Understanding bispecific antibodies and myeloma, a Q&A with Consultant Haemato-oncologist, Dr Premini Mahendra

One of the latest innovations in myeloma treatment are bispecific antibodies, a groundbreaking group of immunotherapy treatments which harness a person’s own immune system to target cancer cells.

We asked Dr Premini Mahendra, a leading blood cancer expert from HCA Healthcare UK The Harborne Hospital, to answer some key questions about bispecific antibodies - from how they work and how they differ from other immunotherapies to the impressive response rates being seen in clinical practice, and the exciting potential of these therapies.

What are bispecific antibodies?

Bispecific antibodies, which are sometimes called T cell engagers, are a type of immunotherapy that help the immune system to find and destroy myeloma cells. They’re designed to bind to proteins on two different types of cells - myeloma cells and a person's own T cells.

What makes this type of immunotherapy different is this dual targeting approach. With traditional treatments like monoclonal antibodies, we're just targeting one specific protein on the myeloma cells. But in bispecific antibodies we’re targeting two proteins simultaneously, a protein on the myeloma cell and a protein on the T cell. This means that in addition to attaching to and attacking the cancer cell directly, the bispecific antibody also brings the patient's T cells into direct contact with the myeloma cells, activating the T cell to destroy the cancer too.

Can you explain what T cells are and why they're important in this treatment?

T cells are white blood cells that form a crucial part of your immune system. They patrol your body, constantly scanning for cells that shouldn't be there - including cells that occur from infections or diseases. 

Normally, when they find something suspicious, T cells can either destroy these cells directly or recruit other parts of your immune system to help eliminate the problem. However, in myeloma, the cancer cells are very clever at hiding from your T cells, making it difficult for your immune system to recognise them as something abnormal.

To overcome this, bispecific antibodies work by bringing your T cells into direct contact with myeloma cells, that they might have otherwise missed. The bispecific antibody acts like a bridge, connecting your T cell to the myeloma cell so that it recognises it as something that shouldn’t be there, and does it job by removing it. 

What's the difference between bispecific antibodies and CAR T-cell therapy?

The key difference between these two treatments is in how they're made and administered. Bispecifics are "off the shelf" – which means they are ready to use immediately and created completely in a laboratory. CAR T-cell therapy is manufactured specifically for each individual patient from their own cells. For CAR T-cell, we remove the patient's T cells, send them to a laboratory to be engineered into CAR T-cells, and then they're returned to the patient through an infusion. The CAR T-cells made for one patient cannot be used for anyone else.

Both treatments harness the patient's immune system, but bispecifics work with the T cells already circulating in the patient's body, while CAR T involves harvesting, modifying, multiplying and reinfusing the patient's own T cells. 

At what stage of myeloma progression would you typically consider bispecific antibodies?

We generally use bispecifics when somebody hasn’t responded to treatment with three other categories of drugs, or has become resistant to them. This is typically at the fourth line of treatment or beyond.

How might bispecific antibodies move into earlier lines of therapy?

There's a lot of discussion about using this treatment earlier. For this group of very refractory patients with myeloma, bispecifics have been an absolute game changer. Because they're so effective later in treatment, there's a strong case for potentially using them earlier. 

However, we'll need to wait for clinical trials to determine the optimal timing. The data from these trials will guide us on whether moving bispecifics to earlier lines of therapy will improve outcomes.

What response rates are you seeing with bispecific antibodies in your practice?

The data is really impressive, showing that roughly 60-70% of patients will respond to bispecific therapy, and about 40% of those will achieve a complete response. Many patients who are having bispecific antibodies today are what we refer to as doctors as being ‘heavily pretreated’, this means they’ve already had many other lines of treatment. So, seeing these response rates in such an advanced patient population is quite remarkable.

I have patients who are doing incredibly well. One lady who developed myeloma at age 39 and is now 64 - who had multiple lines of treatment before bispecifics - is now in complete remission. She’s tells me she’s feeling the best she ever has throughout her entire experience with myeloma.

What makes bispecific antibodies particularly promising compared to other treatments?

Where chemotherapy, for example, essentially gets rid of both good and bad cells indiscriminately, which is what causes a lot of the very unpleasant side effects, bispecific antibodies are targeted treatments that also harness the patient's immune system, resulting in fewer side effects while being more precise in their approach.

What's particularly exciting is how rapidly advancing this area of medicine is. And bispecifics aren't just for myeloma either - we're also using them for other blood cancers. At the recent European Haematology Association meeting, researchers presented data on tri-specific antibodies - targeting two myeloma proteins plus T cells. This is currently in phase one trials, but it shows how quickly this field is evolving from bi-specifics to tri-specifics, potentially offering even more targeted and effective treatments in the future.

Dr. Premini Mahendra is a Consultant Haemato-Oncologist at HCA Healthcare UK with over 25 years of experience specialising in blood cancers and stem cell transplantation. 

Learn more about blood cancer treatment and care at HCA Healthcare UK here.