Each patient with multiple myeloma is different. Within a myeloma support group, one can learn a lot about testing and treatments, but outcomes for individual patients are often very different. These differences must be studied in rigorously designed clinical trials to double-check test results and treatment details. So, while it might be tempting to compare what happened with Joe or Mary to yourself, the best guidance for your individual treatment is based on the best myeloma research, clinical trials, consensus statements, and guidelines.
Establishing an accurate diagnosis
First, the details of the diagnosis must be confirmed. Myeloma is a complex disease, and blood, bone, or kidney testing can be easily misinterpreted, or not done. This is where the standards provided by the International Myeloma Working Group (IMWG), the research arm of the IMF, can provide precise recommendations for baseline testing and diagnostic criteria. In each case, it is important to distinguish between MGUS (monoclonal gammopathy of undetermined significance), SMM (smoldering multiple myeloma), and MM (multiple myeloma).
Selecting the best first therapies
The second step is equally important: Can we pick the best treatment for each individual patient? The surprising answer is yes. We have precise clinical trial information that three-drug combinations work best for more than 90 percent of patients, with an average remission of more than four years to be expected.
Patients these days often ask: Can FiSH-testing results and gene-sequencing or molecular-testing tell us which treatment is best? The answer is no. While this information is interesting, it does not currently drive decision-making. The average number of genes mutated is 55 to 60 per myeloma cell. More detailed studies have revealed that each gene can have many different types of individual mutations. If you fix one mutation, what about all the other mutations that we know are there? Additional complexity results from the typical presence of multiple myeloma clones or sub-clones, each with a different pattern of mutations. These multiple clones must be identified and tracked over time.
Clinical trials are ongoing to determine if specific alternate therapy can work better for high-risk versus standard-risk disease, but these results will not be available for many years.
Beyond the first induction therapy, a single autologous stem-cell transplant (ASCT) is still considered part of “standard of care,” if it is feasible and desired by the patient. Thereafter, maintenance with an IMiD (immunomodulatory drugs), such as lenalidomide ± a proteasome inhibitor (Velcade® [bortezomib], Kyprolis® [carfilzomib], or Ninlaro® [ixazomib]) for higher-risk patients, is recommended as ongoing treatment.
The role of expert consultation
Consultation with a myeloma expert is really helpful to guide patients’ choices and to answer questions such as: Which three-drug combo should be used? Might two drugs be sufficient? Can ASCT be safely deferred? Is maintenance really necessary? These legitimate questions can be answered based on data from carefully designed research studies, clinical trials, plus recommendations summarized in IMWG consensus statements and/or guidelines.
Similarly, at the point of relapse—whether early or later in the disease—myeloma experts can draw on carefully designed research studies, clinical trials, and IMWG publications for patient recommendations.
Connecting research to outcomes
What research can really improve patient outcomes? Brainstorming on this topic led the IMF to create the Black Swan Research Initiative project and to launch a dedicated search for the cure. The first step was to use “CURE trials” to achieve the maximum benefit with currently available therapies, such as KRd ± daratumumab combinations. The second step was the search for new and better therapies for all myeloma patients with persistent relapsing disease.
Although each patient is different, the fundamental genetic mutations leading to myeloma treatment resistance have common features. The most successful treatments, such as daratumumab (Darzalex®), broadly attack and destroy multiple residual resistant myeloma clones, which are positive for CD38 on the surface. The same is true for anti-BCMA CAR-T cell therapies or monoclonal antibodies against BCMA. And this is the key concept of the Black Swan Research Initiative: “How can we wipe out clones left after our best current therapies?”
Precise versus personal approach
There is a precision approach to treating residual disease, but typically not a personal one because residual resistant myeloma cells have features in common. Right now, an IMWG project is studying patients with the t(11;14) translocation. This subtype of patients responds well with a new therapy, venetoclax. But what are the other features of such patients and what will be the most comprehensive way to wipe out residual disease in them?
More than 1,500 patients are being studied for this project. Rigorous statistical analyses are being used to come up with precise answers. We need to know the details of diagnostic testing and all treatments administered along the way. This is the kind of painstaking approach required to achieve progress!
Current research versus basic research
It is important to distinguish this type of “current” research, which will provide answers in a few months, from more basic laboratory research, which gives new understanding but takes between 10 and 20 years or more to lead to new patient treatments. Most molecular myeloma research is equally time-consuming because the complexities are truly daunting.
Speeding things up
If waiting for 10 to 20 years for answers is a bit scary, there are ways to achieve a more immediate impact from research:
- Find out what is causing MGUS, SMM and MM, and start preventing these diseases from happening in the first place. A key part of the iStopMM project in Iceland is to investigate the causes.
- Use knowledge and intuition to repurpose “old” drugs and treatments already developed for other diseases. If this seems like a long shot, remember that thalidomide was approved as a treatment for leprosy, and Velcade was under development as an anti-viral agent. Other examples from the past of this approach are found in a series of articles I wrote on how to overcome resistance to Velcade using the heart medicine verapamil, published in the British Journal of Haematolgy. And in a follow-up study published in The Lancet, we showed that cyclosporine (used for graft rejection) also works. Currently, as part of the Black Swan Research Initiative, a blood-pressure medication, amiloride, is being tested against resistant myeloma with the 17p- high-risk chromosome abnormality.
We must respect rigorous research, keeping in mind that there is probably not a single “silver bullet.” Solid research leads to clear and typically simple guidelines and recommendations. This is the central focus of the IMWG: assessing ongoing research with a critical eye. It has been truly gratifying to see the huge successes from these collaborative efforts.
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