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Things Are Getting Crowded on the Immunotherapy Bandwagon

By Peter Forsberg, MD

The 2018 ASH annual meeting was another exciting one for the multiple myeloma (MM) community. There were several great education and scientific spotlight sessions that highlighted important clinical and research trends in myeloma. As always, the meeting’s brightest focus centered on the presentation of new research findings. In a continuation of a trend from the past few ASH annual meetings, some of the most notable research centered on results from early-phase studies of novel immunotherapeutic agents. Meanwhile, basic science discoveries continued to expand our understanding of the complex genetic, epigenetic, and immunologic underpinnings of the very heterogeneous behavior observed in patients with MM.

As was also the case in 2017, several of the most buzzed-about presentations focused on immunotherapeutic approaches targeting B-cell maturation antigen (BCMA). This included new or updated results from several BCMA targeted chimeric antigen receptor T-cell (CAR-T) constructs. Nina Shah, MD, of the University of California – San Francisco presented initial data on BB21217, a novel BCMA-directed approach. “What’s exciting about BCMA-directed CAR-T therapy in myeloma is that in less than three years, the field has grown in multiple dimensions, as evidenced by the numerous abstracts in this area presented at this year’s meeting,” Dr. Shah said. “We not only have real, durable clinical data, we have more science in the works: deeper correlative studies, novel approaches to T cell engineering, and innovative tactics to improve efficiency and hopefully limit cost in the future.” In addition to CAR-T therapy, one of the most exciting presentations in MM in 2018 reported the initial phase I results of AMG 420, an anti-BCMA bispecific T-cell engager. In this study, all three patients treated at the recommended phase II dose achieved minimal residual disease (MRD) –negative complete responses. It appears CAR-T may have stiff competition from both antibody-drug conjugates and bispecific T-cell engagers in the BCMA-targeting sphere.

In newly diagnosed myeloma, initial results from the three-arm FORTE trial (comparing extended carfilzomib, lenalidomide, and dexamethasone, vs. carfilzomib, lenalidomide, and dexamethasone followed by stem cell transplantation, vs. carfilzomib, cyclophosphamide, and dexamethasone) raised provocative questions about the continued need for upfront transplantation. Meanwhile, the overarching trend continues to be toward incorporating monoclonal antibodies into induction regimens. In younger, transplant- eligible patients, this means four-drug combinations, with definitive trials still ongoing. In older, transplant-ineligible patients, the late-breaking MAIA study demonstrated the superior efficacy and reasonable safety profile of daratumumab in addition to lenalidomide and dexamethasone compared with lenalidomide and dexamethasone alone. These results build on last year’s positive ALCYONE trial, which added daratumumab to bortezomib, melphalan, and prednisone and helped to establish daratumumab-based combinations as likely standards of care in many older patients.

While increasing options in the management of older MM patients is an exciting development, it does contribute to increasing complexity in this setting. Important considerations in the management of older patients with MM were highlighted in a special education session featuring Tanya Wildes, MD, MSCI, of Washington University. Dr. Wildes emphasized that, “within 15 years, three of every four patients diagnosed with multiple myeloma will be older than 65 years. With these shifting demographics, we must appreciate the numerous therapeutic options that are currently available and the challenges of tailoring those options to the unique health status of an individual older patient. There has been a lot of interest in applying the principles of geriatrics, namely geriatric assessment and the concept of frailty, to the care of older adults with myeloma.”

There were several other notable trends on display at the 2018 annual meeting. The role of therapy in high-risk smoldering myeloma remains an urgent consideration, and the year saw new or updated results from several related therapeutic trials. Not to be outshone by immunotherapeutics, several targeted small-molecule agents, including venetoclax and selinexor, continue to show promise in relapsed MM. Particularly notable was the activity of venetoclax in combination with carfilzomib and dexamethasone and of selinexor in heavily pretreated, pentarefractory patients. Important findings that improve risk stratification were described. Notable insights included a description of the aggressive characteristics of disease featuring translocations involving the λ light chain locus on chromosome 22 and further confirmation that “double-hit myeloma” status (defined as biallelic 17p disruption or 1q amplification and ISS 3 status) identifies a subset of patients with particularly poor outcomes.

In short, after the 2018 meeting, the future of myeloma therapy and research looks brighter than ever, even if it is starting to look a little crowded.

Dr. Forsberg indicated no relevant conflicts of interest.

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