Thank you for having me.

This is a beautiful city, my first time.

I’m very pleased to present to you and happy that you selected this abstract.

This is an update on bb2121 which is a promising therapy for heavily pre-treated relapsed refractory multiple myeloma patients.

These are my disclosures; I play with everybody so I’m not partial to anyone, as you can see.

I guess I’ve got to keep it up there for a little bit.

Multiple myeloma, as you all know, is the second most common blood cancer and we’ve had great advances in myeloma over the last decade.

There are many approved therapies and patient survival has improved but unfortunately, despite all this, this remains an incurable disease.

More sobering is as patients use some of these therapies, the more common being the proteasome inhibitors and the immune modulating therapies, as patients become refractory to these and have had more than three prior therapies their overall survival is only eight months.

B-cell maturation antigen belongs to the tumour necrosis factor receptor superfamily.

It is nearly universally expressed in multiple myeloma cells and a few mature B-cells so it makes it a great target to be very specific to multiple myeloma.

bb2121 is a second generation chimeric antigen receptor or a CAR-T cell that targets BCMA and induces a very rapid and sustained response in patients with heavily pre-treated relapsed refractory myeloma.

This is a busy slide but it’s actually relatively simple.

On the top is what the patient actually goes through.

So the patient is screened once they meet a criteria, they are leukapheresed, this is how we collect their T-cells, the T-cells are then sent out for manufacturing of the bb2121 product and this takes about ten days but then you have to have all the releases, make sure it’s not infected etc., and that can take another week or so.

So it’s usually about a 3-4 week process.

Once the CAR-Ts are made the patient is then given what we call lympho-depleting chemotherapy, fludarabine Cytoxan, which is a low dose chemotherapy to try and basically quell their own T-cells so that they don’t compete with the CAR-T cells.

The CAR-Ts are then infused on day zero and that is the only treatment the patient gets.

They’re in the hospital for observation of toxicities and they then get released from the hospital and their first assessment is at month one.

In the dose escalation we had 21 patients that were treated with dose levels as you see there: 50 million, 150 million, 450 million and 800 million cells.

In the dose expansion we had 22 patients and we treated 22 patients at doses between 150-450 million.

These are the results. In terms of the toxicity there are too main toxicities that you worry about with CAR-T cells; one is cytokine release syndrome, which is not too dissimilar from sepsis, and the other is neurotoxicity.

These have been described well in other CAR-T programmes.

As you can see, we saw 63% of our patients had cytokine release syndrome and 33% had neurotoxicity but most of these were grade 1 and 2 which are the lower grades.

So most people just had a fever, some people had very transient low blood pressures that resolved with some fluids.

Then only 5% and 2% of our patients had grade 3 or greater cytokine release syndrome or neurotoxicity.

Most of the patients had drops in their blood counts as is expected; most recovered by day 32.

We had no grade 4 CRS events and we had no fatal CRS or neurotoxicity events.

These are the responses.

As you can see there’s a dose response curve.

So at 50x106, this is what we considered a sub-therapeutic dose level, we had one transient response.

Then at 150x106 we saw an overall response rate of 57.1% and patients who received more than 150 million CAR-T cells had an overall response rate of 95.5%.

These patients, I did not show you, had a median prior therapy of seven to eight prior therapies so very refractory, heavily pre-treated patients.

In terms of the tumour response there is a question of whether you need a certain amount of BCMA expression to be able to respond to CAR-T cells and, as you can see on the right panel, patients at the 450 million CAR-T level there appeared to be no difference in response whether you were BCMA low or BCMA high.

Our median progression free survival in the 18 patients in the dose escalation, which are the ones who are further out, is 11.8 months and in patients who achieved MRD negativity, and this is something that’s a much deeper level of response that we are now evaluating in patients in the front line setting and early relapse, it’s never been tried in this very heavily refractory population so the fact that we can even reach it is impressive.

So 16 patients were tested and 16 patients were MRD negative.

In those patients the median progression free survival is 17.7 months.

So, in conclusion, bb2121 at active doses of greater than 150 million CAR-T cells induces deep and durable responses in heavily pre-treated populations in the relapsed refractory setting of myeloma.

Median progression free survival 11.8 months.

100% MRD negativity in the 16 evaluable patients with a median progression free survival of 17.7 months.

I will just put this in context in that the two last therapies that were approved in multiple myeloma in patients who had more than three prior therapies had median progression free survivals of 3.9 months so this is actually quite an impressive result if you put it in that context.

To date the safety profile of bb2121 has been very manageable at doses as high as 800 million CAR-T cells, mostly grade 1/2 CRS events with infrequent tocilizumab and corticosteroid use, which are the drugs we use when these toxicities become more higher grade.

We had one case of reversible grade 4 neurotoxicity and we have not seen others in the dose expansion.

The next steps are bb2121 is now open in a global pivotal trial called KarMMa.

This trial is open for enrolment in North America and Europe.

Then additional trials are planned in early lines of myeloma including front line therapy in high risk patients.