The title of this post seems to be just a mumbo-jumbo of abbreviations that beg the question as to what all of it means and what its significance is. Well, it hides several developments that should be of interest to us, myeloma patients. So, let’s pick the title apart and get to the bottom of things.

RMAT (Regenerative Medicine Advanced Therapy)

RMAT is shorthand for ‘Regenerative Medicine Advanced Therapy’, a program established under the ‘21^st Century Cures Act’  of 2016’ to expedite the development and review of promising pipeline products for life-threatening diseases. Drugs/treatments are eligible under this program if they meet several standards:

• They must be ‘A cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products.’
• 'The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition.’
• ‘Preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition.’

The grant of RMAT status by the Food and Drug Administration is quite a big deal as Federal records indicate that, since this program’s inception,  more than half of the requests submitted by the pharmaceutical industry  for RMAT designation have been denied.

Allo-715

Allo-715 is an ‘allogenic’ (donor) CAR-T product that targets the protein BCMA on the surface of myeloma cells. The product is being development by the California based company Allogene Therapeutics. An allogenic CAR-T product (also known as ‘off-the-shelf’ CAR-T) is different from the recently approved ide-cel CAR-T for multiple myeloma developed by Bristol-Myers/Celgene or the Johnson & Johnson cilta-cel CAR-T that is currently under review by FDA. Ide-cel and cilta-cel are based on the T-cells harvested from severely sick myeloma patients whereas Allo-715 is manufactured from the cells of healthy patients.

There are several advantages to allogenic CAR-T products, such as:

• Speed of availability: Allogene has reported that, on average, their product is made available within 5 days after a patient is enrolled. Compare that to auto-CAR-T where a patient’s cells first need to be harvested (in a process similar to what is used to harvest stem cells), then the cells need to be engineered to the CAR-T construct, after which they are cultured and expanded to quantities needed for therapeutic use (typically several hundred million cells) and then the cells need to be purified to eliminate extraneous materials that can negatively impact their use. This is a process that typically takes about 3-4 weeks – a critical period for a patient whose myeloma has become resistant to treatment by multiple prior therapies and whose health is possibly worsening rapidly.
• Cost: the currently approved ide-cel CAR-T for MM comes with a list price of $ 419,500 (and that does NOT include the costs of hospital/outpatient treatment that are part and parcel of CAR-T treatment). Some part of that cost reflects that the CAR-T infusion(s) originate from a single patient and are only fit for use for that same patient. Compare that to the process developed by Allogene where the cell harvest of a single healthy patient is translated into + 100 CAR-T doses that can be made available nearly immediately.

• Less product variability: It has been noticed over the past few years that the T-cells of some patients either cannot be engineered into useable CAR-T cells or they cannot be expanded to quantities needed for treatment. One of the reasons for this is ‘T-cell senescence’ or ‘tired T-cells’ that occurs when a patient’s immune system has been hammered by aggressive and/or long-term treatment (something most of us are quite familiar with). The manufacturing and expanding of cells harvested from healthy donors eliminates this problem and will have more consistent quality from patient to patient. 

• Access to treatment is an important consideration for us, multiple myeloma patients. The last thing we need is for our individual treatment to not become available, either because of a manufacturing hiccup or because of poor quality of our cells. Allo-715 can be made available to ALL patients and if repeat dosing is needed we will be ensured of an available supply.

Since we are talking here about donor-based product it is more than reasonable to ask whether the administration of  Allo-715 may trigger Graft-versus-Host (GvHD) reactions/side effects that occur frequently with treatments such as allogenic (donor) stem cell transplants that may be used to treat aggressive and/or high-risk myeloma. The answer is that this is a valid consideration that has been/is being addressed by Allogene. Every CAR-T treatment requires lymphodepletion (the destruction of T-cells and lymphocytes prior to immunotherapy). The drugs typically used as part of the CAR-T process are Cytoxan (and many of us are familiar with this one) and fludarabine. The Allo-715 program calls for the addition of a third compound, also discovered by Allogene called Allo-647. This drug is a monoclonal antibody that is designed to suppress the host immune system to allow Allo-715 to stay engrafted in order to achieve its full therapeutic impact. 

The company has reported early results from part of their Phase I clinical program. Phase I studies are designed to understand the safety of the product and to also pin down the ‘optimal’ therapeutic dose (efficacy). These results can be summarized as follows:

Safety

• No occurrence of Graft-versus-Host Disease
• No occurrence of neurotoxicity event
• Cytokine release syndrome occurred in 45 % of patients, but only at grade 1-2 and readily manageable
• Infection occurred in 42 % of patients (not uncommon with CAR-T treatment)
• Infusion reaction occurred in 23 % of the patients, at grade 1-2 and readily manageable

Efficacy

 (At the expected therapeutic dose of 320 million cells)

• 60 % of the patients dosed achieved a Very Good Partial Response (VGPR) or better
• About 84 % of the patients who achieved VGPR (or better) were also MRD negative

For more details about the study, click here.

All in all, this is an interesting development to monitor over the next two or so years. Allogene still has a way to go as they need to finish up the full Phase I program and move on to an expanded patient pool in their Phase II/III clinical development. As such, we have no certainty that this combination of products will ultimately come to market though we do have a fair amount of information to be cautiously optimistic that, in the not-too-distant future, we may see this product in clinical use as another treatment option for us when things start to come off the rails. 

Those interested in this clinical trial can find it here.