Transcript
Hi, I'm Dr. Thomas Martin from the University of California - San Francisco. I'm here in LA at the Great Debates. We talked about emerging therapy for relapsed refractory multiple myeloma and, thankfully, we have some great therapeutics for our frontline and early relapse.
But once patients go through our standard, I would say, 5 powerful drugs: lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab, then we're in a tough scenario. They have what we call triple-class refractory multiple myeloma. In that circumstance, we need novel agents.
We have quite a few agents that are currently being tested in that space. We have one approved agent. That agent is selinexor, which is an exportin inhibitor. That medication in combination with dexamethasone in a study called the STORM study showed an overall response rate in actually penta-refractory patients, refractory to all of those 5 drugs I previously mentioned, response rate of about 25%.
But really upwards of 50% of people had an arrest of progression of their disease. They had stabilization of their disease or a minor response or a partial response or better.
That's actually a pretty active agent. There are side effects from selinexor together with dexamethasone and you have to watch patients really closely, but I do think that's an agent that we can use today for people that are penta-refractory.
We have a number of other agents that are currently in development. One is called melflufen. It's a lipophilic peptidase containing alkylator based therapy.
That agent actually gets into the cells quicker due to the lipophilic component. Many cancer cells have aminopeptidases inside the cell. It will cleave the lipophilic nature, leaving this alkylator based therapeutic. That alkylator then can cause cellular cytotoxicity or apoptosis.
It's actually a fairly easy agent to give. It's given IV once every 4 weeks together with dexamethasone. In the HORIZON study, a phase 2 study in the relapse-refractory space, greater than 90% being double refractory and over 80% being daratumumab refractory. The response rate was between 25% and 30%, so a very respectable response rate to this new novel alkylator based therapeutic.
We expect that the phase 2 trial may lead to FDA approval and we might have that available in the next three to 6 months.
The next agent we discussed was belantamab mafodotin, otherwise known as bela-maf. This is the first BCMA targeted therapeutic may be approved for use in relapsed refractory myeloma. This antibody drug conjugate binds the cells that have BCMA on the cell's surface and it brings a toxin, MMAF, to the malignant plasma cells and causes apoptosis. It also can induce antibody-dependent cellular cytotoxicity due to the antibody nature of the therapeutic.
In an initial phase 1 trial within expansion cohort, bela-maf as a single agent without any steroids had an overall response rate of 60%. Pretty impressive. But if you took the patients that again were the triple-class refractory, including daratumumab refractory, the overall response rate was about 30% to 35%.
This agent is also easy to give. It's a 30-minute infusion, given IV every 3 weeks. The one special toxicity in this therapeutic is we did see some ocular toxicity, so there can be some corneal toxicity. Patients can have dry eyes. They can have mild blurry vision. It tends to be grade 1 or 2. By ophthalmic exams they can have some changes to the corneum.
Some of this is responsible for dose reduction seen in upwards of half of the patients, but very few patients actually had to stop due to the corneal toxicity of the medication. As a single agent in the daratumumab refractory, a response rate of 30% is really encouraging and we hope to see this agent on the market again in the next 2 to 3 weeks.
This drug as well as melflufen will be combined with a whole host of other anti-myeloma therapeutics. We're hoping that these drugs can have synergy with some of the currently available anti-myeloma drugs.
Another agent we talked about is a next generation immunomodulatory drug that's actually called a CELMoD. The name is iberdomide.
Iberdomide is a little more potent than pomalidomide and more potent than lenalidomide. It both has direct toxicity to the myeloma cells, but it also can induce this immunostimulatory effect with an increased release IL-2 by lymphocytes.
It is more potent than the other immunomodulatory drugs and when used in patients that were refractory to IMiDs. Iberdomide together with dexamethasone showed in early phase 1 trials an overall response rate again of about 30%.
The interesting thing with iberdomide, it was very well tolerated - very little fatigue, minimal neuropathy, minimal other side effects, GI side effects. It's just a mild blood count suppression. That drug is now being combined also with a whole host of other anti-myeloma therapeutics. I think it will work really well synergistically with some of our monoclonal antibody-based therapies.
Lastly, we talked about the immunotherapies. There's 2 really impressive immunotherapies that activate T-cells. One is the bispecific T-cell engagers.
There was an initial drug from Amgen from AMG 420. AMG 420 at the maximum tolerated dose or I would say the optimal biologic dose at 400 micrograms per day by continuous infusion showed an overall response rate in a very refractory population of upwards of 70%. Pretty impressive.
Another bispecific T-cell engager also targeting BCMA and also CD3 on the T-cells showed at ASH this year an overall response rate as a single agent of close to 90%.
These bispecific T-cell engagers, they do induce toxicity. They induce CRS. We really haven't seen much in terms of neurotoxicity but have a pretty impressive response rate. We'll have to see if these responses are durable.
The AMG 420 is probably not going to go forward, but a second-generation bispecific T-cell engager that has a half-life extending molecule so it can be given by intermittent dosing. The AMG 420 was by continuous infusion. Probably not an optimal drug in the myeloma space where we're trying to treat patients intermittently as an outpatient.
Lastly, we talked about CAR T-cells. We're all really excited about CAR T-cells, BB2121. We've seen data over the last 2 to 3 years on it showing overall response rates to CAR-Ts in truly refractory myeloma 70 with 9 prior lines of lines of therapy of upwards of 90%+. Pretty impressive. And a progression free survival rates of about 11 months.
The unfortunate part about CAR-Ts in the myeloma space in contrast to lymphoma is it does seem that patients are relapsing. It doesn't seem to be able to produce a tail in the curve. Meaning, we don't think the current CAR T-cell products are going to be curative for myeloma, but we'll just have to see going forward if we can add agents as maintenance post CAR-T or we can develop better and more persistent products that may be able to enhance the progression free survival.
There was data from a CAR-T that was developed in China, the LCAR-38. It was tested in the CARTITUDE trial that was presented at ASH. Of 29 patients in the phase 1 done in the US, the response rate was 100%. In early follow up only 2 of the 29 patients have progressed, 1 at 4 months and 1 at 7 months.
We'll see if that's any different than BB2121 or any of the other CAR products. But the general take home message is the CAR T-cell products, the bispecific T-cell engagers are very active in relapsed refractory myeloma.
Then these other drugs that I've talked about should be available soon. It will help us in the treatment of triple-class refractory myeloma.
