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Novel Regimens Expand Already Evolving Treatment Landscape of Multiple Myeloma

Danielle Ternyila
Published Online:5:46 PM, Thu March 26, 2020
Gurbakhah Kaur, MD
Gurbakhah Kaur, MD
BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy appears promising as treatment of patients with multiple myeloma, further expanding the treatment landscape that has already seen a number of FDA approvals in the last few years.

One CAR T-cell therapy that has demonstrated strong efficacy in this patient population is bb2121. This therapy has yielded high overall response rates in patients who are heavily pretreated relapsed/refractory. 

CAR T-cell therapy bb21217 has also demonstrated high rates of very good partial responses in patients with heavily pretreated relapsed/refractory multiple myeloma in the phase I CRB-402 clinical trial. This therapy also targets BCMA, but other clinical trials are evaluating CAR T cells with different targets, as well as different agents outside of CAR T cells.

“At John Theurer Cancer Center, we have several of these trials going on,” said Gurbakhah Kaur, MD. “We are a part of many of these trials that are going to be exciting for the world of myeloma.”

In an interview with Targeted Oncology, Kaur, a hematologist/oncologist at John Theurer Cancer Center, discussed the evolution of the multiple myeloma treatment landscape. She also highlighted other agents that are being evaluated in this patient population, both with BCMA targets and different targets.

TARGETED ONCOLOGY: What novel regimens in the myeloma pipeline are you most excited about?

KaurI am most excited about CAR T-cell therapy. In all hematologic malignancies right now, we have had some very good data coming out of therapies like BB2121 and the LCAR-B38M CAR T data as well. That is 1 of the novel therapies that I am excited about because patients with myeloma are treated for a long time. This offers them an opportunity where they get treated once and there was a time period where they don’t have to come into the doctor’s office every week. They get a break from treatment, as well, so I think it is very important. It will be interesting to see, as the data matures, what we see.

TARGETED ONCOLOGY: Could you expand on the CAR T-cell research in myeloma?

KaurThus far, our clinical trial experience with CAR T cells has mostly been with BCMA-targeted agents. BB2121 and the LCAR-B38M CAR T have mostly been tested in patients who have been heavily pretreated. Even in that population, we are getting median progression-free survival rates of less than 1 year or close to it. I think as CAR T cell research matures and we study these agents in the earlier setting, it will be interesting to see what kind of responses we get from them. We will probably get more durable responses, so I think that is where the CAR T cells will come in. I am most excited to see that.

TARGETED ONCOLOGY: What other emerging modalities in myeloma are you interested in?

KaurThe bispecific T-cell engagers (BiTEs), especially with AMG 420, are also BCMA-targeted agents, but that will be an off-the-shelf type of approach, whereas with CAR T cells you need to give lymphodepletion and wait a couple of weeks for the cells to be engineered. Many patients, when they are in crisis and they run out of options, don’t have the time to wait for a CAR T cell to be manufactured. Both of these therapies, CAR T cells and BiTE therapies, will have a major role to play in multiple myeloma treatment.

The antibody-drug conjugate (ADC) with the GSK study has also yielded some good results early on. That is another agent [that is exciting].

TARGETED ONCOLOGY: What other targets beyond BCMA are being evaluated in myeloma?

KaurIn terms of other targets, there are other CAR T cells that target beyond BCMA that have been tested in preclinical settings. These are targets such as CD38, CD138, SLAMF7. The challenges with those, though, are that some of them are present on normal tissues, so you worry about toxicity. In others, they are present on even T-cell precursors, so you worry about how to generate the T cells. I think CAR T-cell therapy is going to go beyond BCMA as well in multiple myeloma.

In addition, venetoclax (Venclexta) has been tested in the BELLINI trial. I think in the 11;14 translocation it will probably have some activity, but that needs to be explored further. There is also this new CC220, which is a newer immunomodulatory drug, that I think will also come to the forefront.

TARGETED ONCOLOGY: We have had a decent amount of approvals in the recent years, including triplet regimens and quadruplets. Has this provided any sequencing challenges in practice?

KaurI think that is the biggest challenge for the multiple myeloma community in general. While we are so lucky to have all these agents to treat our patients with and our patients are living longer than before, how to sequence and what combination regimens to give is the biggest challenge that we all face. The MAIA trial [of daratumumab (Darzalex) plus lenalidomide (Revlimid) and dexamethasone (Rd)] was released, and that provides patients who are transplant-ineligible another treatment option besides lenalidomide plus bortezomib (Velcade) and dexamethasone. You also have the CASAPIA trial with daratumumab and bortezomib, thalidomide, and dexamethasone becoming a frontline induction regimen in transplant-eligible patients as well.

The myeloma treatment landscape is getting complex, and it will not get simpler. I don’t know if we have truly answered how to sequence them because if we use a monoclonal antibody induction, what do we have left to use in the relapsed setting? In the coming years, we will have to answer these questions.

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