There were 935 abstracts related to multiple myeloma accepted into the 2017 American Society of Hematology (ASH) Annual Meeting, or roughly one piece of new research for every 127 multiple myeloma patients in the U.S., according to the National Cancer Institute.
Perhaps the most exciting news at the event came from a diverse class of therapies targeting the B-cell maturation antigen (BCMA) through different mechanisms. Chimeric antigen receptor T-cells (CAR-Ts) being developed for multiple myeloma, along with antibody drug conjugates (ADCs) and bispecific T-cell engagers, by and large have focused on BCMA. The furthest along in development is GSK’s BCMA-ADC, which shared results of its phase I expansion study. Close behind is Bluebird’s BCMA CAR-T, which was deservedly the best-covered multiple myeloma study at ASH, demonstrating a 94% overall response rate and 56% complete response rate in a small cohort of 18 patients with a median of seven prior lines of therapy—eye-popping in the myeloma world. This is the next generation of multiple myeloma treatment that can shift the paradigm from purely survival-focused to quality-of-life-focused, as well.
Many of the multiple myeloma trials focused on new combinations of approved therapies converging on the same few indications. As one example, the popular regimen CyBorD (bortezomib, cyclophosphamide, dexamethasone) was challenged by Kyprolis + cyclophosphamide and dexamethasone or Cd (somewhat successfully) and Revlimid + Cd (unsuccessfully) in separate second-line studies. A third study also tested Pomalyst + Cd in second-line following an RVD triplet, Celgene’s attempt to solidify a Revlimid to Pomalyst progression.
It’s impossible to hear these results and not believe that the treatment algorithm will change, perhaps many times, in the next few years. Together, these studies portend a future of more powerful treatment—earlier and for longer durations—leading to better outcomes for patients. They also portend a future with an exponentially growing number of treatment options. What will physicians do with four choices of molecules that they can combine with Cd?
There’s a broader story developing in multiple myeloma that may help answer this question: Biomarkers in minimal residual disease, cytogenetics and smoldering multiple myeloma have all shown powerful relationships with disease progression and survival. These biomarkers will begin to redefine the goals of therapy, affect treatment selection and expand treatment to new patient types. Here’s what the experts were saying about these biomarkers at ASH 2017, along with my analysis of some of the implications for pharmaceutical companies:
1. Minimal residual disease (MRD) as a biomarker for progression risk: This topic deserves its own blog post. Evaluation of MRD has improved over time and is now measurable in incredible granularity using next-generation sequencing. One remarkable observation of MRD’s predictive power came from a follow-up to the Myeloma XI study on Revlimid as a maintenance therapy post-first-line. This analysis showed that, across trial arms, patients who were MRD positive at the beginning of maintenance had a median progression-free survival (mPFS) of 24 months. Those who were MRD negative had still not reached mPFS after 66 months.
Many clinical trials reporting at ASH across the multiple myeloma landscape included MRD evaluation in the data set but not as a primary endpoint. The implications of a switch to measuring therapy performance using MRD would be profound. MRD can be measured within months of therapy initiation whereas PFS can take years to determine. Trials would be less expensive, and novel therapies could reach the broader patient population more quickly.
Key takeaway: MRD should become a primary endpoint in clinical trials and perhaps even replace PFS. Pharmaceutical companies should be structuring their trials with this in mind and should continue to encourage its adoption by the FDA.
2. Precision medicine coming to multiple myeloma (maybe soon): ASH sessions this year included many studies with a primary objective to evaluate therapeutic performance in patients with specific cytogenetic abnormalities. Most defined cytogenetic risk using some combination of the abnormalities identified by the International Myeloma Working Group: t(4;14), del(17p), t(14;16), t(14;20), nonhyperdiploidy and gain(1q).
One particularly compelling retrospective analysis conducted by the University of Torino focusing on t(4;14), del(17p) and t(14;16) compared standard-of-care induction regimens VMP and Rd. They found that, while patients with no biomarker (standard risk) had equivalent success on either regimen, those with any of the three biomarkers (high risk) had more than double the mPFS on VMP (30.8 months) relative to Rd (15.2 months). If these types of findings can be extended to other standards of care such as VRD, this seems to be a convincing rationale for doctors to take a biomarker-based approach to therapeutic strategy in newly diagnosed multiple myeloma.
An ambitious project also was announced by the Multiple Myeloma Research Foundation after an interim analysis of the foundation’s CoMMpass Study. The foundation hopes to test what they call the “myeloma-developing regimens using genomics master protocol” for sub-classifying high-risk patients for tailored therapeutic approaches.
Key takeaway: With fundamental change in therapeutic strategy comes risk and opportunity for pharmaceutical companies. Brands should start developing evidence and positioning for a future where differential performance in patients with specific biomarkers is a competitive advantage.
3. A new “zero-ith” line of therapy: high-risk smoldering multiple myeloma: ASH also featured a number of agents and combinations, including Darzalex monotherapy and Kyprolis, Revlimid and dexamethasone (KRd) being tested in the large and currently untreated smoldering multiple myeloma population. These trials classified patients into levels of progression risk by their measurement of bone marrow plasma cells, serum M-protein and free light chain ratio, which have been validated as biomarkers of progression risk in numerous recent studies. The results of these studies are still early but seem encouraging, with the KRd trial reporting an 85% rate of complete response or better.
Key takeaway: As pharmaceutical brands attempt to forecast the future multiple myeloma patient landscape, it’s critical to understand the impact of smoldering multiple myeloma treatment. If your brand can be part of a solution for these patients, massive untapped potential awaits. If your brand remains in later lines of therapy, there will be a shrinking pool of eligible patients to treat.
ASH 2017 marked another milestone in identifying more effective combinations and novel mechanisms for extending and improving the lives of patients with multiple myeloma. It also revealed an emerging narrative in multiple myeloma treatment: Biomarkers will play an increasingly bigger role in the coming years. I look forward to the next chapter in this story at next year's meeting.