Subcutaneous daratumumab is generating a huge amount of buzz, but it’s important to realize it’s not just off-the-shelf daratumumab injected under the skin; it’s a completely different formulation.— Amrita Krishnan, MD, FACP
From immunomodulatory agents and proteasome inhibitors to steroids, alkylators, and antibodies, recent years have witnessed an explosion of drug approvals for multiple myeloma. The challenge now, said Amrita Krishnan, MD, FACP, is figuring out how to incorporate them all, particularly in the relapsed setting, where one drug alone is insufficient to achieve remission. At the City of Hope’s annual Hematologic Malignancies Symposium, Dr. Krishnan shared data from the latest multiple myeloma trials and discussed how knowledge of the immune system is guiding research.1
“We need to be increasingly aware of immunosuppression and its role in relapse and learn how to augment the immune system to restore antimyeloma immunity,” said Dr. Krishnan, Director of the Judy and Bernard Briskin Center for Myeloma at City of Hope, in Duarte, California. “This is going to lead us to the best long-term disease control.”
“Myeloma therapy is a lot like cooking,” Dr. Krishnan added. “You have to mix things together, and the recipe for success involves multiple different approaches.”
Combination Therapy With Daratumumab
Based on two open-label phase III trials (CASTOR and POLLUX), daratumumab (Darzalex), an anti-CD38 monoclonal antibody, was approved for use in combination with lenalidomide (Revlimid) and dexamethasone or with bortezomib (Velcade) and dexamethasone in patients with multiple myeloma who have had at least one prior therapy.2,3
In the POLLUX trial, treatment with daratumumab plus bortezomib and dexamethasone resulted in a 63% reduction in the risk of disease progression or death compared with bortezomib and dexamethasone alone, and the trial was stopped early because of “striking improvement” in progression-free survival. Results were nearly as striking in the CASTOR trial: progression-free survival for patients in the daratumumab-bortezomib-dexamethasone arm almost doubled that in the control arm.
“These trials were landscape changing,” said Dr. Krishnan, who noted that the approval of daratumumab has “made things even more confusing for first relapsed patients.”
Antibodies like daratumumab have a direct effect on myeloma cells, she noted, but researchers are increasingly recognizing the indirect effects as well. “Fairly robust data from daratumumab indicate that it affects T-cell ratios and improves them in patients with relapsed myeloma,” Dr. Krishnan explained. “Daratumumab promotes T-cell expansion and activation, depletes immunosuppressive regulatory cells, and has multiple different mechanisms of action.”
However, daratumumab is not the only immunomodulatory agent under investigation in multiple myeloma. Anti–programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors are also being studied, with the aim of improving T-cell function.
CAR T-Cell Therapy
Investigators are also studying chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory multiple myeloma in several ongoing trials, but many questions remain about CAR design.
“When you engineer T cells, you need to incorporate costimulatory molecules to prevent the immune system from eradicating the cells, but we don’t know what the best costimulatory domains to add are,” said Dr. Krishnan, who noted that CD19, CD138, CD38, CD56, Lewis Y, CD44v6, CS1, and BCMA are all targets under study.
According to Dr. Krishnan, the optimal dose and schedule for CAR therapy also remain uncertain, as does the need for chemotherapy prior to administration. “Perhaps ‘cocktails’ of multiple CARs or CAR plus chemotherapy will be required for best outcomes,” she observed.
A phase I study of bb2121 in B-cell maturation antigen–expressing multiple myeloma is still recruiting in cancer centers across the country, but initial results have demonstrated impressive tolerability and response. “There have been no grade 3 cytokine-release syndrome, no neurotoxicity, and no dose-limiting toxicities, which is pretty amazing compared to other T-cell trials,” revealed Dr. Krishnan, who noted that responses have been seen in 100% of patients as well.
“Only nine patients have been treated—and for only 32 weeks—but these early data suggest that bb2121 might be something to consider in advanced refractory disease,” she said.
A separate CAR trial at the University of Pennsylvania has yielded mixed results.4 In extremely refractory myeloma patients, who had failed all previous lines of therapy, T cells targeting B-cell maturation antigen produced severe neurotoxicity in two of nine patients and grade 3 or 4 cytokine-release syndrome in three of nine patients.
“A response up to 12 months was seen in one patient,” Dr. Krishnan added, “but we need to view these results with caution.”
Although daratumumab has been used increasingly as a backbone of several regimens, one of the challenges with it has been lengthy infusion time. According to Dr. Krishnan, however, daratumumab as subcutaneous administration may provide a solution.
“Subcutaneous daratumumab is generating a huge amount of buzz, but it’s important to realize it’s not just off-the-shelf daratumumab injected under the skin; it’s a completely different formulation,” she explained.
The addition of recombinant human hyaluronidase to daratumumab allows the absorption of drugs injected subcutaneously.
“Investigators have observed very good responses so far, and infusion-related reactions seem to be lower. We’re still awaiting additional data, but this could be the way of the future,” said Dr. Krishnan.
Steven T. Rosen, MD
Finally, leflunomide (Arava), an immunosuppressive agent approved for the treatment of rheumatoid arthritis and psoriatic arthritis, is showing activity in advanced refractory multiple myeloma. Steven T. Rosen, MD, Provost/Chief Scientific Officer and Director of the Comprehensive Cancer Center and Beckman Research Institute at City of Hope, discovered leflunomide’s off-label potential and has been studying the drug for 10 years.
“The first patient treated was a woman who’d failed all traditional aggressive therapies and been told to get her life in order,” Dr. Rosen explained. “Within a week, leflunomide had reduced her myeloma protein.”
This remarkable response led to preclinical studies of teriflunomide (Aubagio), the active metabolite of leflunomide, which was shown to inhibit cell growth of multiple myeloma cells in vitro at clinically achievable concentrations. Additional studies have also suggested synergy when leflunomide is used in combination with different classes of antimyeloma drugs, including panobinostat (Farydak), pomalidomide (Pomalyst), dexamethasone, lenalidomide (Revlimid), or ixazomib (Ninlaro).
A phase I/II dose-escalation trial of leflunomide in patients with relapsed or relapsed/refractory multiple myeloma is underway at City of Hope.
“Leflunomide has been extremely well tolerated, and we’ve had several patients achieve long responses,” said Dr. Krishnan. “We’ve been quite pleased with this drug and are looking forward to future trials with it.”
Although the presence of so many viable multiple myeloma therapies is clearly a boon for both patients and providers, the ever-expanding armamentarium does cause the occasional headache for oncologists.
“Choosing between all these different drug options can be very challenging,” Dr. Rosen acknowledged. “Physicians must weigh toxicity and benefits of sequencing and be mindful of mutations that could lead to resistance—all while anticipating what comes next. You don’t want to burn any bridges by causing side effects that will prevent [the use of] another option.” ■
Disclosure: Dr. Krishnan is a consultant for Celgene, Janssen, and Takeda and is on the speakers bureau for Celgene, Takeda, Janssen, and Onyx. Dr. Rosen is on the speakers bureau for Celgene, Pharmacyclics, Imbruvica, The Scienomics Group, Xcenda AmerisourceBergen, Valeant Pharmaceuticals, and Prime Oncology.