CAR-T, Novel Combos Continue to Show Benefit in Multiple Myeloma

Larry Anderson, MD, PhD

A number of therapeutic approaches continue to be explored for patients with multiple myeloma, explained Larry Anderson, MD, PhD, citing CAR T-cell therapy and several combination strategies as treatments that are showing promise.

“The landscape of myeloma is constantly changing, with 12 new drugs approved since 2003 and 8 drugs approved over the past 7 years,” said Anderson. “Every year we have new drugs, and it is an exciting time in myeloma to have all these opportunities. It is also very exciting with all of the immunotherapies on the horizon.”

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Hematologic Malignancies, Anderson, associate professor, Department of Internal Medicine, Division of Hematology/Oncology, at Harold C. Simmons Comprehensive Cancer Center of UT Southwestern Medical Center, discussed emerging therapies for patients with multiple myeloma that were highlighted at the 2019 ASH Annual Meeting.

OncLive: What are some of the new therapies for patients with multiple myeloma?

Anderson: A lot of data were presented at the 2019 ASH Annual Meeting, and there are some recent myeloma papers were published on FDA approvals. There were some data for frontline therapies [because] that is where most of the changes are happening. Lately, some new approvals with daratumumab (Darzalex) are incorporating it into frontline therapy. Studies have looked at incorporating daratumumab into multidrug regimens in the pretransplant setting. as well, and they look very promising.

We are looking at some similar combinations with daratumumab and carfilzomib (Kyprolis) in the relapsed/refractory setting [that have led to complete remissions]. Also, there are data with bispecific T-cell engagers in heavily refractory patients. Basically, it is a way to get patients T-cell immunity without having to generate CAR T cells.

CAR T cells are very exciting, but the problem with CAR T cells is that generating cells take a month. They have to be genetically engineered and grown, and sometimes patients cannot wait 1 month for those T cells because the myeloma is growing so rapidly.

[Investigators have evaluated] an off-the-shelf molecule that helps force patients’ T cells to recognize the myeloma and attack it. Some of the research that we are doing at our institution [involves] a few CAR T-cell clinical trials for myeloma. A couple of the initial trials have shown tremendous responses and deep remissions, but it looks like many of the patients are relapsing 1 or 2 years out.

Now, there are newer trials looking at moving up CAR T-cell therapy earlier into lines of therapy, such as the second- or third-line setting. One of our upcoming trials is looking at first-line CAR T- cell therapy for patients with high-risk [chromosomal abnormalities]. Instead of waiting until relapse, these patients would be given CAR T cells instead of the autologous stem cell transplant.

We have trials looking at mutation-specific therapy, which [are] sponsored by the Multiple Myeloma Research Consortium (MMRC). MMRC has the MyDrug study, which is personalized medicine for patients with multiple myeloma.

What other studies were presented at the 2019 ASH Annual Meeting?

One of the key studies is the GRIFFIN study. That randomized study looked at up-front daratumumab with the standard triplet of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) versus RVd alone. This was for frontline pre-transplant induction in patients who were newly diagnosed with myeloma. In that study, we are seeing significantly more deep remissions and molecular remissions or minimal residual disease (MRD) negativity. However, only time will tell how that translates into progression free survival (PFS) and overall survival, but so far it is very encouraging.

Another study, the CANDOR trial, evaluated daratumumab and carfilzomib in combination with dexamethasone for relapsed/refractory myeloma. Those patients had very deep remissions as well as nice response rates, and they tolerated the therapy quite well. It was a tripling of the molecular remissions with MRD testing, and [the regimen] significantly improved PFS, which has not been reached in the daratumumab group.

What other FDA-approved agents are incorporating into your practice?

The FDA recently approved selinexor (Xpovio), which is a selective inhibitor of nuclear transport. It gives physicians an option for these patients who have failed multiple lines of therapy. It is for triple-class refractory patients who have already had an immunomodulatory agent, a proteasome inhibitor, and a CD38-targeted monoclonal antibody. It does have some tolerability issues with nausea, but as long as physicians are preemptively managing that with a very aggressive antiemetic regimen, most patients will be able to tolerate it fine and stay on therapy.

What key challenges remain in the field of myeloma?

The key one is that most patients become resistant to all of the drugs that they are treated with, so we still need more [drugs to be developed]. Also, as I mentioned previously, CAR T-cell therapy works great in myeloma, but we still have not proved that it is a cure. The biggest challenge is finding a way to use [CAR T-cell therapy] and harness that power to cure our patients.