Elranatamab

What is elranatamab (Elrexfio®)?

Elranatamab is a B-cell maturation antigen (BCMA)-CD3 bispecific antibody that was granted conditional marketing authorisation from the European Commission in October 2023. Conditional marketing authorisation is granted to new drugs based on less comprehensive data than normally required if the medicines address unmet medical needs and if the medicines’ benefits are thought to outweigh their risks. Researchers must provide more comprehensive clinical data in the future to maintain approval status.

Elranatamab has been conditionally approved as treatment on its own (as monotherapy) for adult patients with relapsed/refractory myeloma, who have received at least three prior lines of therapy, including an immunomodulatory agent (IMiD) (such as lenalidomide or pomalidomide), a proteasome inhibitor (such as bortezomib or carfilzomib) and an anti-CD38 antibody (such as daratumumab or isatuximab). Patients must also have evidence of progressed disease since their last therapy.

How does elranatamab work?

Elranatamab is a B-cell maturation antigen (BCMA)-CD3 bispecific antibody that binds to the BCMA protein found on the surface of myeloma cells and the CD3 protein on T-cells (a type of immune cell) at the same time. Through this bispecific interaction, elranatamab facilitates tumor cell elimination by bringing the T-cell and myeloma cell in close contact with one another, allowing the T-cell to initiate an immune response and kill the myeloma cell more effectively.

What are the benefits of elranatamab?

Conditional approval from the European commission was based on the results of the MagnetisMM-3 trial. This trial assessed two different cohorts consisting of cohort A with patients who had no prior exposure to a BCMA directed therapy and cohort B with patients who had prior exposure to a BCMA directed therapy (antibody drug conjugates (ADC) such as belantamab mafodontin or CAR T-cell therapy, but not bispecific antibodies).

In cohort A, 61% of patients responded to therapy and among those 75 patients, the median time to response was 1.2 months. 89.7% of patients also achieved negative minimal residual disease (MRD), meaning that advanced laboratory methods did not detect any cancer cells after treatment. The duration of response and time until progression of myeloma are still being investigated in this group, and more than half of the patients are still benefiting from the medication. Patients who did not have extramedullary disease (myeloma outside of the bones), or who were refractory to five lines of therapy, also appeared to respond better to therapy.

In cohort B, 41.4% of patients with prior exposure to a BCMA ADC and/or CAR T-cells responded to therapy. Approximately 67% of patients who had received BCMA-directed ADCs maintained a response to treatment after nine months, while close to 79% of patients with prior CAR T-cell therapy showed a similar benefit. These findings suggest that elranatamab can be effective, even in patients who have undergone challenging, prior therapies. Additionally, more than half of these patients were still benefiting from the therapy after nine months of treatment.

Further research is needed to compare this new therapy to other treatments for myeloma. The phase 3 trial MagnetisMM-5, comparing the efficacy and safety of elranatamab alone and in combination with daratumumab, compared to a combination of daratumumab, pomalidomide and dexamethasone, is currently underway. This study will recruit patients with relapsed/refractory myeloma who have received at least one prior line of therapy, including lenalidomide and a proteasome inhibitor.

The phase 3 trial MagnetisMM-6 is also underway to assess the combination of elranatamab, daratumumab and lenalidomide compared to daratumumab, lenalidomide and dexamethasone in patients with newly diagnosed, transplant ineligible myeloma.
The results of these trials will be considered by the European Commission when making approval decisions in the EU.

What are the side-effects of elranatamab?

According to the MagnetisMM-3 trial results, the most common side effects of elranatamab are:

• Cytokine release syndrome (CRS)
• Neutropenia, low levels of white blood cells
• Anaemia, low levels of red blood cells
• Lymphopenia, low levels of a type of white blood cell
• Thrombocytopaenia, low levels of platelets
• Increased infection rate
• Diarrhoea
• Fatigue
• Decreased appetite
• Fever
• Reaction at the injection site
• Nausea
• Low potassium levels in the blood
• Cough
• Headache

Infections occurred in 69.9% of patients with 39.8% having severe symptoms and 6.5% of infections leading to death.

CRS is considered to be a serious side effect and occurs when the immune system reacts aggressively to certain types of medications, including immunotherapy drugs such as elranatamab or CAR T-cell therapy. This can cause severe, sudden symptoms such as fever, nausea, fatigue, pain and shortness of breath. The incidence of severity of CRS was reduced by the use of pre-medication with paracetamol, dexamethasone and diphenhydramine (a type of antihistamine). Most CRS events were of low grade and limited to first infusions.

Another serious, adverse event of elranatamab is immune effector cell-associated neurotoxicity syndrome (ICANS), which can cause confusion and disturbances in speech and writing. This side effect occurred in four out of 119 people.

For those who developed either CRS or ICANS, tocilizumab, a medication that inhibits the release of inflammatory substances in the body was given alongside corticosteroids, if deemed necessary. Additionally, antiepileptic medications such as levetiracetam were given to control ICANS.

How and when is elranatamab given?

Elranatamab is administered subcutaneously, as an injection under the skin, and should be given in increasing doses (also called step-up doses) starting with 12mg on day one increasing to 32mg on day four and 76mg on day eight. The dose of 76mg is then given once a week for 24 weeks and then once every two weeks thereafter, if at least a partial response to treatment is achieved, which corresponds to a 50% reduction in the tumour burden.

Due to potentially life-threatening, adverse events such as CRS and ICANS, elranatamab should be administered by an experienced doctor who can monitor patients and provide medical support if necessary.