Discerning Myeloma’s Murkiness
Robert Kyle’s Relentless Quest (Part 2 of 2)
When Bob first started, myeloma was a very small club because no one was interested. Now people think it’s interesting because there’s good treatment. He was there before there was any treatment. That didn’t matter.
As linear, orderly, and inevitable as Robert Kyle’s life may seem with nostalgic hindsight, his story of reaching a medical Everest couldn’t be distilled into a made-for-tv movie. Nor does it have the guile that might fit the aphorism attributed to Otto von Bismarck: “Laws are like sausages, it is best not to see them being made.” Nothing he ever did was sinister or reeking of crass political intrigue.
His intellectual tenacity, innate sense of diplomacy, discipline,[1] and unwavering ethical consistency weren’t glamorous or immediately obvious. It wasn’t the stuff of a George Clooney- or Bryan Cranston-like role. Yet for countless subsets of people throughout the globe whose lives would be upended by diseases they would otherwise never have heard of, it is – or should be – a compelling story.
After returning to the Mayo Clinic from Boston as the fall of 1961 was approaching, Kyle finally started making a real living at age 33. His days at the Mayo Clinic were packed with patient care, not exclusively in hematology.
Kyle’s singular interest in rare diseases few knew about and being a disciple of the world’s leading hematologist, William Damashek, would soon get him invited to lecture at prominent medical institutions in the United States. It didn’t hurt that he was at the Mayo Clinic. He used these opportunities to learn how his colleagues did things.
One was to the National Institute of Health (NIH), in Bethesda, MD. He used some of the time to visit the lab of William “Bill” Terry, who worked at NIH and had his own lab in northern Virginia. Kyle visited “to learn how to perform immunoelectrophoresis.”
Another was to New York’s Columbia University Presbyterian Hospital’s[2] lab run by one of the nation’s top hematologists, Elliot Osserman. “A major reason for visiting was that his technician, Sylvia Lawler, produced beautiful arcs when the antigen and appropriate antisera met in the gel.” For Kyle, it was the equivalent of a budding sculptor going to Florence to see Michelangelo’s David for the first time. He was inspired.
Upon returning to Mayo, Kyle put in a request “to spend six months in Mayo’s Immunology Laboratory.” It was approved and sent down the administrative chain, “but nothing happened.” Finally, “in frustration,” he wrote Mayo’s Board of Governors to ask for “two hours daily to perform immunoelectrophoresis to identify the monoclonal proteins in serum and urine,” recalling in his memoir, “I was not shy about requesting permission to start the laboratory.”
Kyle set up the Special Protein Laboratory in 1968 and began testing samples of not just Mayo patients, but also from institutions throughout the United States. When he was asked by Mayo’s business office how much should be charged, he suggested $10 per test, which they arbitrarily upped to $15. “There certainly was no attempt to determine the actual cost of the test to figure out an appropriate charge,” Kyle thought back. “Many things were much simpler at that time.”
The lab moved to a newly built facility “with funds donated by Conrad Hilton” in 1974. Despite the new digs, Kyle’s office location in the basement with no windows may as well have been in of one of the Cold War nuclear missile silos being excavated in his native North Dakota. But it did have one perk, one any North Dakotan/Minnesotan would appreciate: “My office [was] directly over a large fuel tank that had to be heated in the wintertime. This kept my office floor warm, so I was never troubled with cold feet.”
Soon after, Kyle successfully lobbied for one-month rotations by Mayo hematology and pathology fellows in the lab. “I emphasized how important it was for pathology and clinical chemistry fellows to become familiar with the clinical features of patients. “I told anyone within earshot that laboratory-based fellows should be exposed to the clinical histories because as future laboratory directors they would receive telephone calls from clinicians who wanted to know more about the laboratory results.”
Kyle recruited a cadre of scientists, technicians[3] and support staff that would eventually be moved to the upper floors of the new, now primary, Mayo Clinic building. Its dozens of workstations were filled with technicians who handled hundreds of samples received weekly[4] from all over the nation.[5]
Kyle soon realized his lab needed to be more directly connected to his primary mission, treating patients. In 1969, he created the Dysproteinemia Clinic (Dyspro clinic), which would be located in the daylight of the Mayo building’s 15th floor. “I wanted to see more multiple myeloma and other dysproteinemia patients for prospective studies.”
Kyle asked his Mayo mentor, Ned Byard, and Robert “Bob” Pierre, who graduated a couple of years after Kyle from Northwestern’s medical school, to join him. They were supported by devoted a secretary, Bev Motzko, who stayed with Kyle until her retirement in 2004. Over time, he would add and mentor colleagues who would make their own significant contributions to the field.
He recruited Jerry Katzmann, a PhD, as co-director of Mayo’s Special Protein Laboratory in 1999 to look into a method to use antisera, blood serum that housed antibodies, “to measure free kappa and lambda light chains in a patient’s serum.” This was suggested to Kyle by a British professor, Arthur “Jo” Bradwell, cofounder of the company The Binding Site.
Katzmann soon told Kyle, “it works,” and tested more samples “to measure the free light chain (FLC)…thus establishing the FLC reference levels and ranges that are still used by Binding Site today.” Now FLC is a part of the acquired jargon used by virtually every educated myeloma patient.
In later years, S. Vincent Rajkumar identified and linked risk factors for MGUS patients to kappa and lambda FLC levels. Thanks to the large amount of data accumulated by the protein lab, “he was able to complete the project in five or six weeks, whereas, if we had not had the serum bank, it would have taken 25 years!”
The Binding Site’s tests were applied to the ongoing Olmstead study (see below) to help Angela Dispenzieri identify and define “a new entity, Light Chain Monoclonal Gammopathy of Undermined Significance (LC-MGUS), which is a precursor of Light Chain Multiple Myeloma (LC-MM).”
Today the Dyspro clinic’s staff of 18 doctors sees approximately 5,000 patients a year. Kyle’s deliberate persistence was proof of Lao Tzu’s ancient maxim, “A journey of a thousand miles begins with a first step.” So, let’s go back to those first steps he took upon returning to the Mayo Clinic for the first and last “real” job he ever had.
Coming back from Boston after training under hematology icon Damashek and shattering a Mayo Clinic maxim, that you actually could go home again, Kyle could have been forgiven if he let it go to his head. But his 33 years – in Bottineau, North Dakata, at Northwestern’s medical school, becoming a “real” doctor in Alaska that was bookended by his Mayo training, his wife Charlene, and three, soon to be four, children – kept his feet firmly grounded. He wasn’t just doing rounds and teaching at Mayo, but also at St. Mary’s Hospital, less than a mile west on Rochester’s Second Avenue SW, immediately behind which was the house his family would live in for the next 47 years.
Knowing he was “just” another talented doctor among many, Kyle learned an important lesson from Walter Bowie, his partner in his daily clinical rounds. A common issue for hematologists was bleeding. Treating it required knowledge of coagulation, “a rather complex subset of general hematology [that] many consultants felt a bit insecure about managing.”
I always joked that coagulation consults were quite easy and explained that I only had to ask two questions. First, I asked Dr. Bowie what coagulation tests I should order, and second, I asked him what to do when the test results were available. This approach worked out very well for the patients and myself.
As Kyle became better known within Mayo, he was asked to see a 7-year-old girl who had been treated there for aplastic anemia since 1961. While she was sitting on the examination table, he noted “another little girl in the room. I asked the parents who she was, and they replied that she was the patient’s twin sister. Immediately I asked what kind of twin. They said ‘identical.’”
He recalled the trip Damashek sent him on to learn how to conduct a bone marrow transplant from Don Thomas, the singular pioneer of the nascent procedure. Knowing, thus far, the only proven success transplanting marrow was from one taking it from one identical twin to put into another, this would be his first time he would try. A young girl’s life was at stake.
Kyle and a colleague conducted the first bone marrow transplant in Mayo’s history on June 28, 1963. In short time, the girl’s blood counts went back to normal. Since then, he has
…been in touch with the transplanted twin many times with our last conversation being in early 2022. In 1969, we performed a bone marrow transplant on a young woman, also from her identical twin sister. Her blood counts became normal and have remained so to the present time.
It was a heady and, at the same time, humbling experience. Nonetheless, Kyle knew he would never know everything, and he was quite comfortable with that. Listening, learning, and collaborating with colleagues, mentors, mentees, and especially patients, whether at the Mayo Clinic or in meetings or consultations around the world, was essential to his very being.[6]
Research was still a high personal and professional priority. He fit in time for it whenever possible while keeping up with his clinical work. When Clinic administrators ended the practice of seeing patients on Saturdays in 1968, his Saturday mornings routinely became his quiet refuge “to review histories, analyze data, and work on papers [and] write without interruption.” He was likely spurred on by his memory of his first globally significant achievement in 1959.
Kyle’s paper, recognizing and describing electrophoretic patterns he as M-spikes, was published two years before Swedish hematologist Jan Waldenström defined “benign monoclonal gammopathy of unknown etiology [cause].” That term replaced one Waldenström first coined in 1952 published paper, “essential hyperglobulinemia.” He described “two patients” with “elevated” numbers of proteins in the blood associated with inflammation that was present “for several years but [with] no evidence of multiple myeloma.” For years Waldenström was convinced these abnormalities were benign; they existed but didn’t do anything.
Kyle recalled, after going through Damashek’s files, a similar prevailing mindset, that chronic lymphocytic leukemia (CLL) was a benign disease. It was a memory revived by an experience in reviewing another file years later.
Engaged one day in one of his most personally satisfying activities,[7] going through case histories, he found a female patient who came to Mayo in 1963 complaining of back pain. She was diagnosed with myeloma in 1964 and treated before passing away in 1965.
“In reviewing her records,” wrote Kyle, “I saw that she first came to the Mayo Clinic in 1945 reporting weakness and fatigue…but had no other symptoms.” Looking at her test results, he realized she had the “benign” condition Waldenström described. When she came back to the Mayo Clinic in 1958, she was found to still have some abnormalities in her blood sample, but “she was feeling well” and “no treatment was advised” until 1964.
“This is an important reminder that physicians should always review the past history of a patient,” Kyle wrote, echoing one of the most valuable lessons he learned from Damashek. Together with “Ned” Bayrd, who had suggested Kyle “look into” the electrophoresis pattern a few years earlier, he published a case study based on that one patient[8] in 1966. It was the first demonstrating that the condition Waldenström described was not necessarily “benign.” Over the next years, Kyle would continue to observe this progression in many patients.
“The term Monoclonal Gammopathy of Undetermined Significance (MGUS) was coined in 1978” in a study of 241 patients diagnosed with it. Twenty-seven of them progressed to myeloma, four each to AL amyloidosis and Waldenström’s macroglobulinemia, and one to a lymphatic disorder. Regardless, “many physicians did not accept the findings” since it was based on a relatively small sample. Even Kyle “was not completely confident.”
Definitive confirmation came in a 1994 in what has become known as “the Olmstead study,” named after the county where Rochester is located, one continues to be updated annually through today. The original study of 1,394 patients diagnosed with MGUS from 1960-1994 found they had a median age of 72.
Over a 40-year period, approximately 1 percent of these patients annually progress to multiple myeloma or a related disorder. Multiple myeloma developed in two-thirds of patients who progressed with the remainder of the diagnoses almost equally divided between lymphoma, AL amyloidosis, and macroglobulinemia. It is important to realize the risk of progression persisted unchanged throughout nearly four decades of follow-up.
Kyle defers taking credit, as he writes in his memoir: “In my opinion at least, Dr. Waldenström’s seminal contribution was worthy of a Nobel Prize.”
As I wrote last year, “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.” Complicating the matter, the patient had congestive heart failure.
When the patient developed symptomatic, or active, Kyle faced a difficult decision due to the congestive heart failure issue. “After considerable thought,” wrote Kyle, “I took a deep breath and told him since the potential side effects of treatment would probably aggravate” his heart condition which, in turn, would exacerbate problems with myeloma. Twelve months later the patient died of congestive heart failure, not due to his myeloma.
Kyle began recognizing more MGUS patients whose lab values progressed to what should have been active myeloma but did not. He called the category between the two smoldering multiple myeloma (SMM). A study “of 276 Mayo Clinic patients with SMM” found patterns that have proven to be consistent over time:
…their progressions to serious disease requiring therapy was at a rate of 10 percent per year for the following five years, and then the rate of progression fell to that approaching that of MGUS. This suggests that a number of these patients actually fulfilled the diagnostic criteria of multiple myeloma, but as time went on, the illness behaved more like MGUS.
MGUS and SMM patients are generally not treated. However, in recent years, significant research activity has focused on determining which patients are at risk of progressing. Clinical trials have been implemented to treat these patients before they develop active myeloma, leading many to question if SMM will still be a classification in future years. As of now, though, Kyle’s findings still hold in clinical practice.
Given Mayo’s stature in oncology, it seems almost ludicrous to think it hired its first staff oncologist in 1963 or didn’t become a cancer center until November 1973. When preparing an article last year about the impact of the Kennedy administration’s New Frontier funding initiatives in the early 1960s, I mentioned to Kyle how it was the first of three large federal infusions of cash into cancer, to which he replied, “Now that I think about it, we did have a lot of money coming in back then.”
The creation of Mayo Clinic’s cancer center was made possible by a second infusion of federal money from the Nixon Administration’s War on Cancer program in the early 1970s.[9] This had a great impact both on Kyle’s legacy and the fate of myeloma and other dysproteinemia patientssdecades later.
At the time, “80 new cases of multiple myeloma, 15 to 20 primary amyloidosis, 5 to 10 with Waldenström’s macroglobulinemia, and approximately 200 cases of so-called ‘benign’ monoclonal gammopathies were seen at Mayo Clinic each year.” For such relatively rare diseases, at that time, those numbers put Mayo near the top among clinics around the world.
In 1974, as a part of the full menu of cancer-related research the Mayo Clinic proposed, the Dyspro clinic sought funding for “11 projects designed to increase our understanding of monoclonal gammopathies.” It was an ambitious goal for a disease like myeloma that had hardly any improvement in patient survival since the first known myeloma patient was identified as having been in the early 1840s. On the other hand, it fit with President Nixon’s goal of “launching of our great crusade against cancer [which] should be a cause for new hope among people everywhere.”
The aims of the first proposed project still have a ring that resounds strongly to anyone familiar with myeloma 51 years later:
1) differentiate between multiple myeloma and “benign monoclonal gammopathy”;
2) classification of the IgG heavy chain subtypes and the correlation with the clinical picture, response to therapy, and survival;
3) correlation of kappa and lambda light chains with survival in multiple myeloma;
4) recognition of possible new immunoglobin classes and subclasses; and
5) better characterization of multiple myeloma and the closely related monoclonal gammopathies.
A blue-ribbon panel of cancer center directors and experts – which included MD Anderson’s myeloma expert Raymond Alexanian – came to Mayo in May 1974 for the first of many annual site visits to evaluate proposals. Similar panels evaluated other departments’ proposals at Mayo and each of the NCI-designated cancer centers.
They approved the project described above, noting it to be “an integral part of the entire program and agreed that recordkeeping and patient follow-up were essential for other projects.” Some other proposals were approved, but most were not because, as Kyle summed up, “no single project ‘fired’ the imagination of the reviewers and was not truly an ‘inspired research undertaking.’”
One reviewer “wrote that our proposal was ‘enormously broad in scope’ with a ‘certain lack of penetration into any single area.’” The mixed bag of results provided a new infusion of money, part of which led to the recruitment of Katzmann and other staff to build the capacity and reach of the Dyspro clinic.
These site visits, which often included at least one top myeloma expert, challenged, evaluated, approved, or denied, helping to refine future proposals. Program project grants provided support for infrastructure and administrative personnel, investigator-initiated grants – i.e., ideas generated by individuals’ personal professional research preferences deemed important by visiting panels, and fostered collaboration between and among NCI-designated cancer centers, which now number 75.
Kyle’s memoir provides detailed information about these site visits through 2009. Many of the proposals were submitted by young, unknown researchers who currently populate and lead myeloma programs throughout the nation.
The rigor and accountability of the entire process, not just at the Mayo Clinic, but at every cancer center – NCI-designated or not – is a massive undertaking of human capital, not just federal funding. This highlights the terrifying absurdity and existential nature of the capricious decision-making in the first two months of the Trump administration.
Anonymous staffers at DOGE (sic) end billions of dollars of complex, vetted research proposals about which they have no clue with the stroke of a computer keyboard. Inappropriate meddling in venerable, medical institutions including, but not restricted to, Columbia, Johns Hopkins, and NIH – not to mention recent social security shenanigans that have taken place in Maine – are baselessly driven by politically-motivated retribution and ideology.
Physicians, nurses and support staff are being demoralized and fired with no due process, explanation, plan, or, most consequentially, regard for their experience and professionalism. Once gone, they may be gone for good; the costs and effort to bring back future capacity to that which existed two months ago would dwarf any short-term “savings.”
One doesn’t have to think too hard to understand how dire the situation would be for myeloma and other dysproteinemia patients today if this frivolous mindlessness had existed decades ago. There would have been no New Frontier, War on Cancer, or NIH doubling-driven progress. Which is largely responsible for many experts credibly predicting cures and chronic treatments for once-certain death sentences.
Kyle’s achievements and impact are too numerously consequential to distill in a few words. Perhaps they are best summed up by his role in founding and existence of the International Myeloma Society (IMS), now the premier professional organization of myeloma specialists worldwide.
Although the IMS was formally founded in 2007, its roots stretch back to 1986, when Kyle received a call from British myeloma pioneer Tim McElwain proposing to host a meeting of myeloma experts at Blenheim Palace, just north of Oxford, England. Initially skeptical, Kyle wondered if there would be any interest at all, but finally agreed it was worth a try.
McElwain and his colleague Jim Malpas hosted about 30 experts in Blenheim’s ornate library in 1987. At the end “everyone was in favor of having a second round. Bart Barlogie volunteered to organize it, and it was held two years later at MD Anderson in Houston.” The participants liked it, and it was decided to hold the International Myeloma Workshop IMW) every two years, but the organizing them was haphazard. At the conclusion of the 1995 IMW on Labaule, France just west of Nantes, funding and leadership issues threatened to stall the meetings, but they carried on nonetheless.
Kyle convened a meeting in 2007 at the 11th IMW, held in Kos, Greece, an island within sight of the eastern Türkiye coastline. It was the founding of the IMS, which then took over organizing future IMWs. Kyle was elected IMS president, serving until 2011. The IMW became the IMS meeting, which remained a biannual event until the 2021 meeting in Vienna, Austria, after which it became annual. Each meeting has one highlight.
Jan Waldenström never received the Nobel Prize Kyle believed was due to him. Instead, the Waldenström Lifetime Achievement Award has become the most prestigious award in the myeloma research and treatment community. It has been presented at every IMW/IMS meeting since 1989.[10]
The last IMS meeting I attended, in Athens, Greece in 2023, conducting interviews for a book on myeloma history I hope to publish, and the inspiration for creation of this Substack, one question I posed got a universal answer. I noted the IMS meeting seemed incredibly friendly and cooperative.
Every single person agreed and noted the exact same reason why, without much prompting from me: much like George Washington at the Constitutional Convention, the personality of Robert Kyle pervaded everything the IMS did and does. Kyle’s example of fostering collegiality, organization, purpose, and most of all, a core sense of decency and respect for each other was as just as present when he stopped attending after the Covid pandemic as it was when he attended.
Kyle is largely the reason a meeting in 1987 that had about 30 participants in now attracts more than 3,000 and may be approaching 4,000 for this year’s planned meeting in Toronto, Canada. Physicians and researchers working on myeloma and other dysproteinemias from every continent attend to get the latest updates to guide them in their work.
He's largely the reason why the major myeloma presentation at the annual American Society (ASH) is now split into two repeating sessions attracting audiences approaching 16,000. (It still doesn’t seem right going to ASH oral presentations on myeloma and not seeing Kyle settled in the middle of the first row attentively soaking in every word.)
The real reason, however, is best summed up by one of Kyle’s many protégés, one who knows him best, Morie Gertz:
Bob came up with MGUS, he coined smoldering myeloma. He was a pioneer in so many different areas: first descriptions of AL amyloidosis, first to recognize that somehow amyloid had something to do with monoclonal gammopathies. I mean Bob was first in so many different things, but then people said, “What a great guy, he doesn’t have a mean bone in his body.” He’s kind, he’s empathetic, and he saw patients – they loved him and the way he explained things. The guy moved from famous to legend.
Robert A. Kyle, A Physician’s Journey: The Memoir of Robert A. Kyle, M.D., The Digital Press of the University of North Dakota, 2023.
[1] Kyle, at 97, still weighs the 160 lbs. he was at 22.
[2] Where Suzanne Lentzsch now heads the myeloma program.
[3] Recalling one of his most gifted technicians, Kyle recalled, “In the ‘unregulated’ days, one of my techs had a cigarette in one hand and a bottle of Coke in the other and still was working effectively.”
[4] Not everything ran smoothly, “…we would mail a 24-hour urine container and ask the patient to collect a specimen and return it to us. This worked out well in most instances, but, occasionally, the urine jug cap became loose in transit and the packages became very messy. After a number of years, the Post Office refused to accept the large mailing containers, so the patient was instructed to collect and measure a 24-hour urine specimen and then remove a small amount and return it by mail to Mayo Clinic.”
[5] On my first visit with Kyle at the Mayo Clinic, he showed me the vast room and about how he worked closely with the architects to design it. I’ll never forget the proud fatherly-like glow of joy he exuded as he explained it to me.
[6] Among the most memorable experiences I had in traveling with Kyle on our trips to Europe was a visit to Bergen, Norway. I had arranged for him to give a professional lecture with Dr. Roald Lindås of the Haukeland University Hospital to a small, invited group of hematologists from southwestern Norway. Some traveled three-to-four hours to attend. After the lecture, Kyle spent hours in individual consultation with many of them, going over case studies to discuss.
[7] Kyle once told me he would often take lunch breaks and what little free time he had in the Mayo medical library of cases stretching back to Mayo’s inception. One of the more memorable ones was of a very prominent member of Franklin Roosevelt’s wartime cabinet who was secretly treated for a hematological malignancy in the mid-1940s.
[8] “Today, few reputable medical journals accept and publish a case report describing a single patient.”
[9] The third infusion came with the doubling of National Institutes of Health funding over the period from 1998-2003.
[10] The first Waldenström Lifetime Achievement Award was presented to Daniel Bergsagel, Kyle received the second in 1991. Honorees featured in past stories on this Substack include Raymond Alexanian (1997), Bart Barlogie (1999), Kenneth Anderson (2003), and Jean-Luc Harousseau (2007). The most recent recipient, at the 2024 IMS meeting in Athens, Greece, was Sundar Jagannath. Additional honorees will be featured in future stories.
Due to the increasing pace and volume of advances in myeloma, amyloidosis, and related dysproteinemias, the meetings became annual starting with the 2021 IMS meeting in Vienna, Austria.
just a kindly tip from someone who's a proofreader-- it's = it is, its = belonging to it