2022 In Review: Breakthroughs in Multiple Myeloma

Adriana Rossi, MD
Physician
Assistant Professor
Co-Director, CAR T and Stem Cell Transplant Program
Mount Sinai Center of Excellence for Multiple Myeloma

Many pivotal developments in the multiple myeloma space left their mark on 2022, according to Adriana Rossi, MD.

In a recent interview with CancerNetwork^®, Rossi, a physician, assistant professor, and co-director of the CAR T and Stem Cell Transplant program at the Mount Sinai Center of Excellence for Multiple Myeloma, pinpointed the most important breakthroughs for myeloma and spoke about the treatment paradigm’s evolution. She also discussed developments within her own practice, the potential changes on the horizon for 2023, and potential solutions to persistent unmet needs this population.

A Year in Review

CancerNetwork^®: What was the biggest breakthrough this year in the treatment of multiple myeloma?

ROSSI: This was a big year. The biggest breakthrough was the approval of our first bispecific antibody, teclistamab [Tecvayli], based on data from the MajesTEC-1 study [NCT03145181; NCT04557098].¹ We’ll have to learn how to pronounce some new words! Bispecific antibodies are set to change the landscape of myeloma therapy, similar to other T-cell–redirecting therapies.

What were some highlights from the 2022 European Hematology Association Congress regarding multiple myeloma?

[There were] many exciting highlights in T-cell­–redirecting therapies, either bispecifics or CAR T-cell therapies in the treatment of relapsed and refractory patients who’ve received prior immunomodulatory drugs, proteasome inhibitors, or anti-CD38 monoclonal antibodies. In the CAR T cell therapy space, there have been 2 approvals for B-cell maturation antigen [BCMA]–targeting agents.

There are exciting developments in G protein–coupled receptor, class C, group 5, member D [GPRC5D]­–targeting agents, [as well]. It will also be very interesting to keep an eye on [developments in] dual targeting, for example combining a BCMA-targeting agent with a CD19-targeting agent.

[There have also been investigations into] alternative manufacturing procedures. So far, we have 2 autologous products that can require anywhere from 4 to 8 weeks of manufacturing. It’s therefore important to examine either allogeneic agents or those developed on the FasT CAR T platform, which have a much quicker turnaround time and thereby abrogate the wait period.

The [myeloma] field is grappling with some very interesting questions such as duration of therapy. We still abide by [the standard of] continuous therapy until progression, at least in the United States, for many patients. [We also] have to learn how to use these new tools to abrogate treatment toxicities.

Especially in the United States, clinicians favor quadruplet therapy up front, [mainly] daratumumab [Darzalex] plus lenalidomide [Revlimid], bortezomib [Velcade], and dexamethasone [D-RVd] based on data from the phase 2 GRIFFIN trial [NCT02874742]. I was very happy to see an alternative quadruplet emerge: daratumumab, carfilzomib [Kyprolis], lenalidomide, and low dose dexamethasone [DKRd]. It’s still early days, but it will be very interesting to see the readout of data on that.

Are there any data slated for presentation at the 2022 American Society of Hematology Annual Meeting and Exposition that particularly excite you?

I’m most excited about the abstracts presenting real world data on CAR T-cell therapy. Much of our knowledge [on these therapies] comes from clinical trial data, but we now have sufficient real-world experiences to assess the differences, both in terms of patient selection and outcomes.

I’m also eager to see data on GPRC5D-targeting agents and those developed on the FasT CAR T platform. In addition, there are several presentations planned on using the end point of [minimal residual disease] MRD negativity to either escalate or deescalate therapy during induction, consolidation, or maintenance. This is something many of us aspire to do, but there hasn’t yet been sufficient evidence to support it.

Were there any FDA actions in the multiple myeloma space that have significant practice-changing potential for your patients?

The most important FDA actions this year were the approval of teclistamab, our first bispecific antibody targeting BCMA and CD3, [as well as] the breakthrough therapy designations for 2 other products: talquetamab [JNJ 7564]—targeting GPRC5D—and elranatamab, another BCMA bispecific that should come to market quite soon.^2,3

Clinical Practice

What combination regimen do you normally employ for patients with multiple myeloma who are eligible for transplant?

Though I feel we will outgrow this nomenclature soon, I base my therapies on the GRIFFIN data, which support a quadruplet of D-RVd followed by transplant. This treatment has established itself as a good standard of care. Given that I’m in academia, I also use carfilzomib up front with lenalidomide and dexamethasone, based on data from the phase 2 FORTE trial [NCT02203643].

What about for patients who are ineligible for transplant?

For those patients, I lean on data from the phase 3 MAIA study [NCT02252172].

There are some patients who can’t tolerate the quadruplet of D-RVd, so I will often start with 1 or 2 cycles of the quadruplet and then deescalate. However, for those with coverage issues or toxicity concerns—[i.e.,] for a diabetic patient who should preferably avoid a proteasome inhibitor—I use daratumumab with lenalidomide and dexamethasone, based on MAIA.

What factors help you decide which agent is right for heavily pretreated patients?

It’s a very good problem to have; in heavily pretreated patients, we now have several options.

The BCMA-targeting therapies are at the forefront of everyone’s mind because BCMA has proven to be a very effective new target. We have an approved antibody-drug conjugate, a bispecific antibody, and 2 CAR T-cell products all targeting BCMA.

The limitation on CAR T-cell therapy is availability. Most centers have many more eligible patients than available slots. The [greater] availability of bispecific antibodies, which afford similar benefits, [provides an alternative that can reach] many more patients. The antibody-drug conjugate belantamab mafodotin [Blenrep] is unfortunately marred by a high rate of keratopathy, which has limited its use.

That’s another area in which there are exciting data. We’re now evaluating different treatment schedules, different dosing, and different combinations that would enable better use of a powerful, underused drug.

What are the optimal treatment options in patients with relapsed multiple myeloma?

I don’t think there’s a single optimal treatment option in the relapsed setting; the joy of our work is that there are several options. We can now [plan treatment] based on the patient’s history [rather than just] the features of the disease. Myeloma [also] tends to be slightly different with every relapse.

[Helpfully], in the relapsed setting, you can examine prior therapies for efficacy and tolerability to identify which may best serve the patient going forward.

Looking Forward

Are there any trials that clinicians treating patients with multiple myeloma should consider enrolling their patients on?

There are so many options. Early human studies of novel CAR-T cell therapies are sometimes challenging to accrue to, but there are impressive early data coming from several different products, which should boost confidence. As I mentioned, there are also several clinical trials of bispecific antibodies currently under development. These [trials] would all be excellent ways to access these powerful tools before they’re widely available.

What further developments are you hoping to see in 2023 and beyond?

We’ll likely have an expanding armamentarium of T-cell–redirecting therapies. Increasing our manufacturing to better meet demand [for these therapies] will be a great development that I expect will happen in 2023.

Also, now that there are so many BCMA-targeting agents, what are we going to do in the post-BCMA setting? There are several early studies investigating that question.

In addition to our CAR T-cell and bispecific antibody therapies, the newest kid on the block will be natural killer cell therapy [NK therapy]. I’m looking forward to those [being developed], hopefully as soon as 2023.

Is there anything else you’d like to mention?

One of the big concerns we can’t lose focus on is the financial toll [these treatments] can inflict on patients, especially if we’re now relying on a 4-drug therapy up front and still holding on to the practice of treating until progression. This can cost a patient many hundreds of thousands of dollars. Similarly, CAR T-cell therapies cost many hundreds of thousands of dollars.

Most patients with myeloma should have at least the opportunity to receive a CAR T-cell therapy as part of their treatment. [As such], our health care systems must find a way to ensure equal access for all patients regardless of their background or disease state.

Transcript edited for clarity.

References

1. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. News release. FDA. Octber 25, 2022. Accessed November 30, 2022. https://bit.ly/3EUesTw
2. Janssen announces US FDA breakthrough therapy designation granted for talquetamab for the treatment of relapsed or refractory multiple myeloma. News release. Janssen Pharmaceutical. June 29, 2022. Accessed November 30, 2022. https://prn.to/3GWeEEv
3. Pfizer’s elranatamab granted FDA breakthrough therapy designation for relapsed or refractory multiple myeloma. News release. Pfizer. November 3, 2022. Accessed November 30, 2022. http://bit.ly/3h9I9YM