot more promising data.

Just like in the lymphoma world, there are a lot of therapies with antibody-drug conjugates and bispecific antibodies that are also being tested right now. We will hopefully see data on those that will potentially challenge the CAR T cells.

References

1. Mateos M-V, DA Meletios, Cavo M, et al. Phase 3 randomized study of daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) in newly diagnosed multiple myeloma (NDMM) patients (Pts) ineligible for transplant (ALCYONE). In: Proceedings from the 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract LBA-4.
2. Berdeja JG, Lin Y, Raje N, et al. Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: updated results from a multicenter study of bb2121 anti-Bcma CAR T cell therapy. In: Proceedings from the 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 740.