Kyle's Keen Observations Led to a Lifetime of Discoveries in Plasma Disorders

Robert A. Kyle, MD

Myeloma survivors owe much to Robert A. Kyle’s reluctance to perform autopsies or to undergo cardiac catheterization.

Those natural aversions led Kyle to choose hematology over two other research options toward the end of his Mayo Clinic residency, and launched Kyle on a course of research that has transformed our understanding of dysproteinemias, the family of plasma cell disorders related to multiple myeloma (MM).

The 86-year-old doctor, who has now been at the Mayo Clinic more than 60 years, not only discovered how such disorders progress to serious diseases such as MM, but also worked out the appropriate medical response at every step. Those and hundreds more breakthroughs stemmed from a unique combination of clinical practice, data mining, and sheer effort. Kyle has put in nearly 80-hour weeks for six decades now, and colleagues say he’s still working close to full speed. “It would be nearly impossible to overstate Robert Kyle’s impact on multiple myeloma research and treatment,” said Kenneth C. Anderson, MD, Harvard Medical School, Jerome Lipper Multiple Myeloma Center, and LeBow Institute for Myeloma Therapeutics. “He is my hero, my inspiration, my role model. He is a giant.”

A Landmark Paper

When Kyle began to study dysproteinemia in 1960, routine blood tests frequently found monoclonal gammopathies in patients with no symptoms of MM or other disease.

Researchers had tracked some of those patients for a few years, found no tendency to develop disease, and dismissed the condition as benign. Kyle began the work that would change all that in 1964, when he saw that a patient had developed MM 19 years after first being diagnosed with what was then called “benign monoclonal gammopathy.” He wrote up that single case and published it, along with a warning that doctors might want to follow up on patients they diagnosed with a condition that might not be so benign.

He returned to the issue 14 years later with a landmark paper demonstrating that the condition, while sometimes genuinely benign, was also the precursor to dysproteinemia ranging from MM to Waldenström macroglobulinemia and primary amyloidosis. This finding definitively demonstrated the need to monitor, rather than simply ignore, the misunderstood condition, which, Kyle later demonstrated, afflicts 3% of European Americans and 6% of African Americans who are 50 years and older.

Unfortunately, that same paper, which mined data from thousands of patient files, did not find any way to determine which cases would progress to which diseases over what timetable. Indeed, the analysis specifically found that there was no way to make predictions in individual cases, which is why Kyle rechristened the diagnosis monoclonal gammopathy of undetermined significance (MGUS).

Two years later, Kyle and his protégé, Philip R. Greipp, MD, professor of Laboratory Medicine and Pathology at Mayo, traced the next step on the road to MM with a paper on six unusual patients.

Those patients had lab results that would then have prompted an MM diagnosis, but none of them had any symptoms, even after five years without treatment. Kyle and Greipp differentiated their condition from full MM with the label smoldering multiple myeloma (SMM).

“All of those papers, and hundreds more I’ve published, began with a clinical observation,” Kyle said. “I noticed something I could not explain and then went back into the records looking for patterns.”

A Treasure Trove of Data

When Kyle talks of going back to his records, he speaks of an incredible asset. Kyle’s longevity and work ethic, combined with some early success with data mining, led him to amass an unprecedented collection of patients with dysproteinemia and to invent breakthrough strategies for teasing insight from their files.

His data management efforts began in the 1960s, when no doctors kept files on computers, with an early IBM punch card system and progressed from there. The system now has records on more than 46,000 patients seen by Mayo’s dysproteinemia group, which now numbers 12 physicians. The database includes over 26,000 patients with MGUS, more than 8000 with myeloma, and nearly 4500 with AL amyloidosis.

Better still, the data on many of those patients span decades because Kyle set up a research survey system that automatically requests updates from every patient who hasn’t been to Mayo Clinic in a year. If the patient doesn’t respond, then a second letter goes out, and if the patient doesn’t respond to that, someone places a telephone call.

Kyle’s “files” also include serum samples—every single one that he and his colleagues have collected since the 1960s. The group now has 250,000 samples, frozen in storage, and fully correlated with patients’ medical records, often from first diagnosis to death. Mayo officials once begged Kyle to discard those samples, but recent advances in biological analysis have made them an obvious treasure trove.

Unique Value of the Mayo Clinic

In addition to mining records from his own patients, who all have dysproteinemias of some type, Kyle made a series of discoveries about the incidence and development of such conditions in the general public by taking advantage of Mayo Clinic’s unique standing as a large medical institution in a small community.

One way or another, Mayo Clinic provides medical services to most people who live in Olmsted County, Minnesota, and that has given Kyle access to what amounts to a random population sample, numbering in the tens of thousands, that sends every case of dysproteinemia to Mayo.

What’s more, because he has been at Mayo for so long, Kyle has often been able to trace the incident or absence of disease through several generations of the same family. “We’ve used that data to figure out how common various dysproteinemias are in many different populations and how quickly they progress,” said Kyle, who added that the numbers illustrate why doctors and patients must resist the urge to treat early-stage problems rather than simply monitor them.

“We’ve figured out that whenever a doctor diagnoses an MGUS, it has, on average, existed inside the patient for 15 years and will probably never cause any problems at all. It’s less of a risk than any treatment we have now.”

A Precocious Mind Destined for Medicine

Kyle was born in Bottineau, North Dakota, on March 17, 1928. He grew up with four brothers on a farm six miles outside of town and attended a one-room elementary school, where a single teacher juggled 15 to 20 children in all eight grades. On most days, particularly when there was snow on the ground, he rode a pony to class.

Kyle moved on to high school in Bottineau when he was just 12 years old and, during winters, rented a room in town and did his own cooking rather than dealing with weather—40-degree -below-zero temperatures and deep snowfall—that often made the short commute home impossible.

Science interested Kyle throughout school, and he always had a vague inclination toward medicine, but his interest grew serious when one of his younger brothers got meningitis. The two were sharing a room in Bottineau that winter and, when Kyle rose one morning, his brother could hardly speak. The 16-year-old Kyle took his 14-year-old brother to a doctor, who made the diagnosis and treated him with sulfa. The doctor gave Kyle detailed nursing instructions, which he helped carry out for two full weeks.

His brother recovered and, when Kyle graduated from the University of North Dakota, he decided to go on to Northwestern Medical School, and in 1953 to a residency at Mayo Clinic.

Myeloma Breakthroughs

“My plan, right up until the end of my residency, was to go to Southern California, set up as an internist and enjoy a comfortable life in paradise, but I got hooked doing research on spent a lifetime changing that, not only through his research but also by training quite literally thousands of clinicians and researchers over the decades.”

A Man of Many Interests

When his four children were young, Kyle led local chapters of both the PTA and the Boy Scouts, but his only long-standing hobby, one begun when a bad back kept him bedridden for 40 days, is stamp collecting. He has a huge collection of medically themed stamps and has written hundreds of monographs on the subject.

Kyle’s other non-medical passion is travel. He still spends three weeks every summer driving the American West, and still flies more than 125,000 miles a year to conferences and gives lectures all around the globe.

For most of his life, Kyle’s working day began when he reached his office at 7:30 am, where he stayed for 11 hours before going home to eat dinner with his family. After the kids went to bed and his wife, Charlene, settled in to read a book, he’d wedge in another two hours of work before going to bed at 11:00 pm. He has worked slightly shorter weeks since turning 80 but, according to colleagues, not much shorter.

“I’m very excited about the work I’m now doing on how smoldering multiple myeloma progresses,” he said. “About half of all cases become full myeloma in five years but a third haven’t progressed in 10 [years], which suggests it may actually be two different conditions. The trick will be differentiating them in advance.”

“Dr Robert Kyle’s research has had a far-reaching effect on the understanding of dysproteinemia and multiple myeloma. Many of the breakthroughs that have come about in the last 60 years have stemmed from his efforts that combined clinical practice, data mining, and sheer effort.

I consider him a mentor in my own career, and his seemingly boundless curiosity and energy have been an inspiration to the thousands of clinicians and researchers he has trained over the course of his career.”

Saluting a Trailblazer

Parameswaran Hari, MD

Armand J. Quick/William F. Stapp Professor of Hematology Director, Adult Blood and Marrow Transplant Program Froedtert Hospital Medical College of Wisconsin Milwaukee, WI

“Dr Kyle is the undisputed father figure of modern myeloma care. Patients, caregivers, and physicians dealing with plasma cell disorders such as myeloma, MGUS, and amyloidosis owe an enormous debt of gratitude for his contributions. Spanning many decades, his observations and studies gave us disease definitions, established diagnostic criteria, and defined the natural history of these disorders. In addition to countless path-breaking studies, he is also to be credited with building the Mayo Clinic dysproteinemia group of outstanding researchers who have carried on his work across three institutions. The best of all is that Dr Kyle remains active, approachable as a collaborator and sounding board for ideas. Hats off to Dr Kyle’s life and work.”

S. Vincent Rajkumar, MD

Professor, Medicine Division of Hematology Mayo Clinic Rochester, MN

“Dr Robert Kyle’s research has had a far-reaching effect on the understanding of dysproteinemia and multiple myeloma. Many of the breakthroughs that have come about in the last 60 years have stemmed from his efforts that combined clinical practice, data mining, and sheer effort. I consider him a mentor in my own career, and his seemingly boundless curiosity and energy have been an inspiration to the thousands of clinicians and researchers he has trained over the course of his career.”

DR KYLE’S SELECTED PAPERS

• Roeker LE, Larson DR, Kyle RA, et al. Risk of acute leukemia and myelodysplastic syndromes in patients with monoclonal gammopathy of undetermined significance (MGUS): a population-based study of 17 315 patients [published online February 5, 2013]. Leukemia. 2013;27(6):1391-1393.
• Kyle RA, Therneau TM, Dispenzieri A, et al. Immunoglobulin m monoclonal gammopathy of undetermined significance and smoldering Waldenström macroglobulinemia [published online March 13, 2013]. Clin Lymphoma Myeloma Leuk. 2013;13(2):184-186.
• Kyle RA, Benson JT, Larson DR, et al. Progression in smoldering Waldenström macroglobulinemia: long-term results [published online March 26, 2012]. Blood. 2012;119(19):4462-4466.
• Kyle RA, Durie BG, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management [published online April 22, 2010]. Leukemia. 2010;24(6):1121-1127.
• Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study [published online January 29, 2009]. Blood. 2009;113(22):5412-5417.
• Melton LJ 3rd, Kyle RA, Achenbach SJ, et al. Fracture risk with multiple myeloma: a population-based study [published online November 29, 2004]. J Bone Miner Res. 2005;20(3):487-493.
• Kyle RA. Sequence of testing for monoclonal gammopathies. Arch Pathol Lab Med. 1999;123(2):114-118.
• Kyle Ra, Gertz MA, Greipp PR, et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997;336(17):1202-1207.
• Kyle RA. ‘Benign’ monoclonal gammopathy: a misnomer? JAMA. 1984;251(14):1849-1854. Also translated and published in Italian and French JAMA editions.
• Kyle RA. Long-term survival in multiple myeloma. N Engl J Med. 1983;308(6):314-316.
• Kyle RA, Bayrd ED. The Monoclonal Gammopathies: Multiple Myeloma and Related Plasma-Cell Disorders. Springfield, IL: C.C. Thomas, 1976.
• Kyle RA, Herber L, Evatt BL, Heath CW Jr. Multiple myeloma: a community cluster. JAMA. 1970;213(8):1339-1341.