Elranatamab Sparks Remarkable Responses in Relapsed/Refractory My...

Elranatamab is an investigational, off-the-shelf, humanized BCMA-CD3-directed BsAb, a novel form of cancer immunotherapy that binds to and engages two different targets. One arm binds directly to specific antigens on cancer cells and the other arm binds to T-cells, bringing both cell types together. The binding affinity of elranatamab for BCMA and CD3 has been engineered to elicit potent T-cell-mediated anti-myeloma activity.

Patients who had previously received BCMA-directed treatments were included in studies under the MagnetisMM programme (MM-1, NCT03269136; MM-2, NCT04798586; MM-3, NCT04649359; MM-9, NCT05014412). Elranatamab's effectiveness and safety in patients with RRMM who had previously received BCMA-directed treatment were assessed in a pooled analysis from these studies. For the pooled analysis, investigators evaluated the efficacy and safety of the bispecific antibody in patients enrolled in one of the four MagnetisMM trials who received at least one proteasome inhibitor, one immunomodulatory drug, one anti-CD38 monoclonal antibody, and one BCMA-directed antibody-drug conjugate (ADC) and/or CAR T-cell therapy. The pooled analysis included 4 clinical trials:

Clinical Trials Description of Studies considered for Pooled Analysis
NCT ID	Trial Acronym	Phase	Patient Number	Elranatamab Monotherapy Dose
NCT04649359	MagnestiMM-3	II	64	76 mg QW SC with step-up doses of 12 mg and 32 mg
NCT03269136	MagnetisMM-1*	I	13*	215-1000 µg/kg SC, QW or Q2W*
NCT04798586	MagnetisMM-2	I	1	1000 µg/kg SC, QW with a step up dose of 600 µg/kg
NCT05014412	MagnetisMM-9	I/II	9	76 mg QW SC with step-up doses of 4 mg and 20 mg
*included only patients who receive elranatmab within the efficacious dose range in the MagnetisMM-1 study

Based on the data presented at ASCO 2023, the median follow-up duration was 11.3 months. In the group of patients (n = 87) treated with elranatamab following any prior BCMA-directed therapy, an overall response rate (ORR) of 46% was achieved. This included a stringent complete response (sCR) rate of 4.6%, a complete response (CR) rate of 13.8%, a very good partial response (VGPR) rate of 24.1%, and a partial response (PR) rate of 3.4%.

In patients with prior ADC treatment (n = 59), ORR was 42.4% (sCR at 5.1%, CR at 13.6%, VGPR at 20.3%, and PR at 3.4%)
In patients with prior CAR-T Treatment (n = 36), ORR was 52.8% (sCR at 2.8%, CR at 16.7%, VGPR at 27.8%, and PR at 5.6%)

Among the patients who experienced a response (n = 40), the median time to achieve a response was 1.7 months.

At data cutoff, the median duration of treatment was 3.5 months

Parameter	Any prior BCMA therapy (n=87)	Any prior ADC (n=59)	Any prior CAR-T (n=36)
Ongoing treatment	23%	18.6%	30.6%
Duration of treatment
≤6 months	60.9%
>6 and ≤12 months	18.4%
12 months	20.7%
Discontinued treatment	77%	81.4%	69.4%

Additionally, 65.5% of patients had standard cytogenetic risk, while 24.1% had high cytogenetic risk. Cytogenetic risk data was not available for 10.3% of patients. Furthermore, 54% of patients had extramedullary disease, with information regarding extramedullary disease status missing for 3.4% of patients. In terms of bone marrow plasma cells, 70.1% of patients had levels below 50%, while data regarding bone marrow plasma cell percentages was not available for 11.5% of patients.

Further data revealed that 50% of patients who responded to the treatment (n = 20/40) remained in response at the time of data cutoff. It is important to note that the duration of response (DOR) data was not yet fully matured after censoring data for 23 patients (57.5% ). The median duration of response was 17.1 months. Specifically, patients who had received a prior BCMA-directed antibody-drug conjugate (ADC) or CAR T-cell therapy had a median duration of response of 13.6 months each.

In the overall patient population, the median progression-free survival (PFS) was 5.5 months. However, among individuals who had previously received a BCMA-directed antibody-drug conjugate (ADC), the median PFS was 3.9 months, whereas those who had undergone prior BCMA-directed CAR T-cell therapy experienced a longer median PFS of 10 months. Regarding overall survival (OS), the median OS for the entire population was 12.1 months. Interestingly, patients treated with a prior BCMA-directed ADC and those who had received a prior BCMA-directed CAR T-cell therapy demonstrated an identical median OS of 12.1 months.

The safety analysis indicated that the adverse events associated with elranatamab were comparable to those reported in patients who had not previously received BCMA-directed therapy and were treated in the MagnetisMM-3 trial.

In a significant proportion of patients, the most frequently observed hematologic treatment-emergent adverse events (TEAEs) included anemia, neutropenia, thrombocytopenia, lymphopenia, and leukopenia. Non-hematologic TEAEs encompassed cytokine release syndrome (CRS), COVID-19-related diarrhea, decreased appetite, cough, injection site reaction, and fever.

KOL insights

“Based on the compelling data observed for elranatamab, we are continuing to progress and expand the MagnetisMM clinical development program to reach a rapidly growing number of patients globally across the treatment paradigm.” – Expert Opinion.

“These results support elranatamab monotherapy as a treatment option for patients with relapsed/refractory myeloma post–BCMA-directed therapy.” – Expert Opinion.

Conclusion

Regarding cutting-edge treatments for relapsed/refractory multiple myeloma, the future is quite promising. The bispecific antibodies will be the new cornerstone of therapy, reaching far beyond what is already approved, for patients with multiple myeloma who have undergone quite a bit of prior treatment and have relapsed or become refractory. Elranatamab is not the only bispecific antibody under research; others potential candidates also seem to have pretty reliable overall response data. Responses seem to be rapid, deep, and frequently appear durable. Elranatamab, which is now being studied in multiple myeloma, has established a favorable clinical profile, according to newly released data from the MagnetisMM clinical research programme. Elranatamab received FDA Breakthrough Therapy Designation in November 2022, according to a Pfizer press release. Elranatamab has also been designated as an orphan drug by the FDA and the EMA for the treatment of MM. Elranatamab has received Fast Track Designation from the FDA and the EMA, as well as the PRIME scheme, for the treatment of patients with RRMM, respectively. Elranatamab has been given the Innovative Medicine Designation and the Innovation Passport by the UK's Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of MM. Elranatamab has been accepted by the FDA for Project ORBIS. Additionally, the FDA and EMA accepted Pfizer's Elranatamab's BLA and MAA. Elranatamab's BLA and MAA depend primarily on data from MagnetisMM-3's cohort A (BCMA-naïve - n=123).