ASH 2017 update
Due to UKMF very kindly awarding me a travel grant, I was able to attend the annual ASH meeting in Atlanta from 9th-12th December 2017. My abstract was selected for a poster presentation, which I found was well received with interest from several people, leading to useful discussions and constructive comments which will be useful for me moving forward in helping me design future experiments and directions.
All the sessions were very well attended with my favourite sessions being focused around the genomic landscape of myelomawhere talks revealed for example, the identification of novel oncogenes such as PTPN11, IDH1 and IDH2 and tumour suppressor genes in newly diagnosed multiple myeloma. Some of this data was further validated in another talk which also revealed that in addition to identifying novel genes that may be useful in characterizing the pathophysiology of myeloma, such analyses could also highlight relevant therapeutic options in patients; for example, they also observed a sub-population that had complete BRCA2 loss, indicating that a specific sub-population of myeloma patients may benefit from PARP inhibitors in the clinic. These genomic studies were also extended to characterize the clonal evolution in SMM and MGUS patients to predict which patients are more likely to progress to myeloma. These studies have uncovered that MYC translocations are involved in the progression from SMM to MM and its presence is a significant risk factor for disease progression along with MAPK and NFKB mutations. This is exciting because drugs already exist for some targets identified. Overall, acquiring more information about the mutational landscape of myeloma would be beneficial in allowing the identification of novel therapeutic targets and highlight further subpopulations of myeloma that can be targeted with a specific inhibitor to create a more personalized treatment regimen for myeloma patients. For example, patients with a t(11;14)translocation express BCL-2, which venetoclax targets, which already shows promising data in myeloma.
There were other sessions discussing emerging options in multiple myeloma including targeted and epigenetic therapies. Dr Shaji Kumar very concisely summarized the most exciting therapeutic options in myeloma at the moment. These ranged from novel immunomodulatory drugs such as CC-220to evaluating PIM kinases as a therapeutic target so it would be good to follow this research to see how this develops further.
Despite all this exciting data being presented, immunotherapies took centre stage with a focus on ongoing CAR-T cell therapies which have been most developed in B-cell malignancies, including multiple myeloma. CAR-T cells targeting CD19 were initially studied in myeloma and unsurprisingly wasn’t as promising as that seen in non-Hodgkin lymphoma due to a small percentage of myeloma cells expressing CD19. In this meeting, studies were presented by Berdeja et al, and Cohen et al using CAR-T cells developed to target BCMA, which is more highly expressed in myeloma cells. Results from an updated Phase I trial using bb2121 BCMA CAR-T cells was presented and it showed an overall response rate of 94% with 56% achieving complete response if they received a dose level of 150 million cells or greater out of 21 heavily pretreated myeloma patients. Cohen et al also presented results from another phase I trial using different BCMA CAR-T cells showing an overall response rate (out of 24 patients) of 53% for the patients that received more than 100 million cells. These discrepancies could be accounted for by the fact that different CAR-T cells used as well as different chemotherapy regimens given prior to cell infusion. A third very interesting study also presented utilized two different CAR-T cells simultaneously with each one targeting either CD19 or BCMA. The idea behind using both CAR-T cells is that it is thought that disease relapse occurs due to the presence of myeloma stem cells, which are thought to be resistant to therapy and more like mature B-cells with CD19 positivity. Therefore, dual targeting of CD19 and BCMA should in theory target both the myeloma stem cells and the myeloma cells. This was a smaller study with only 10 patients out of which 9 patients achieved a partial response or better, however cytokine release syndrome, a toxicity unique to CAR-T cell therapy was observed in all the patients. In keeping with this theme, several other studies were also presented in a session discussing pre-clinical immunotherapystrategies in myeloma to address some disadvantages of this therapeutic approach. An obvious disadvantage is that these CAR-T cells need to be produced following harvesting from each individual patient which can be time consuming and laborious. An alternative approach suggested was to produce universal CAR-T cells from an allogeneic donor whilst making sure that the obvious problems such as graft vs host disease or rejection by the patient’s immune system didn’t occur by utilizing the TALEN gene editing technology to modify the CAR-T cells. Overall, these studies demonstrate some exciting research that looks promising in myeloma and would be worth following future developments.
Additionally, a first randomized trial to evaluate the use of the monoclonal antibody daratumumab (DARZALEX) in addition to standard regimens (such as bortezomib, melphalan and prednisone (VMP)) in newly diagnosed multiple myeloma showed a reduced risk of progression by 50% compared with VMP alone in transplant-ineligible patients with newly diagnosed multiple myeloma. Progression free survival was improved with the addition of daratumumab irrespective of myeloma subgroups. Based on this data of the Phase III ALCYONE trial, a Biologics License Application was submitted to the FDA for use of daratumumab in combination with the VMP regimen in transplant-ineligible patients with newly diagnosed myeloma.
Some other topics discussed was the concept of early intervention in clinical management of myeloma, with the inclusion of treatment of high risk smouldering multiple myeloma (SMM) in clinical trials with the hypothesis that early intervention may lead to better responses in some of the cases studied. A lot of trials and studies are currently focusing on this so it would be interesting to see how this develops. Another question that was also discussed was how to assess treatment response in myeloma, with a particular focus on minimal residual disease (MRD) assays using more sensitive assays such as sequencing instead of the more traditional flow cytometry assays.
Overall, I found the meeting a very enriching experience and once again thank the UKMF for awarding me a travel grant to support my attendance.