乌鸦传媒

CHICAGO -- More than 70% of patients with heavily pretreated multiple myeloma had responses to the novel bispecific antibody talquetamab plus subcutaneous daratumumab (Darzalex Faspro), a preliminary trial showed.

The higher of two doses of talquetamab led to an overall response rate (ORR) of 84%, including very good partial response (VGPR) or better in 74%. The lower dose plus daratumumab resulted in an ORR of 71.4% and a VGPR or better of 57.1%. A majority of the 65 patients had received five or more prior lines of therapy and had triple-refractory disease. More than 80% of the patients had prior exposure to anti-CD38 agents, including daratumumab.

At 12 months, more than 80% of responses were ongoing, including 93.3% of complete responses (CRs), reported Bhagirathbhai Dholaria, MD, of Vanderbilt University Medical Center in Nashville, Tennessee, at the American Society of Clinical Oncology (ASCO) annual meeting.

"The GPRC5D-directed bispecific monoclonal antibody appears to offer an off-the-shelf treatment option for patients with heavily pretreated relapsed/refractory multiple myeloma," said Dholaria. "Promising response rates were seen even among patients with anti-CD38-refractory disease, as well as patients who had other prior T-cell redirection therapy, such as CAR T-cell therapy, or other bispecific antibody therapy."

"There were no new clinically significant increases in AEs [adverse events] when daratumumab was added compared with what we know about talquetamab monotherapy," he added. "It appears that the peripheral blood B-cell counts are preserved with this therapy. That makes talquetamab potentially a good partner drug [that] can be combined with other currently available -- as well as currently under development -- anti-myeloma therapies."

Two other small studies showed promising early results in heavily treated myeloma with CAR T-cell therapies prepared from rapid-production platforms that cut the preparation time from weeks to days.

PHE885, targeting B-cell maturation antigen (BCMA), led to an ORR of 98% in 50 patients (47 with triple-refractory disease), including a VGPR or better in 80%. Responses deepened over time, as conversion from CR to stringent CR occurred as late as 18 months after infusion, reported Adam S. Sperling, MD, PhD, of Dana-Farber Cancer Institute in Boston.

GC012F, targeting BCMA and CD19, achieved objective responses in 93.1% of the first 29 patients treated at different dose levels. All 29 patients achieved minimal residual disease (MRD)-negative status, reported Wanting Qiang, MD, of Shanghai Chang Zheng Hospital.

Collectively, the studies showed "impressive efficacy" in heavily treated myeloma, said ASCO-invited discussant Francesca Gay, MD, of the University of Torino in Italy. Anti-BCMA agents already have FDA approval for late-line therapy, and emerging data in earlier treatment are promising.

As immunotherapy strategies continue to evolve in myeloma, improved patient access and safety are priorities along with continued research on strategies to improve efficacy, Gay continued.

"We must provide novel options for patients refractory to lenalidomide [Revlimid] and to anti-CD38 antibodies, as there is increased use of both agents in the first line," she added.

Talquetamab targets GPRC5D, an antigen uniquely overexpressed on malignant plasma cells, and CD3, which mediates lysis of GPRC5D+ myeloma cells. Dholaria reported updated findings from the trial evaluating subcutaneous talquetamab and daratumumab in patients with multiple myeloma with a treatment history of at least three prior lines of therapy or refractory to a proteasome inhibitor (PI) and an immunomodulatory (IMiD) agent. Eligibility criteria allowed enrollment of patients with disease refractory to anti-CD38 agents.

The investigators evaluated two doses of the bispecific antibody, 0.4 mg/kg weekly or 0.8 mg/kg every 2 weeks. Key objectives were identification of the recommended phase II dose, safety, and antitumor activity.

The patients had a median disease duration of 6-7 years and an extensive treatment history. More than 80% of the patients had a prior stem-cell transplant, and about half of the patients had exposure to BCMA-targeted therapy.

Both doses of talquetamab, plus daratumumab, achieved high-level activity. The median time to response with both doses was 1 month. All eight patients with no prior anti-CD38 exposure responded, as did more than 70% of patients with prior anti-CD38 exposure and a similar proportion of the anti-CD38-refractory patients.

The FDA has approved two BCMA-targeted CAR T-cell therapies for multiple myeloma -- idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti) -- but both involve prolonged manufacturing times that may limit patient access, said Sperling.

PHE885 is an autologous, fully human, BCMA-directed CAR-T therapy manufactured in less than 2 days by means of the T-Charge platform, which facilitates in vivo cell expansion and eliminates the need for prolonged ex vivo expansion. The process also preserves T-cell stemness.

Sperling reported findings from 50 U.S. patients treated with the therapy and followed for a median of 6.7 months. All but 10 of the patients had one or more prior stem-cell transplants, all but three had triple-refractory disease, and almost two-thirds were penta-refractory. Across five dose levels, 49 of the 50 patients had objective responses. Rates of VGPR or better ranged from 50% to 100% across the doses (80% overall).

The median time to first response was less than a month, and median time to best response was 2.76 months, said Sperling. Responses deepened over time, converting from lower- to higher-level activity.

Thus far, no unexpected safety findings have emerged, said Sperling. The most common grade ≥3 AEs have been neutropenia (80%), anemia (56%), thrombocytopenia (50%), and leukopenia (22%).

"PHE885 reliably expanded in vivo and showed prolonged persistence with preserved T-cell stemness," Sperling concluded. "PHE885 is expected to be delivered in less than 10 days in the U.S., with potential for outstanding clinical impact in myeloma. A phase II study is underway in patients with relapsed/refractory myeloma, and evaluation in earlier lines is about to begin."

GC012F offers the promise of "next-day manufacturing" by means of the FasTCAR platform, which compresses T-cell activation, transduction, and expansion into a single process, said Qiang. The therapy was evaluated in a phase I trial involving patients who had received three or more prior lines of therapy or had disease that was refractory to a PI and an IMiD.

The investigators evaluated three dose levels, and the primary endpoint was occurrence of AEs. Secondary objectives included objective response rate and MRD assessment at various time points after infusion.

The 29 patients included in the data analysis had received a median of five prior lines of therapy; more than 90% had PI- and IMiD-refractory disease, and more than 80% were refractory to the most recent therapy.

Across all three doses, 27 of 29 (93%) patients had objective responses, including 83% who had a stringent CR plus MRD-negative status. All 29 patients achieved MRD-negative status some time during follow-up. Responses were durable, as indicated by the 38-month median duration.

"GC012F, targeting BCMA and CD19, shows very promising activity in relapsed and refractory multiple myeloma, including high-risk and heavily pretreated patients with prior exposure to anti-CD38 antibodies, proteasome inhibitors, and IMiDs," Qiang concluded.