EMA Recommends Personalised Gene Therapy for Multiple Myeloma

Dr Sheena Meredith

March 28, 2022

A new gene therapy for multiple myeloma has been recommended for conditional marketing authorisation (CMA) by the European Medicines Agency (EMA). The Agency recommended authorisation for ciltacabtagene autoleucel (Carvykti, Janssen) for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least three prior therapies and whose cancer has worsened since their last treatment.  

The three major classes of drugs used for multiple myeloma are immunomodulatory agents, proteasome inhibitors and monoclonal antibodies. If patients have received all three and have not responded, there are limited therapeutic options remaining.

Ciltacabtagene autoleucel, also known as cilta-cel, is a chimeric antigen receptor (CAR)-T cell drug that works by collecting and modifying patient’s own T-cells to create a personalised treatment that is then infused back.

Two-thirds of Patients Have Complete Response

The main study on which the recommendation for a CMA was based showed a durable response in around 84% of patients, with 69% showing a complete response. However side-effects were common and included neurological toxicity, prolonged cytopaenia, and serious infections. Cytokine release syndrome (CRS), a systemic response to the activation and proliferation of CAR-T cells, was very common. It causes high fever and flu-like symptoms, infections, and encephalopathy, and in some cases can include life-threatening or fatal reactions. In the trial, CRS occurred in 95% (92/97) of patients receiving ciltacabtagene autoleucel. Grade 3 or higher CRS occurred in 5% (5/97) of patients, with grade 5 CRS reported in 1 patient.

Additional risk minimisation measures required from the marketing authorisation holder will ensure that centres that dispense the therapy are qualified to recognise and manage CRS and neurotoxicity associated with the treatment of ciltacabtagene autoleucel.

The Route to Licensing

In December 2017, Janssen entered into an exclusive worldwide license and collaboration agreement with Legend Biotech, USA, to develop and commercialise ciltacabtagene autoleucel. The drug was supported through the EMA's PRIority MEdicines (PRIME) scheme, which provides early and enhanced scientific and regulatory support to medicines that have a particular potential to address unmet medical needs. The EMA granted PRIME designation to ciltacabtagene autoleucel in April 2019 and the drug was designated an orphan medicinal product in early 2020.

Because ciltacabtagene autoleucel is an advanced-therapy medicinal product (ATMP), it was assessed by the Committee for Advanced Therapies (CAT), an EMA expert committee for cell- and gene-based medicines, and EMA’s human medicines committee (CHMP), which recommended approval based on the CAT assessment. Manufacturer Janssen stated that it would file a UK marketing authorisation application once it had obtained a CHMP opinion.

The opinion, now adopted by the CHMP, is an intermediary step on the path to patient access for ciltacabtagene autoleucel, the EMA said in a statement. It will now be sent to the European Commission for an EU-wide marketing authorisation decision. The drug was approved by the US Federal and Drug Administration (FDA) for the treatment of adult patients with relapsed and/or refractory multiple myeloma in February this year, based on findings from the phase 1b/2 CARTITUDE-1 trial. Following the positive CHMP opinion, the Committee for Orphan Medicinal Products (COMP) will assess whether the orphan designation should be maintained.

Pivotal Trial Results

In the pivotal CARTITUDE trial, 97 patients who had received a median of six prior treatment regimens (range, 3-18) received a one-time dose of ciltacabtagene autoleucel. This resulted in a 98% overall response rate at 18 months. In 76 (78%) of responders this was a stringent complete response, meaning that after treatment physicians were unable to observe any signs or symptoms of disease via imaging or other tests. Overall survival in the latest reported results was 81%.

Principal study investigator Sundar Jagannath, director of the Center of Excellence for Multiple Myeloma and professor of medicine, hematology and medical oncology at the Tisch Cancer Institute of the Icahn School of Medicine at Mount Sinai, said: "The responses in the CARTITUDE-1 study showed durability over time and resulted in the majority of heavily pretreated patients achieving deep responses after 18-month follow-up.

"The approval of cilta-cel provides physicians an immunotherapy treatment option that offers patients an opportunity to be free from anti-myeloma therapies for a period of time."

The CARTITUDE study is ongoing and the longer-term efficacy and safety profile of ciltacabtagene autoleucel will continue to be assessed.

Disease Usually Incurable

The incidence of multiple myeloma in Europe is 4.5 to 6.0 per 100,000/year, and it carries a mortality rate of 4.1 per 100,000/year. While survival has markedly improved in recent decades, it remains usually incurable. As the second most common haematological cancer, it is responsible for 15-20% of deaths from haematological cancer and about 2% of all cancer deaths.

According to the National Institute for Health and Care Excellence (NICE), most patients respond to initial treatment and their disease becomes stable, with some surviving progression-free for 10 years or more. However, around 10% die within 1 year of diagnosis, and with time relapses become less responsive to treatment and frequently lead to end-stage disease.

Of those diagnosed with myeloma between 2013 and 2017 in England:

  • 82.7% survived for 1 year or more

  • 52.3% survived for 5 years or more

  • 29.1% are predicted to survive for 10 years or more

Since the UK left the EU with Brexit, as of January 1, 2021, EU pharmaceutical law as laid out in the 'acquis communautaire' applies to and in the UK in respect of Northern Ireland only. As part of an agreed transition period, for a further 2 years, the UK will continue to adopt decisions taken by the European Commission on the approval of new marketing authorisations. 


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