Novel Therapies Surge Forward in Relapsed/Refractory Multiple Myeloma

Thomas G. Martin, MD

Several novel agents are under investigation in relapsed/refractory multiple myeloma, including bispecific T-cell engagers (BiTEs), chimeric antigen receptor (CAR) T-cell therapies, and antibody-drug conjugates (ADCs), all of which have shown significant potency in heavily pretreated patient populations, explained Thomas G. Martin, MD.

“Immunotherapy is going to be where much of the focus of novel drug development is going to be in myeloma,” said Martin, a clinical professor of medicine in the Adult Leukemia and Bone Marrow Transplantation Program at the University of California, San Francisco (UCSF). “In the relapsed/refractory space, we have shown really good responses with BiTEs, CAR T-cell therapies, and now ADCs.”

In an interview with OncLive, Martin, who is also associate director of the Myeloma Program at UCSF and co-leader of the Hematopoietic Malignancies Program at Helen Diller Family Comprehensive Cancer Center, provided insight into novel therapies under evaluation in relapsed/refractory multiple myeloma and the steps that need to be taken prior to and upon the use of these approaches in clinical practice.

OncLive: Could you shed light on emerging BiTE therapies?

Martin: On clinicaltrials.gov, there are over 40 ongoing clinical trials of BCMA-targeted therapeutics. The majority of these studies are [testing] CAR T-cell therapies, but more than 5 ongoing clinical trials are assessing novel BiTE therapies in myeloma. Most of these bispecific therapies target BCMA. The other binding domain of the bispecific antibody is typically CD3; these molecules vary in how tightly they bind to BCMA and in how much they activate the T cell. Some are mild, some are moderate, and some activate the T cell more substantially. They’re not created equal; they’re actually very different. It’s going to be extremely interesting to see which BiTE will emerge as the best [option] over the next 2 to 5 years. It may be that they all emerge as really good therapeutics.

We have some early data from Amgen on their BiTE, AMG 420. Those findings were presented just over 1 year ago and showed some very deep responses, including stringent complete responses and minimal residual disease (MRD) negativity in patients with relapsed/refractory disease. Those data were really quite impressive. The drug was evaluated at lower doses in the phase I trial and was then escalated to higher doses. At the maximum-tolerated dose of 400 micrograms, 5 of the 7 patients who were treated had a response and were MRD negative; that’s pretty impressive for a BiTE. Very few therapeutics in that refractory patient population would have [induced] that good of a response, so we’re pretty excited about that.

The drug is given continuously for 4 weeks on and 2 weeks off. A lot of inconvenience is associated with the continuous infusion dosing. As such, [Amgen decided] it was too difficult of a dosing strategy to continue to develop that drug. Amgen has the ability to extend the half-life of some of their early BiTEs. They have a half-life—extending molecule that can be added to these BiTEs to potentially allow intermittent dosing. Now the [drug might be given] on a weekly or every-other-week basis. However, the next-generation molecule, AMG 701, is still in phase I trials. We’re really looking forward to those results. I suspect we’ll see presentations on BiTEs from Amgen, Celgene, Janssen, Regeneron, and Pfizer at the 2019 American Society of Hematology Annual Meeting. All these companies have novel therapeutics being tested in phase I trials in this space. It’s a really exciting time for BiTEs.

Could you discuss the use of CAR T-cell therapy? What have we learned from the use of bb2121 and bb21217?

The CAR T-cell therapeutics have been evaluated over a longer time frame [than other novel agents] in acute lymphocytic leukemia and non-Hodgkin lymphoma, [areas] in which they’re now approved for use. We are a little late to the game in myeloma.

We’re at the point where several hundreds of patients have been treated with CAR T-cell therapy. The early data are certainly positive. We know from the initial phase I and expansion cohorts of bb2121 that anti-BCMA CAR T cells can result in an overall response rate (ORR) greater than 90% in very refractory patients, meaning patients who have had 5 to 7 prior lines of therapy. In 1 to 3 months after receiving CAR T-cell therapy, the majority of patients achieve MRD negativity.

[We believed we would see] a flattening of the curve where patients would have long-term disease control and be cured. However, over time patients are experiencing a relapse on bb2121. On average, these relapses occur about 12 months after patients receive the product. As time goes on, we’re also seeing later relapses after 1.5 years or 2 years.However, some patients are more than 3 years out and remain in remission. We don’t know whether there will be a subpopulation of patients who [are progression free for] over 5 years and will potentially be cured. We’ll have to follow these patients more. Our initial enthusiasm for CAR T-cell therapy was based on ORR; the progression-free survival (PFS) is a little disappointing.

However, that tells us that we have room to improve. One [way to do that] is to develop novel ways to bind the BCMA target. Legend Biotech [Corporation] in China has a different binding domain based on a heavy chain antibody from llamas; it binds to 2 separate epitopes on BCMA. Whether 1 CAR can bind to 2 different myeloma cells or to the same myeloma cell in 2 different places is hard to know, but the initial data suggest that this is going to be a very active CAR.

[The product is] currently being evaluated in a phase I trial in the United States, so we don’t have those data just yet. The data from China show a PFS of about 15 months; whether that’s different from bb2121 is hard to know. Celgene elected to take over the rights to bb2121 and has developed a different way to manufacture it. In the new bb21217 protocol, the cells are manufactured in the presence of PI3K to augment the number of effector and stem cell memory T cells in the product prior to giving it to the patient.

Whether manipulating the manufacturing process will result in improved PFS remains unclear. We saw an initial report of bb21217 that suggested very high response rates and excellent T-cell expansion. However, we don’t have PFS data yet. Another way to potentially augment the effects of CAR T-cell therapy is to combine [that modality] with other agents. [To that end,] studies are combining CAR T cells with immunomodulatory drugs, such as lenalidomide (Revlimid), and checkpoint inhibitors to keep the T cells active for a longer period of time. There are many avenues for us to explore and try to improve on what has been done so far.

How could ADCs affect the landscape?

We have seen 1 product from GSK [GlaxoSmithKline], belantamab mafodotin, which has shown really good responses in a phase I and expansion cohort study. In 35 patients with relapsed/refractory disease who had seen 4 to 5 prior lines of therapy, we saw an objective response rate of 60%. The majority of patients achieved very good partial remissions with over a 90% reduction in their myeloma proteins. This is an extremely active single agent.

However, the drug does have some unusual toxicity. For example, some ocular toxicity exists, which we believe is a result of the monomethyl auristatin F poison. Patients experience corneal irritability and corneal ulcers. Some patients have described dry eyes, painful eyes, and sometimes blurry vision or a decrease in vision. It’s a troublesome adverse event (AE) that needs to be mitigated. GSK is actively pursuing ways to alter the administration of the drug to see whether they can limit this toxicity. That said, several trials are combining this ADC with other novel drugs, such as lenalidomide, bortezomib (Velcade), and pomalidomide (Pomalyst). Those combinations are going to be really interesting because the activity of the single agent is so high. We might be able to give a lower dose of the ADC in combination with some of these other agents.

Notably, among the BiTEs, CAR T cells, and ADCs, CAR T-cell therapy is the hardest to administer. Currently, [this therapy is] being given in academic centers that are poised to administer cellular therapy and take care of the treatment-related AEs, including cytokine release syndrome and neurotoxicity.

Some limitations exist in terms of access because patients have to go to the transplant center to receive the therapy. The other drugs are going to be off the shelf, which will make them easier for you to give. In fact, many patients [could eventually] receive an ADC or a BiTE prior to seeing CAR T-cell therapy. Right now, we don’t know whether CARs will work post BCMA therapy. These are things we’re going to have to assess over the next 2 to 5 years. It’s going to be interesting to see what the appropriate sequence of all these immunotherapeutics will be.

If these agents are all approved, how might you determine which drug to give?

It has been proposed that the anti-BCMA ADC and the bb2121 CAR T-cell product could be approved for use as early as next year. When they are approved, it will be an individual decision with the patient and their doctor regarding which drug to [choose] first. For many patients, it may be easier to get the BCMA-targeted ADC because it’s off the shelf and can be given locally, whereas the CAR T-cell therapy has to be administered in an academic center or a specialized hospital. The toxicities from the CAR T-cell therapy are more substantial than those experienced with the ADC.

Patients who may not be candidates for CAR T-cell therapy because of comorbidities may be eligible to receive the ADC. A younger patient who is triple-class refractory or pentarefractory might go right to a CAR T-cell therapy, whereas an older patient who is refractory to multiple therapies might want to try the ADC before considering CAR T-cell therapy.

Could other novel drugs play a role in myeloma?

Open clinical trials are evaluating the use of venetoclax (Venclexta) in patients with relapsed/refractory myeloma. Venetoclax is a BCL-2 inhibitor that’s approved for use in leukemia. [The agent is] being tested specifically in a subgroup of patients with translocation 11;14 (t[11;14]). This subgroup of patients is more likely to overexpress BCL-2 and has shown increased responses to venetoclax monotherapy as well as to combination therapy with bortezomib and dexamethasone. Ongoing trials are evaluating venetoclax in this subgroup of patients. It’s going to be an important therapeutic for patients with relapsed/refractory t(11;14) disease. I do believe it will get approved for that subgroup of patients.

The other drug that’s being evaluated is melflufen, which is a novel alkylator-based therapy. This agent has shown preclinical activity, even in alkylator-refractory cell lines. [Melflufen] is currently being tested in a phase III trial with dexamethasone versus pomalidomide and dexamethasone, and it may be another option we can use, one that we can combine with other therapeutics.

Isatuximab is a CD38-directed antibody that’s likely going to be approved for use. The drug binds to a different epitope on CD38, but whether that results in differential effects in the newly diagnosed or relapsed/refractory myeloma space is unclear. In the phase III ICARIA-MM trial, the addition of isatuximab to pomalidomide and dexamethasone resulted in a PFS approaching 12 months versus 6 months with pomalidomide and dexamethasone alone. These data will likely result in an FDA approval either later this year or early 2020.

In the next 2 to 3 years, we will have 3 to 4 additional therapeutics that will be approved for use in the relapsed/refractory space. Once these drugs show benefit in the relapsed/refractory space, they will be moved up into early relapse setting, and eventually they will be tested in the newly diagnosed setting. It’s a really exciting time for clinical trials and novel therapeutics in myeloma.

Could you discuss other important targets that have emerged in the space?

Selinexor (Xpovio) was recently approved for use in the relapsed/refractory setting. It’s a fi rst-in-class molecule that inhibits the translocation of certain oncogenes from the nucleus to the cytoplasm. There’s a chaperone protein, XPO1, that helps move proteins in and out of the nucleus. Cancer cells sometimes overexpress XPO1 and can take some of the regulatory cell cycle proteins from the nucleus, like p53, and put them into the cytoplasm; this allows cells to undergo continuous cell cycle growth.

Selinexor stops the translocation of many oncogenic proteins from the nucleus to the cytoplasm and helps induce apoptosis. The agent has been combined with dexamethasone in patients who had triple-class refractory disease and has shown a response rate of just over 25%. Typically, we’re using it in patients who have tripleclass refractory disease, as those patients currently represent an unmet medical need. Outside clinical trials, we don’t have any great therapeutics available for those patients; selinexor is certainly an option for them.

Selinexor does have some AEs, including hyponatremia, nausea, diarrhea, anorexia, and fatigue, so patients have to receive signifi cant supportive care. We put them on 2 antinausea medications, and we’ll bring patients into the clinic once or twice a week to receive intravenous fl uids. Sometimes patients need to be on salt tablets. Patients can also have blood count suppression, which we have to watch closely because many patients already have low blood counts. You can’t start a patient on selinexor and tell them to come back in 4 weeks. You have to see these patients on a weekly or even twice-weekly basis.

A next-generation XPO1 inhibitor is also in development. We’ll see whether that agent has a better toxicity profi le. [Investigators are currently combining selinexor] with several other agents, including daratumumab (Darzalex) and bortezomib, in the BOSTON trial. The regimen is administered on a weekly basis, which may mitigate some of the AEs we’re seeing. We’re looking forward to seeing the results of the trial and results of other combinations with selinexor.