Mapping Myeloma Trails
I always have done the best I could for a patient each time that I see them. I also emphasize that new things will be found and encourage them to “keep going.”
- Robert Kyle, email to author
We classify stuff. Maybe categorize is a better word. It’s a human necessity. Perhaps a compulsion.
Aristotle, Mendel, and Darwin were classifiers, a testament to the “one percent inspiration and ninety-nine percent perspiration” quote attributed to Edison. Ask any scientist.
Over time, scientists classify, organizing ever-narrowing fields of study. In medicine, that translates into specialization. Pioneers in scientific fields are compilers, organizers and statisticians with the education and imagination to interpret random or yet unknown facts into something recognizable.
Talent for patience and process, recognizing and deciphering patterns and probabilities where no one else saw them, required a different kind of passion; one less flashy that didn’t bring blazing trails to mind. What Robert Kyle accomplished when it came to plasma cell-based diseases like myeloma, for example.
As we saw earlier, Kyle found his niche in hematology-oncology in the 1950s. To make the most of it, he had to specialize.
Expertise that could grow and translate into a solid reputation was often tied to mentors who became gurus of sorts, excelling in training others. Substantive lineage mattered as much or more than titles or degrees.
Two of the most highly regarded hematological labs in the U.S. in the late 1950s were run by Max Wintrobe at the University of Utah in Salt Lake City—where Daniel Bergsagel went—and William Damashek at the New England Medical School in Boston, Massachusetts. Wintrobe was well-known in professional circles as brilliant, albeit with an arbitrarily mercurial temper. Kyle remembered a cardiology professor at Northwestern like that and it wasn’t for him.
In an era when substantive lineage mattered as much or more than just titles or degrees alone, nothing – no resumé or paper citation – in hematology could match being known as one of Damashek’s disciples. Nothing.
Dameshek’s family, with three-year old William in tow, emigrated from Voronezh, Russia, about 280 miles south of Moscow, to Boston, Massachusetts in 1903. Boston would remain at the center of most of the rest of his life, from English High School to graduating from Harvard Medical School in 1923 before finding his passion for hematology in his postgraduate internship at Boston City Hospital. By the age of twenty-eight, he was Chief of the Blood Clinic at Boston’s Beth Israel Hospital. In 1939, Dameshek began a twenty-seven-year stint at New England Medical Center, now the Tufts University School of Medicine.
Over his career, he identified chronic lymphocytic leukemia (CLL) and was first to classify myeloproliferative neoplasms – the collection of various diseases in which bone marrow-produced abnormalities makes too many or two few red or white blood cells or platelets, fragments in blood essential to clotting – by phenotype: organizing, classifying, and describing to get as full a picture as possible of each patient.
Damashek’s most lasting influence on hematology, seen from today, was to build a professional hematology community. With it, over time, came standards to educate professionals as their disciplines evolved. In 1946, he became the founding editor of BLOOD, which would soon become the preeminent journal in hematology, until his death in 1969.
More significantly, he was the driving force behind the creation of the American Society of Hematology (ASH). Some dissenting voices felt not enough was going on in hematology to justify having an organization devoted to it. They were quickly proven wrong.
The first annual ASH meeting was held in 1958 in San Francisco, California. It would soon go on to become the preeminent meeting not just for Americans, but it also became the biggest de facto international hematology meeting. Many expect this December’s 66th annual meeting in San Diego to attract more than the pre-pandemic levels of 35,000 attendees.
Since 1974, ASH has been presenting the William Damashek Award to an individual making an outstanding contribution in hematology. It is one of the few accolades Kyle will never receive. He was 48 old by then. Only those under the age of 50 are eligible.
The 2022 Damashek Award went to Irene Ghobrial from the Dana-Farber Cancer Institute. In a sense, it was the completion of a circle. She worked closely with Kyle during her post-graduate training at the Mayo Clinic.
Although Damashek had no real interest in myeloma, every ASH presentation or publication has his virtual watermark.
Kyle wasn’t expecting to go back to Mayo after Boston, but he couldn’t resist an offer to come back in 1961. He would spend the rest of his life at Mayo organizing and giving direction to distinct hematological disciplines involving abnormalities of plasma cells, much as Damashek had done with hematology itself.
When he got back to Mayo, myeloma was still very much a blank page seemingly filled with more emptiness for patients. Their despair became his sense of purpose.
But first he had to do the job of doctoring any patient who came through Mayo’s doors to see him. Most patients he saw on a typical day in the clinic – or any physician anywhere, for that matter – were not in his “specialties.” First and foremost, his responsibility was to practice internal medicine and be ready to treat anyone who came into the clinic.
Looking at it realistically, there weren’t many myeloma or amyloidosis patients who lived long enough to keep a physician busy full time. The benefit of working at Mayo was that there were specialists for just about every medical condition known, so any doctor could refer patients to a colleague who was more conversant with it.
It is estimated that more than 30,000 patients were treated by Kyle or by those who worked under him during his time as a clinician at Mayo from 1961 into the early 2000s.
Kyle’s expertise, personality, and devotion to detail quickly earned him a national and international reputation; he was among the biggest fish in a fairly small pond. Understanding how proteins became paraproteins – abnormal proteins found in cancers and diseases – became an obsession.
High levels of paraproteins are called gammopathies, in diseases like myeloma they are repeating single cells that crowd out other cells in bone marrow – monoclonal gammopathies. But in those cases, the condition was in the blood but didn’t seem to be doing anything. It was just there, generally concluded to be benign, with no particular purpose.
As Kyle tracked cases coming through Mayo over the years, he was beginning to note some progressed to myeloma and amyloidosis. The vast majority of those with a monoclonal gammopathy lived with it until they died, unaware of its presence. This could not, however, be predicted.
By 1978, Kyle published a paper showing monoclonal gammopathies were not always benign. They were, more accurately, mysterious, or in medical language, undetermined, which is not benign. A monoclonal gammopathy of undetermined significance (MGUS). Kyle later determined that every myeloma case developed from an early stage MGUS, whether it was known about or not.
One patient confounded Kyle for two decades. His MGUS was progressing, tests indicated disease was becoming active, but he didn’t exhibit any symptoms of myeloma. The patient felt just fine even though Kyle was sure he shouldn’t.
He would see more and more patients with similar experiences in coming years, realizing they inhabited a no-man’s land between MGUS and myeloma. He felt confident enough to call it smoldering myeloma in 1980. This group had an increased risk to develop myeloma as compared to those with MGUS, especially in the first five years after they were determined to be “smoldering.”
Strangely, not all of them would develop myeloma either. No one understood why. Found in up to 5% of aging populations, uncertainty widens the reach of myeloma’s Sword of Damocles, of knowing when or if it would fall at all.
Knowing what was happening biologically and how long it took to progress took on a new urgency, leading Kyle to convince Mayo to establish a new Dysproteinemia Group in 1982 to research and treat diseases with abnormal proteins in the blood, myeloma being the most prominent. Kyle’s intellectual reach and influence would attract the best minds in those diseases. We’ll delve into some of their stories in coming months.
Kyle initiated one of his most lasting legacies in 1990, an annual survey of Olmstead County, Minnesota – Mayo’s home – to track births and deaths and identify those diagnosed with MGUS. Data accumulated over the years have provided valuable information about the rates of progression from MGUS and smoldering myeloma to active myeloma. The study continues to be updated annually in the prestigious New England Journal of Medicine.
Over time, Kyle attracted exceptional people to mentor in Rochester. Many went on to lead clinics around the nation and the world, some stayed, all became familiar names in professional publications covering the range of diseases related to Kyle’s group.
They developed a strategic treatment approach adopted by the majority of physicians treating myeloma. Known as “watch and wait,” i.e., treat conservatively, doing as little toxic damage as possible to healthy tissue through long-term or limited administration of medications, and keep options in reserve for expected relapses. It remained a treatment paradigm for decades.
Before continuing that story, however, I’m going to take another detour in the next Substack article. I’ll discuss a book not about myeloma, but still an important part of myeloma history.
Should you be impatient to learn more detail about Dr. Kyle’s story, his autobiography was recently published by the University of North Dakota Press. I’ll review it this summer.
Copies are available for purchase here.
Photo: Dr. Kyle in Heidelberg, Germany (ca. 2009).