As we grapple with the outcomes from the myeloma research presented in San Diego last week at the 2018 Annual Meeting of the American Society of Hematology (ASH), it is worth pondering the future for myeloma therapies. So many options, so much excitement—but where does it lead us?
For example, it is obvious that immune therapies, such as CAR T-therapy and “BiTEs” (bispecific T-cell engagers) can have a dramatic impact. But used at what time point in treatment? And can we ever afford CAR T therapy, at a cost of about $1 million per infusion treatment, including supportive care? BiTEs can be an “off-the-shelf” alternative, readily available, as are other monoclonal antibody therapies. With phase I – II data available now for the first BiTE in myeloma, benefits, and toxicities must be fully explored. Many questions remain unanswered.
On more solid ground, we can look at the long-term outcomes with VRd (Velcade + Revlimid + dexamethasone) in the frontline setting. This current “standard of care” produces responses in more than 90 percent of patients, with more than 55 percent of the patients alive at seven-plus years out. Building upon that, ASCT (autologous stem cell transplant) increases the fraction of patients achieving undetected MRD (minimal residual disease) status, prolongs remissions, and, as most believe, will ultimately produce longer survival. Right now, alternatives to VRd can be VTd (Velcade + thalidomide + dexamethasone) or VCd (Velcade + cyclophosphamide + dexamethasone). A doublet such as Rd can be used for older and/or frail patients.
What Is Next?
The broad concept is that treatment in the first six months, as with the VRd, really does matter, and that type of early intervention is ideal. To achieve the best response aiming for undetected MRD level is a primary goal. This rapid reduction in myeloma tumor burden early on short-circuits the evolution of many resistant subclones. The earlier the intervention, the fewer myeloma clones to be dealt with later.
This means great anticipation and excitement surround the outcomes of the CESAR and ASCENT trials for HR SMM (high-risk smoldering multiple myeloma). For the CESAR trial, Dr. María-Victoria Mateos showed at ASH that 94 percent of patients are in remission at 3 years, with a majority having an undetected MRD status at 10-6 level (less than one in one million cells). This is with KRd plus ASCT. The ASCENT trial uses KRd + daratumumab, with an option for ASCT (autologous stem cell transplant) later. With accrual ongoing for this Black Swan Research Initiative-supported trial, even better outcomes are expected.
Eliminating Resistant Disease
Using these best agents, such as Velcade or Kyprolis, Revlimid, and daratumumab, early on, approximately 60 to 70 percent of patients can be anticipated to achieve MRD undetected at 10-6 level. This means that 30 to 40 percent of patients still have a resistant disease. This is the challenge for 2019 and the coming years. The long-term follow-up of patients in the CASTOR (DRd) and POLLUX (DVd) trials (in patients with 1-3 prior therapies) at ASH showed the sustained value of achieving MRD-negative status in the early relapse setting in patients progressing after initial induction therapy.
This sets the stage for the future. Can we design definitive treatment combinations for such relapsing and/or higher-risk patients? This is where the roles of CAR T-cell therapies, BiTEs, and other options come into focus. There is clearly an “unmet need” to eradicate residual, resistant disease— if it can be achieved safely with a dramatic impact, as noted, with immune therapies in later disease settings. Something to consider for sure. Other “non-immune” therapies in development may also find a niche. Venetoclax, for example, provides added benefit in patients with the t(11;14) translocation. Selinexor synergizes with several novel agents. The new type of alkylating agent melflufen may contribute to better cytoreduction.
So, What Does the Future Hold?
In thinking about this, I could swear I hear laughing in the background—as the old Yiddish proverb says, “Man plans and God laughs.” We must have the humility to recognize our many failures in predicting the future. Twenty-five years ago, nobody anticipated the role of IMiDs (immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide) in myeloma therapy. Thalidomide was for treating leprosy!
So, beyond saying I am very optimistic, I will refrain from definitive prediction. But using the best treatments early on will always be a preferred approach. Only the future will tell us what the magic cocktails will be. And in the meantime, from studies in Iceland (the Black Swan Research Initiative-supported iStopMM project) and, perhaps, elsewhere, we may learn how to start preventing myeloma in the first place.
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®.