Subcutaneous Cevostamab Shows Promise in Relapsed/Refractory Multiple Myeloma with 38.8% Response Rate
核心洞察
Subcutaneous cevostamab, a novel FcRH5 (搜索)/CD3 (搜索) bispecific antibody, achieved a 38.8% overall response rate in heavily pretreated relapsed/refractory multiple myeloma patients in the phase 1b CAMMA 3 study.
BCMA (搜索) therapy-naive patients demonstrated superior outcomes with a 52.0% response rate compared to 25.0% in BCMA-exposed patients, suggesting potential T-cell exhaustion effects.
The subcutaneous formulation showed a manageable safety profile with mostly mild adverse events, offering a more convenient treatment option compared to intravenous administration.
Subcutaneous administration of cevostamab, a novel FcRH5 (搜索)/CD3 (搜索) bispecific antibody, demonstrated clinically meaningful activity and a manageable safety profile in patients with relapsed or refractory multiple myeloma (R/R MM), according to initial results from the phase 1b CAMMA 3 study presented at the 67th American Society of Hematology (搜索) Annual Meeting and Exposition.
The study, led by Phoebe Joy Ho, MBBS, DPhil, of Royal Prince Alfred Hospital and University of Sydney, evaluated 52 efficacy-evaluable patients and found that cevostamab induced deep, durable antitumor responses at target doses of 120 mg or greater. The overall response rate (ORR) reached 38.8% (95% CI, 24.1%–53.4%) across all tested dose levels, with a median duration of response of 12.3 months (95% CI, 8.3–not estimable).
Response Depth and Quality
The therapeutic responses demonstrated notable depth, with 14.3% of patients achieving stringent complete response (sCR), 6.1% complete response (CR), 10.2% very good partial response (VGPR), and 8.2% partial response. Among the 12 patients who achieved sCR/CR, a majority (n = 8) exhibited minimal residual disease (MRD) negativity, while the remaining 4 patients were either MRD-positive or had baseline calibration failure.
BCMA Exposure Impact on Efficacy
A striking finding emerged regarding prior B-cell maturation antigen (BCMA (搜索)) therapy exposure. BCMA therapy-naive patients achieved significantly higher response rates at 52.0% (95% CI, 30.4%–73.6%) compared to 25.0% (95% CI, 5.6%–44.4%) among BCMA-exposed patients. The median duration of response was not reached in BCMA-naive patients (95% CI, 11.7-not evaluable) versus 8.3 months (95% CI, 4.9-not evaluable) in BCMA-exposed patients.
Ho noted potential mechanisms behind these differences, stating, "Those patients who received another bispecific therapy and then received cevostamab had a shorter duration. One could hypothesize whether there is evidence of perhaps T-cell exhaustion in those patients with a short duration as low as approximately 7 weeks, whereas in the other 2 categories of antibody-drug conjugates as well as chimeric antigen receptor T-cell therapy, the durations were much longer."
Safety Profile and Tolerability
Adverse events were predominantly grades 1 or 2 in the total dose-escalation population of 58 patients. The most common any-grade adverse events included cytokine release syndrome (CRS; 69.0%), injection site reactions (ISR; 58.6%), neutropenia (31.0%), anemia (29.3%), pyrexia (25.9%), and rash (17.2%). CRS events were mostly low-grade and effectively managed with tocilizumab, steroids, or both, while ISR events were mainly mild and occurred early in treatment.
Treatment-related adverse events led to cevostamab discontinuation in only 3 patients. Three fatal adverse events occurred, though none were deemed treatment-related. Ho emphasized that "the majority of adverse events were mild and cytopenias were generally reversible, while treatment-related adverse events leading to discontinuation were infrequent."
Study Design and Patient Population
The CAMMA 3 study enrolled heavily pretreated patients with a median of 5 prior lines of therapy (range, 2–11). Nearly half (48.3%) had received prior BCMA (搜索)-targeted therapy, including CAR T (10.3%), antibody-drug conjugates (32.8%), and bispecific antibodies (8.6%).
The treatment regimen followed a fixed-duration schedule over 13 28-day cycles spanning approximately 12 months. Patients received stepped-up dosing on days 1 and 8 of cycle 1 with mandatory hospitalization, followed by target doses ranging from 40 to 300 mg administered every 2 weeks for 5 cycles, then every 4 weeks until cycle 13. Premedication included IV corticosteroids during the first 2 cycles, plus acetaminophen and diphenhydramine for all cycles.
Clinical Implications
The subcutaneous formulation addresses a key clinical need for more convenient administration. Ho noted that safety and efficacy figures were "generally comparable with that of intravenously administered cevostamab monotherapy, supporting the potential of subcutaneous cevostamab to offer a more convenient treatment option for providers and patients."
The study was motivated by findings from a previous phase 1 study that demonstrated efficacy and safety of IV cevostamab in heavily pretreated R/R MM patients, with the goal of developing a more accessible formulation to expand treatment access and utilization.
Ho concluded that "on the basis of these data showing a clinically active compound given in the subcutaneous route, cevostamab is the subject of an ongoing development program aiming to establish its efficacy and safety, either IV or subcutaneous, when given alone or in combination with standard-of-care novel therapies."