Discussion
multiple myeloma, neutropenia, neuropathy, toxicity, toxicities, extramedullary disease, infections, CRS, TEAEs, anemia, penta-refractory disease
MULTIPLE MYELOMA, NEUTROPENIA, NEUROPATHY, DISEASE, EVENT, INFECTIONS, COMPLICATIONS, COMPLICATION, ANEMIA, EVENTS, REFRACTORY MULTIPLE MYELOMA
In this phase 2 study in patients with relapsed or refractory multiple myeloma, subcutaneous elranatamab at a dose of 76 mg weekly following a two step-up priming dose regimen of 12 mg and 32 mg during the first week of treatment induced early, deep and durable responses with a manageable safety profileA consistent benefit was observed across clinically relevant subgroups, including in patients with an ECOG performance status of 1 or 2, at least 50% bone marrow plasma cells at baseline and high-risk cytogenetics. Although lower ORRs were observed in patients with extramedullary disease at baseline, R-ISS stage III disease and penta-refractory disease, the response rate in these subgroups was clinically meaningful in these typically poor prognosis subgroups. In responders with extramedullary disease and penta-refractory disease, the benefit of elranatamab was maintained over time as DOR was generally consistent compared to the corresponding better prognosis subgroup. The lower response rate observed in patients with extramedullary disease reflects the historically poor prognosis in this subgroup and has also been observed with other anti-BCMA-targeted agents such as belantamab mafodotin and teclistamabThe results of this study are consistent with results reported from the phase 1 MagnetisMM-1 study in which a response rate of 64% and a median DOR of 17.1 months were observed in patients receiving elranatamab at the efficacious dose range (≥215 to 1,000 µg kgThe most common TEAEs reported in MagnetisMM-3 were CRS, hematologic-related events and infections. Patients who switched to Q2W dosing experienced fewer grade 3 or 4 TEAEs compared to the same time period before switching. However, the interpretation of these findings is limited as no QW comparator group is available to understand the change in AE incidence over time.With premedication and a two step-up priming dose regimen during the first week of treatment, CRS occurred in 56.3% of patients. All CRS events were grade 1 or 2, with no events grade 3 or higher. CRS events generally occurred early in treatment, with 90.6% limited to the step-up doses. Only one patient had a CRS event after the fourth or later dose, and few patients had more than one CRS event. ICANS was infrequent (occurring in 3.4% of patients) and limited to grade 1 or 2 events. Although the study protocol required hospitalization for the step-up priming doses (48 h after the first dose, 24 h after the second dose), the predictable and manageable profile of CRS and ICANS supports the potential for outpatient administration.Although the toxicities associated with BCMA-targeted T-cell-redirecting therapies are similar due to their mechanisms of action, the frequency and severity may vary between agents. CRS is the most frequent AE observed with T-cell-redirecting therapies; however, the incidence and severity are lower with bispecific antibodiesPeripheral neuropathy is a common complication of multiple myeloma and its treatment, especially with early-generation proteasome inhibitors and immunomodulatory drugs such as bortezomib and thalidomide, respectivelyHematologic AEs were frequent, with the most common AEs being neutropenia and anemia. In comparison to other BCMA-targeted T-cell-redirecting therapies, the rate of hematologic AEs with elranatamab was similar or lower after a similar follow-upBCMA-targeted T-cell-redirecting therapies have been linked to a heightened susceptibility to infectious complications due to their mechanism of actionThe interpretation of the results in this study is limited by its single-arm design and lack of direct comparison with other treatment options, as well as by the small sample size in some subgroups. Longer-term follow-up is required to confirm benefits in DOR, PFS and OS. However, current results support further investigation of elranatamab. An ongoing open-label, randomized phase 3 study is evaluating elranatamab monotherapy versus elranatamab + daratumumab versus standard of care daratumumab + pomalidomide + dexamethasone in patients with relapsed or refractory multiple myeloma who have received lenalidomide and a proteasome inhibitor (In this phase 2 study in heavily pretreated patients with relapsed or refractory multiple myeloma, elranatamab demonstrated a high rate of deep and durable responses, including in patients achieving ≥CR, with a manageable safety profile. Administration of a two step-up priming dose regimen successfully mitigated the rate and severity of CRS with a predictable profile supporting the potential for outpatient administration. Although additional follow-up is needed, maintenance or deepening of response was observed with elranatamab following the switch to a biweekly schedule. Biweekly administration may provide greater patient convenience with potentially less toxicity. Elranatamab is also a readily accessible, off-the-shelf therapy, which provides an option for patients unable to access CAR T-cell therapy. These results support the continued development of elranatamab as monotherapy and its further investigation in combination with standard or new therapies for patients with multiple myeloma.