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.