The American Society of Hematology (ASH) Annual Meeting will take place Dec. 7 through Dec. 10 in Orlando, Florida, and the abstracts for the meeting—always eagerly awaited—were released yesterday. Among the over 700 abstracts dealing with or mentioning myeloma, it is extremely difficult to highlight just 10 of interest. This year, 92 abstracts were selected for oral presentation and there is a clear preference for the high-profile, new, and emerging immune therapies, including CAR T-cell approaches. This should not distract from the huge poster sessions on Saturday, Dec. 7, Sunday, Dec. 8, and Monday, Dec. 9, which include numerous new and important reports. These will be a source of many “takeaways” from ASH when we have a chance to see full details. In the meantime, I will preview some of the top oral presentations which focus on new observations that may have an impact on the future of myeloma care.
1. Abstract #49
There is perhaps the greatest pre-ASH buzz about this abstract, which reports the use of the new CRISPR gene-editing technology (called multiplexed gene-editing) to modify CAR T cells for treatment. The team at the University of Pennsylvania is the first to embark upon this approach and report early phase I results, in which three patients were treated. A key observation was that the genetically modified T cells persisted in the treated patients and tracked to sites of disease. Patients tolerated the treatment without neurotoxicity or CRS (cytokine release syndrome). One myeloma patient remained stable, while a second patient progressed, despite treatment. These are very early results, but there is enthusiasm that the technique worked without any unexpected problems. Much more to come, I am sure!
These important CAR T-cell presentations are linked together because they indicate the evolution of the Chinese LEGEND CAR T-cell product (#579), with subsequent U.S. Johnson & Johnson trial results (CARTITUDE-1: #577 and #928) and fully humanized CAR T-cell data (#582). There is the greatest interest in #577, which reports the results of the LEGEND product manufactured by Johnson & Johnson for the CARTITUDE-1 trial, which accrued 25 patients at the time of reporting. The target dose of 0.75 x 106 CAR T cells/kg produced early and deep responses, with a very manageable safety profile, thus confirming the earlier Chinese data. The longer-term results of the Chinese phase I LEGEND CAR T trial reported in Abstract #579 are quite encouraging with, for example, a median PFS (progression-free survival) of 28 months for CR (complete response) and MRD- (minimal residual disease) negative patients. In Abstract #928, evaluation of the infused T cells in the CARTITUDE-1 trial showed that there was excellent persistence of the T cells in the treated patients, and that the T cells had a central memory immune pattern. A follow-on study in China demonstrates early efficacy with a fully humanized CAR T-cell product (Abstract #582).
3. Abstract #927
This abstract presents the results of the updated Celgene CAR T-cell product, bb21217, an anti-BCMA CAR T-cell design that enriches for memory T cells. The efficacy and tolerability profiles are similar to the original bb2121 product (generic name idecabtagene vicleucel, or ide-cel for short). Longer-term follow-up is required to assess ongoing benefit.
4. Abstract #143
A follow-up to the prior discussion about the Celgene CAR T product is this presentation about their new BiTE (bi-specific T cell engager), a BCMA – T cell engager called CC – 93269. This bispecific T cell engager is unique in its design, with two arms instead of one to bind to BCMA on myeloma cells, and one arm to bind to T cells. In this first clinical trial, 19 patients were treated. Overall, the results were promising with regard to both efficacy and safety. A high level of MRD-negativity (at the 10-5 level) was noted in 10 responding patients. This is very encouraging in a heavily pretreated population of patients.
5. Abstract #506
After these exciting immune-therapy updates, it is very timely to have a report on the types of T cells found in the bone marrow and blood of myeloma patients. This study from the University of Pamplona reports that T cells that react against myeloma cells have a particular pattern, which is negative for an antigen called CD27. These T cells build up in patients responding to treatment, which is good to know!
6. Abstract #509
In another presentation from the University of Pamplona team, an important observation is reported for the first time. It is noted that mutations are found in early (“progenitor”) cells in the bone marrow, which are CD34 positive. This means that damaged B cells in the bone marrow could be an ongoing source of myeloma cells. This is a very important insight that will play a role in efforts to develop curative therapies.
In these two reports, results from the CESAR trial are presented. The CESAR trial uses KRd + ASCT for HR-SMM (high-risk smoldering multiple myeloma) and is a trial with curative intent. The update of the overall results (#781) shows that 98% of patients are alive at more than 30 months, with 93% in remission and 56% MRD-negative at the 10-6 level. This is extremely encouraging. The ongoing question has been to identify patients who will have sustained MRD negativity out to 5 years and beyond (and are potentially cured) versus those who might relapse. In Abstract #581, the results of mass spectrometry (Qip) of serum samples is reported. A key observation is that 18 patients who were MRD-negative were noted to be positive using the very sensitive Qip technique to detect very low levels of myeloma protein. Further follow-up is required to know what this means. However, thus far, only one patient has relapsed, and this patient was Qip positive. So, much more to follow for sure.
8. Abstract #692
This abstract reports the results of PET-CT scanning in the CASSIOPEIA trial (Dara VTd versus Vtd). The key points are that: 1. Baseline PET-CT has prognostic value; 2. More dara-VTd patients achieved negativity by MRD testing along with PET-CT scanning, and this is linked to better outcomes for these patients. Clearly, detecting both initial disease and residual disease outside the bone marrow is very important.
These abstracts assess the value of adding daratumumab to triplet therapy in the frontline setting. All show significant added value. Abstract #860 shows the sequential benefit of Dara-KRd plus ASCT (autologous stem-cell transplantation) in the frontline setting. In this study of 69 patients, the assessment at best response after ASCT showed that 65% of patients had achieved MRD-negative status at the 10-6 level--quite a remarkable level of benefit with a regimen that was well tolerated. Important added benefit is also noted in the longer follow-up of the ALCYONE trial (dara-VMP Abstract #859), as well as in the GRIFFIN study (Abstract #691), in which dara is added to VRd.
These two studies report results with venetoclax combinations. In the study summarized in abstract 926, venetoclax/dexamethasone is evaluated in patients with t(11;14)-positive disease. The results were excellent, with very good tolerability and safety. In abstract #925, venetoclax was added to daratumumab and dexamethasone, with and without bortezomib. Again, the treatment benefit was excellent and the regimens were well tolerated.
Be sure to tune in to IMF-TV’s video interviews with top myeloma researchers from ASH 2019 in Orlando, which will be posted throughout the annual meeting here. And don’t miss the IMWG round-up of all the research news from ASH 2019, “Making Sense of Treatment,” which will be livestreamed on Dec. 9 here.
Dr. Brian G.M. Durie co-founded and now 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®.