Multiple myeloma's treatment arsenal has been greatly boosted in recent years, and chimeric antigen receptor (CAR) T-cell therapy is now one of the latest options on the horizon for this blood cancer. In particular, CAR T cells targeting BCMA, an overexpressed protein in multiple myeloma that promotes disease progression, have attracted much interest, with several investigational agents spotlighted during the 2019 American Society of Hematology (ASH) Annual Meeting in Orlando, FL, in December.
All three candidates—JNJ-4528 (Janssen/Legend Biotech); BM38 (Cellyan Therapeutics), a bispecific product that also targets CD38, another key multiple myeloma antigen; and bb21217 (bluebird bio)—showed potential in treating relapsed/refractory disease. Across these trials, patients had already received multiple rounds of multiple myeloma's therapeutic mainstays: proteasome inhibitors, anti-CD38 drugs such as daratumumab (Darzalex; Janssen), and lenalidomide or an immunomodulatory counterpart. The number of prior therapies was as high as 18, so “considering the population, it's quite amazing to have seen deep responses” to CAR T-cell therapy, said Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai in New York, NY, who presented findings from CARTITUDE-1, a phase Ib/II study of JNJ-4528.
JNJ-4528 latches on to BCMA at two domains instead of one, for tighter binding. It is identical to LCAR-B38M, under evaluation in China. At ASH, an updated analysis of the related Chinese trial, LEGEND-2, bolstered preliminary results that were first disclosed during the 2017 American Society of Clinical Oncology Annual Meeting. That said, “these patients were less heavily pretreated, having not seen drugs like daratumumab and lenalidomide,” noted Adam Cohen, MD, of the University of Pennsylvania in Philadelphia. CARTITUDE-1 was necessary to assess this therapy “in a population that better represents what we're used to seeing” in the United States.
Madduri reported that among 29 patients given JNJ-4528 at a median dose of 0.73 million cells/kg body weight, the objective response rate (ORR) was 100%; 66% were classified as stringent complete responses (sCR), and another 17% were very good partial remissions (VGPR). The latter two benchmarks are unique to multiple myeloma: sCR is defined as no detectable tumor cells in the bone marrow and no M protein—used to estimate the extent of disease—in serum or urine; VGPR is defined as decreases in both by more than 90%. Further analyses indicated preferential in vivo expansion of central memory CD8+ T cells, “a phenotype we think does not get exhausted as often, resulting in sustained effector function,” Madduri said. “It may explain the high therapeutic activity seen at a relatively low dose.” At 6 months, 27 of 29 patients were progression-free, she added, and based on these data JNJ-4528 has earned breakthrough therapy designation from the FDA.
Chinese biotech Cellyan's dual-targeting BM38 CAR T-cell therapy aims to “address antigen loss and increase effector cell persistence,” said Yu Hu, MD, PhD, of Huazhong University of Science and Technology in Wuhan. “Otherwise, with CAR T cells that only target BCMA, short-term relapse is a major challenge.” He presented results from a phase I trial in which 22 patients were infused. The ORR was 90.91%, including 12 sCRs and two VGPRs. Of nine patients whose disease had spread beyond the bone marrow, eight saw their extramedullary lesions resolved partially or completely, Hu said. Phase II studies in China and the United States are being planned.
“It's an interesting approach that may have merit,” Cohen remarked of this bispecific strategy. Due to wide expression, including on hematopoietic progenitor cells, “there's been concern that targeting CD38 with a really potent CAR could wipe out patients' blood counts and immunity for a long time. At least in [Cellyan's] trial, this wasn't seen, which I think is promising.”
Jesus Berdeja, MD, of Sarah Cannon Center for Blood Cancers in Nashville, TN, reported preliminary results from CRB-402, a phase I trial evaluating bluebird's bb21217. This is a twist on idecabtagene vicleucel (ide-cel/bb2121), the Cambridge, MA–based biotech's main CAR T-cell therapy—with a PI3K inhibitor added during manufacturing to boost memory-like T-cell subsets in the final product. The hypothesis is that such enrichment could prolong bb21217′s persistence and improve potency. Three flat doses were given: 150 million, 300 million, or 450 million cells. Efficacy was seen at all dose levels; the ORR among 38 patients was 52.6%, including five CRs/sCRs and 12 VGPRs. David Davidson, MD, bluebird's chief medical officer, observed that “it looks like our hypothesis is holding up—at 6 months, patients with robust expansion of memory T cells were more likely to have and maintain therapeutic responses.”
Safety-wise, all three agents had profiles typical of CAR T-cell therapy, with cytokine release syndrome (CRS) being the main issue, albeit mostly low-grade and mitigated with steroids or tocilizumab (Actemra; Genentech). Another side effect was neutropenia; neurotoxicity, which can occur with this treatment, was uncommon.
“We're getting better at managing CRS, and therefore the therapeutic index is improving,” said Kenneth Anderson, MD, of Dana-Farber Cancer Institute in Boston, MA. He, too, considers the results so far “truly remarkable, given that patients in these trials often had no other options. But the follow-up is still very early, so how durable the responses are remains to be seen.”
On December 6, bluebird also announced topline data from its phase II KarMMa study of ide-cel, under joint development with Bristol-Myers Squibb. Among 128 patients given the same doses used in CRB-402, the ORR was 73.4%, including 40 CRs/sCRs. The median progression-free survival was 8.6 months; it improved to 11.3 months at the highest dose of 450 million cells. This will be the dose used as bb21217 moves into phase II, Davidson said. Meanwhile, “we expect to proceed with regulatory filing for ide-cel in 2020 and hope to see it become the first-in-class CAR T-cell therapy targeting BCMA.”
Ide-cel “will likely be the first approved by virtue of longer experience” clinically, Anderson noted. “But progress really continues even after approval,” he added, and, in deploying this form of immunotherapy against multiple myeloma, there are still many questions to be addressed—whether enriching for certain T-cell subsets is important, for instance; or how much persistence matters in response durability.
“Hopefully we'll get smarter about how and when to use CAR T cells,” Cohen agreed. Cellular therapies for multiple myeloma have burgeoned of late, he observed, with T cell–engaging bispecifics also showing potential in early trials. “So stay tuned, because the field is only going to get more crowded.” –Alissa Poh
- ©2020 American Association for Cancer Research.
Volume 10, Issue 2
