At the 2017 Annual Meeting of the American Society of Hematology (ASH) in Atlanta (December 9th -12th), 981 abstracts dealt with myeloma-related topics. Among all of these— some of which were discussed on the  IMWG Conference Series broadcast on Monday, December 11th, and which I will discuss in more detail during the  ASH Highlights Teleconference on January 11th-- the “big buzz” was about the CAR T-cell (chimeric antigen receptors) clinical trial results.

From a medical standpoint, results in the CAR T-cell trials were very similar to what we have seen for several years: Small studies with some evidence of deep responses, but definite concerns about serious toxicities. The “buzz” was largely coming from financial analysts who have a legitimately different perspective: Will CAR T-cell therapy in myeloma succeed and become a new massive revenue generator, costing possibly $1 million per CAR T-cell treatment?

Investors saw enough evidence of deep responses and manageable toxicity from the bb2121 (Bluebird Bio/Celgene) CAR T-cell presentation of 21 patients (abstract #740), to be encouraged. Stock prices rose. From a medical standpoint, however, many questions remain about this and the other CAR T-cell studies presented at ASH:

1. How many patients have deep responses?
   The numbers are unclear. In the bb2121 trial, 28 patients signed up; 21 received treatment and 18 were evaluable for response. Seventeen patients had a response, which is 94% of 18; 81% of 21 and 61% of 28. Using 18 as the denominator, there were 56% CRs (complete responses), which is very similar to results in many CAR T-cell therapy protocols, but the percentage could be lower using a different denominator.

2. Which patients are actually treated in the trial?
   CAR T-cell trials are very attractive to patients in desperate need of lifesaving salvage therapy. Unfortunately, many patients who sign up (and are waiting) must move to other options because of disease progression. In addition, during the 3- to 4-week T-cell processing time, patients end up having complications and/or need alternate therapy. For example, in ASH abstract #505 (“Safety and Efficacy of B-Cell Maturation Antigen [BCMA]-Specific Chimeric Antigen Receptor T Cells [CART-BCMA] with Cyclophosphamide Conditioning for Refractory Multiple Myeloma [MM]”), 34 patients consented, but only 24 were treated.

   Bottom line: Patients who end up being treated are refractory for sure, but are in a less aggressive subset of those who do not have progressive disease while waiting weeks for their custom-engineered T cells to be manufactured: a definite bias.

3. Are toxicities with CAR T-cell therapies manageable?
   Overall, the reported toxicities in the studies presented at ASH, particularly the occurrence of severe cytokine release syndrome (CRS), were low: 2 or 3 cases. However, the case of a 46-year-old woman who developed brain hemorrhages and kidney failure was notable. She survived and ultimately achieved VGPR (very good partial response). This type of toxicity is a departure from the norm in new drug development and would typically derail further expectations. However, the chance of sustained deep responses has not only kept drug development alive, but fed huge expectations in the financial community. 

4. What do we know about deep responses in the CAR T-cell trials so far?
   Not much. Very few details are provided about minimal residual disease (MRD) testing. What do we need to know?

   • Which method: Next Generation Sequencing (NGS) is used most often. With this method, there can be false negatives because the sample may not contain bone marrow (therefore, obviously no myeloma will be found). In addition, with the emphasis on “durability,” MRD-negative patients need follow-up testing at 1, 3, and 5 years before any statements about “cure” can be made. At a minimum, 1-year re-testing is required, plus a whole-body PET/CT to assess for residual disease outside the bone marrow. Such extramedullary disease is quite common in patients with advanced disease.

   • Which patients: Since there is a risk of life-threatening toxicity, it is urgent to determine which patients can truly benefit and to exclude patients who are unlikely to benefit but would be exposed to a dangerous risk.

   • Which product: There are several CAR T-cell products with different efficacy/toxicity results so far. It is likely that further refinement will result in the development of a more ideal product. Such a product may utilize CRISPR technology, allowing fine-tuning of the engineering. Then, treatment with serial MRD testing can be broadly studied in a larger population where safety is less of a concern.

5. What about alternatives? Besides newer CAR T-cell products, are there other approaches to target the same BCMA target?
   Yes, results were presented in abstract #741 (“Deep and Durable Responses in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (MM) Treated with Monotherapy GSK2857916, an Antibody Drug Conjugate Against B-Cell Maturation Antigen (BCMA): Preliminary Results from Part 2 of Study BMA117159”). In this study, “GSK 2857916” was evaluated in 35 patients in a part-two expansion of a previously reported trial. The overall response rate was 60 percent, with 1 sCR (stringent complete response); 2 CRs and 15 VGPRs. This was quite a promising depth of response, with very acceptable toxicity. The only unique toxicity is corneal irritation, which was common but reversible. The PFS (progression free survival) was approximately 8 months, encouraging at this phase I – II stage of development.  Further trials with this new antibody-drug conjugate will certainly include combination therapy approaches, which may prove even more effective. The advantage is that this is much simpler therapy than CAR T, one which can lead to excellent outcomes alone or in combination.

6. What does the future hold?
   Certainly, more CAR T-cell and anti-BCMA MoAb (monoclonal antibody) trials are anticipated. More time and studies are required. In the meantime, the hype is huge, the hope is real, but the caveat remains that more work is needed. I will continue to track all the new developments. As always, stay tuned.

Dr. Brian G.M. Durie serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.