In my first pre-ASH blog, I explained one of my main interests would be how myeloma experts approach sequencing of treatments for their patients. In an ASH Education Program, Dr. Niels van de Donk of Amsterdam explained the burgeoning number of choices available in 2020, with 190 different doublets and 1140 different triplet combinations to choose from. (See Slide #1).
As a myeloma survivor since 1997, I am astounded (in a good way) at how we have moved from dex, Thalidomide, Vincristine, Adriamycin, and autologous transplant to this amazing array of treatments. I will quickly add that the numbers will explode even more in 2021 as all the new immunotherapy drugs and approaches (BiTEs, ADC’s, CAR-T) come to market.
Now consider the actual sequencing of these marvelous treatments.
In Slide #2, Dr. van de Donk calculates 1.3 x 10(6) possible sequences of 2 different triplet therapies, and 1.5 x 10(9) possible sequences of 3 different triplet therapies. For those not inclined to math, that is 15,000,000,000 possible combinations! Do you think we all need a myeloma expert on our treatment team? Duh…..yes!!
In Slide #3 he states the obvious conclusion that treatment selection and sequencing becomes tremendously complex with the increasing number of therapeutic options. From the first day of medical school, we physicians were taught that medicine is both an art and a science. Some things are exact (science), but countless variations between patients exist. We need to consider EACH patient as an individual (art). That is especially true with multiple myeloma. Dr. van de Donk explains that, although optimal sequence and choice of drugs is not established, better understanding of sequencing therapies is important. This will lead to better clinical outcomes.
Every patient is different, and we have heard Dr. Brian G.M. Durie explain that every patient’s myeloma is different too. Various patient characteristics which must be considered include performance and frailty status, age, comorbidities, and patient preferences. Tumor characteristics to consider include whether high-risk cytogenetic aberrations are present or not. Is there extramedullary disease? Is the patient experiencing a rapid increase in tumor load? There are also the considerations of which drugs are available based on insurance approval status. Which ones will be reimbursed as Medicare part B outpatient or as part D orally administered? When a patient’s first-line therapy fails him/her, and it is time to choose second-line therapy, the physician must consider what was the response from first-line therapy and how long did that response last.
Some general statements can be made. Sequencing of drugs with different mechanisms of actions is important. Triplet regimens are superior to doublet regimens. Dose-adjusted doublets can be the best options for frail patients and reusing a drug can be considered based on prior response and length of treatment-free intervals.
Slide #4 illustrates an important factor in drug selection. The best anti-myeloma drugs should be used upfront, and not saved for later. While a bit confusing, it indicates that in going from the first-line treatment (1L) to second-line treatment (2L) only 61% of patients get there. In other words, about a third of patients die or become too frail to continue the planned treatment. This is especially true in elderly patients and those with comorbidities who experience adverse events. In going from second-line treatment (2L) to a planned third-line (3L) only 38% of patients actually receive that third line! On the right side of the slide, we find that induction of deep responses leading to minimal residual disease negative (MRD-) status should be the goal of treatment. Don’t wait until later to use the best available. Early deep responses can also lead to better quality of life (QOL). Treatment after treatment can lead to a cumulative burden of therapy and disease-related complications.
Dr. van do Donk and many other great ASH presenters make it obvious that myeloma is a bewildering cancer. I tell my support group members that it is a ‘wily foe’. While we have a thankfully large number of treatment approaches myeloma remains deadly, especially for triple or penta-refractory disease patients and for those who acquire high-risk cytogenetics. We must rely on the art and the science of skilled specialists to keep us alive with the best QOL available, until we finally get to what both Dr. Duries have promised will happen……a cure for myeloma.
Jim Omel MD