“True wisdom is knowing what you do not know.”

                                    Attributed to Confucius

“We’re missing half the story right now,” according to Dr. Kenneth Anderson of the Dana-Farber Cancer Institute at the Inaugural Plasma Cell Disorder Congress in Charlotte, NC on August 10-11, 2019, “but we’ll repair that.”  His comment summed up the Congress’s presentations—myeloma researchers and clinicians are more certain about what they don’t know now more than ever. 

Three Key Themes

In the big picture that’s good news, but impatience about speeding up progress in myeloma adds to the anxiety of today’s patients and caregivers, regardless of the optimism of experts.  Three themes recurred over and over again.

• Knowledge of each patient’s specific genomic characteristics is essential to guide treatment decisions, but much work still needs to be done to create narrower disease classifications to inform physicians and provide optimal, targeted treatment options for each patient. As these categories become ever smaller, it is essential to begin to reform the current clinical trials

• The application of minimal residual disease (MRD) into clinical practice will likely become more of an essential prognosis and effectiveness measurement tool for myeloma treatment, but it’s not quite ready for prime time.

• Drug resistance—becoming refractory to a particular treatment—is generally uniform across drug categories; being resistant to one iMiD will likely make one resistant to other iMiDs, being resistant to one proteasome inhibitor will likely make one resistant to other proteasome inhibitors, and so on. It is a problem that must be and is being confronted.

Taken together, the Congress underscored the idea that rapidly changing treatment paradigms means having a specialist in a patient’s corner—whether as the primary physician or having one consult with a community oncologist—is essential for myeloma patients.

Myeloma Genetics and Individualized Therapy

Understanding of chromosomal features about the subclassifications of standard- and high-risk are continuing to be refined, but “there is no unifying mutation in myeloma” and “no consensus on prognostic signatures” according to Dr. Pieter Sonneveld of the Erasmus MC Cancer Institute in Rotterdam, The Netherlands.  Moreover, he commented, “Many patients don’t show specific mutations in a way that can be addressed in clinical trials.”

Building on Dr. Sonneveld’s observation, Dr. Anderson noted in a discussion forum that reforms of the clinical trials process are crucial because, with ever-increasing subclassifications of genomic signatures and treatment regimens that will multiply accordingly, “there is no longer a need for phase 3 trials that are too large and take too long” to complete.  Indeed, for experts like Dr. Sagar Lonial of Emory’s Winship Cancer Institute, “phase 3 trials are not relevant in our decisions.”

Dr. Anderson stressed the need to have tools to attack multiple genomic targets in myeloma treatment because, “trying to block individual mutations doesn’t seem to have a long-term future.”

Additionally, the “International Myeloma Working Group’s (IMWG) high-risk [disease] criteria needs to be urgently updated,” noted Dr. Saad Usmani of the Levine Cancer Institute and Congress Chair, on behalf of Hervé Avet-Loiseau from Toulouse, France.

With ever-increasing understanding of the gradations of smoldering myeloma, it may be well become an obsolete category.  High-risk smoldering myeloma trials and studies like the Promise Study, led by Dr. Irene Ghobrial of Dana-Farber, are leading the way.  If the disease becomes treatable to prevent progression, high-risk features might be classified as myeloma and lower risk smoldering would be grouped with MGUS (monoclonal gammopathy of undetermined significance) or renamed early multiple myeloma.

Dr. Peter Voorhees, co-chair of the Congress and from Levine, even noted the “tragedy” of use of the term plasma cell leukemia, noting that “it is actually the highest-risk type of myeloma” and confusion about its name might “be preventing those patients from seeking clinical trials” that fit them.

MRD Negativity

Dr. Nikhil Munshi of Dana-Farber summed up the near unanimous consensus that “MRD negativity is an important endpoint [and has] to be put into practice to make clinical treatment decisions,” noting that, “data suggests transplant can aid reaching lower MRD negativity [and is] great by whatever means it is achieved.”

But Dr. Lonial cautioned, “using MRD at random is a complicated therapy decision” since no objective, consensus standards exist.  Physicians have to ask, according to Dr. Lonial, “What’s the difference between biochemical and symptomatic relapse?  Do we treat because a number goes up?”  While some specialists are comfortable with their experience to interpret MRD, how is a non-specialist to decide?  And what is the threshold?  Does early relapse—within two years—need different treatment as compared to late relapse—six-to-eight years, for example?

Dr. Sonneveld urged more research to “focus on MRD as a prognostic factor.”  Dr. Jens Hillengass of the Roswell Park Comprehensive Cancer Center suggested imaging techniques would be key, “combining PET(positron-emission tomography)-negativity with MRD is significant.”

“Long-term disease-free survival and potential cure of myeloma will require both MRD negativity, and the restoration of anti-myeloma immunity,” summarized Dr. Anderson, “the goal is to have all patients off all therapy.”

Drug Resistance

A fundamental focus of future myeloma research will be to understand how to overcome drug resistance—becoming refractory to a therapy.  “We really don’t understand drug resistance very well,” noted Dr. Voorhees.

Dr. Anderson highlighted the development of “drugs to overcome resistance [is] on the horizon, to stimulate cells that resist drugs like iMiDs [lenalidomide/Revlimid] to become active again.”  As Dr. Voorhees emphasized, “we want to avoid drug-resistant clones.”  Dr. Sonneveld noted the key is to “find disease driver mutations [and] individualize treatment and avoid non-effective treatment.”

Another key element of this approach is to create “vaccines with the goal of preventing smoldering myeloma from progressing,” said Dr. Anderson.  “People used to say you can’t do that.”

Myeloma's Future

Or, as Dr. Shebil Atrash of Levine summed up in one of the final comments of the Congress, “the time from bench to clinic is getting shorter.”  Probably as short as it has ever been.

Optimism is a two-sided coin for myeloma patients.  On the one hand it offers hope. On the other, the visible future is not now.  A famous verse from the T.S. Eliot poem The Wasteland came to mind as I considered this conflict:

“Who is the third who walks always beside you? When I count, there are only you and I together. But when I look ahead up the white road, there is always another one walking beside you.”

The “one walking beside you” has been called the “third man factor,” which is an “an unseen being that intervenes at a critical moment—when people are in great stress or in a life-and-death struggle—to give comfort, aid or support.”

The Charlotte Congress demonstrated that we should pay more attention to the hopeful side of the coin, our third man factor.  The more one is certain about what one doesn’t know also implies that one knows a lot…a whole lot more than yesterday with a clearer vision for the future.