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0:00 - Segment 00A: Interview Identifier

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Partial Transcript: "All right. So now we are recording, and I am Tacey Ann Rosolowski, and today is May 15, 2014, and the time is 9:47 a.m. I’m in the Reading Room of the Historical Resources Center on the twenty-first floor of Pickens Tower, the Research Medical Library, and I am interviewing Dr. Raymond Alexanian for the Making Cancer History Voices Oral History Project run by the Historical Resources Center at MD Anderson Cancer Center in Houston, Texas. Dr. Alexanian joined MD Anderson in 1964 as an assistant professor of medicine, and you were in the Department of Hematology at the time. Is that correct?"

Segment Synopsis: Interview session information

Keywords:

Subjects:

1:48 - Segment 01: An Early Interest in Medicine: Seeking a Well-Rounded Liberal Education

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Partial Transcript: "So why don’t we just start with some general background, and let me ask you when you were born and where, and where you grew up."

Segment Synopsis: Dr. Alexanian begins this segment with some comments about his family background and the family’s focus on education. Dr. Alexanian explains that he wanted to be a physician form the time he was a child, motivated by a childhood illness and exposure to doctors, and by his mother’s stories of his great uncle, who was a famous dental surgeon.

Keywords:

Subjects: 1. Segment Code – A: Educational Path 2. Story Codes – A: Personal Background A: Influences from People and Life Experiences A: Inspirations to Practice Science/Medicine

15:13 - Segment 02: College, Medical School, and a Brief History of Medical Education in the U.S.

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Partial Transcript: "Yeah. So tell me about the balance. So you created this liberal education for yourself. What were the classes that helped you develop your interests in the direction that they would go in, in terms of your research or your understanding of yourself as a doctor focused on patients?"

Segment Synopsis: Dr. Alexanian talks about his undergraduate experience at Dartmouth College. Dr. Alexanian explains that he wanted a broad, liberal arts program during college because he believed that the well-educated physician is a well-educated human being, sensitive to society and able to contribute to society beyond his medical sphere. He briefly talks about his classes and then explains the accelerated program at the Dartmouth Medical School (MD ’53). Dr. Alexanian also sketches the history of medical education and explains the impact of the Flexner Report in closing down a number of programs. He then compares the medical training at Dartmouth and at Harvard University and briefly discusses his internship at the University of Washington.

Keywords:

Subjects: 1. Segment Code – A: Educational Path 2. Story Codes – A: Personal Background A: Character, Values, Beliefs, Talents A: Inspirations to Practice Science/Medicine D: Understanding Cancer, the History of Science, Cancer Research

24:50 - Segment 03: Committed to Academic Medicine

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Partial Transcript: "I also spent two years in the army. In those days, there was a required draft of physicians, so that I was classified as an obligated volunteer, if you can see the kind of inconsistency there. (Rosolowski laughs.) That was the designation."

Segment Synopsis: Dr. Alexanian begins with a discussion of his military service (US Army, Captain, 1956−1958). He discusses his reason for specializing in anesthesia. He comments on serving as part of the occupying force in Japan.

Next, he sketches his path from a research fellowship (1960−1962) in Hematology at the University of Washington School of Medicine in Seattle, Washington to a second fellowship (1962−1963) in Radiobiology at the Christie Hospital and Holt Radium Institute in Manchester, England. He explains that his interest in cancer research emerged as he sought opportunities for positions in academic institutions. At the end of the segment, Dr. Alexanian talks about his comic book collection.

Keywords:

Subjects: 1. Segment Code – A: Professional Path 2. Story Codes– A: Military Experience A: Character, Values, Beliefs, Talents A: Inspirations to Practice Science/Medicine A: Personal Background A: Professional Path

37:03 - Segment 04: Early Research on Stem Cells and Erythropoietin

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Partial Transcript: "So can I ask, I’m sure many of these itineraries are similar to what—you’ve heard others like this?"

Segment Synopsis: Dr. Alexanian explains how he came to MD Anderson in 1964, then then talks about the evolution of his research, beginning with his experiences working on stem-cell kinetics while working with Dr. Laszlo Lajtha when he was on fellowship in Manchester, England. This focus enabled him to make the move to his second research fellowship in Seattle, where he worked with Dr. Clement Finch, a specialist in red cells, who taught him to focus on disease from a clinical perspective. Dr. Alexanian explains the skills he learned from these two mentors. He also notes that his experience enabled him to apply for grants for his own projects, and initiated work on erythropoietin. He describes his research and notes that he was the first person to measure normal levels of this hormone in human urine.

Keywords:

Subjects: 1. Segment Code – A: The Researcher 2. Story Codes – A: The Researcher A: Career and Accomplishments A: Definitions, Explanations, Translations A: Influences from People and Life Experiences A: Joining MD Anderson A: Professional Path C: Discovery and Success

49:41 - Segment 05: MD Anderson In The Mid-Sixties

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Partial Transcript: "So, coming to MD Anderson."

Segment Synopsis: In this segment, Dr. Alexanian provides a snapshot of MD Anderson when he arrived in 1964. He explains that Dr. Bergsagel wanted to combine clinical and basic research and the institution president, R. Lee Clark, MD, wanted to shorten the time between laboratory discoveries and delivery of treatment to patients. Dr. Alexanian lists the programs he inherited on arrival. He tells some history of the Department of Developmental Therapeutics and explains why he joined the Department of Leukemia.

Keywords:

Subjects: 1. Segment Code – B: MD Anderson Past 2. Story Codes – B: MD Anderson History B: Multi-disciplinary Approaches B: Research, Care, and Education in Transition C: Portraits

61:26 - Segment 06: Focusing on Myeloma and Perspectives on Myeloma Research and Treatment

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Partial Transcript: "So tell me about how your research evolved once you came here, because you obviously had expanded the array of research you had done."

Segment Synopsis: Dr. Alexanian discusses his work with erythropoeinin and its impact. He then talks about how myeloma emerged as a research focus. He explains the mindset he uses when he approaches patients as subjects of research. He then explains how competition for patients with blood diseases was controversial at MD Anderson: administrative decisions eventually distributed between departments and eased some of the tension (though this took about ten years).

Dr. Alexanian then traces the evolution of his research on myeloma, noting that clinical trials were conducted through the Southwest Oncology Group. In 1969, he was the first to combine melphalan and prednisone, which became the worldwide standard of care for many years. He describes how he worked with others to devise drug combinations.

Keywords:

Subjects: 1. Segment Code – A: The Researcher 2. Story Codes – A: The Researcher A: Definitions, Explanations, Translations A: Overview B: Controversy B: MD Anderson History C: Collaborations C: Discovery and Success C: Evolution of Career C: Professional Practice C: The Professional at Work D: The History of Health Care, Patient Care D: Understanding Cancer, the History of Science, Cancer Research

81:10 - Segment 07: Myeloma: Breakthroughs with Transplant Supported Chemotherapy

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Partial Transcript: "Anyway, but also that doctor—the major influence then, the next thing was when Dr. Barlogie joined me. Dr. Barlogie was a very important scientist who worked in Dr. Freireich’s department in the laboratory, but he was also interested in clinical matters and was a very inspiring person to work with, who thought of a number of imaginative things and felt that if we could exploit a—there was an Englishman named McElvain, M-c-E-l-v-a-i-n, who presented a paper that showed that if you gave Melphalan in very high dose, very high toxic dose, severely toxic doses, you could recontrol the myeloma in patients who would otherwise be dying of myeloma, but with a high mortality of about 25, 30 percent."

Segment Synopsis: Dr. Alexanian discusses the transplant supported program in myeloma. He sketches the history of the program and the rationale of the treatment: administering extremely high doses of melphalan and then “rescuing” the patient from toxicity with stem cell transplants, a procedure resulting in 25 – 30% complete remission lasting four years. He explains how willing patients were to participate in these studies and he describes his interactions with patients as he explained procedures.

Dr. Alexanian next talks about the challenges of obtaining insurance coverage for experimental therapies. He then goes on to note that this chemo-transplant procedure is still the standard of treatment for some patients. Dr. Alexanian then explains how Dr. Barlogie left MD Anderson.

Keywords:

Subjects: 1. Segment Code – A: The Researcher 2. Story Codes – A: The Researcher A: The Clinician B: Multi-disciplinary Approaches C: Collaborations C: Discovery and Success C: Patients C: Professional Practice C: The Professional at Work D: Fiscal Realities in Healthcare

95:06 - Segment 08: A Breakthrough Myeloma Treatment with Thalidomide

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Partial Transcript: "Anyway, but still we carried on here. It turns out that the double transplants were not any better than the single transplant. Then the notion was, well, how about giving a double transplant with the first transplant your own cells and the second transplant from a matched sibling donor, so you can get a graft versus tumor effect. There are all kinds of variations on that, and that didn’t turn out to be successful."

Segment Synopsis: In this segment, Dr. Alexanian talks about the treatments he innovated using thalidomide. He explains that thalidomide can inhibit angiogenesis, and Dr. Barlogie used it on dying patients with good results. Dr. Alexanian explains that he was looking at the next step: to use thalidomide in combination with Velcade and dexamethasone, supported by stem cell transplantation. He notes that over forty years of working with drug combinations, the treatment of myeloma at MD Anderson has gone from no remissions to remissions that last an average of six years. He also notes that he has been following patient for twenty years and there are some who have not relapsed in twelve years.

Keywords:

Subjects: 1. Segment Code – A: The Researcher 2. Story Codes– A: The Researcher A: The Clinician B: Critical Perspectives on MD Anderson B: MD Anderson and Government B: Multi-disciplinary Approaches C: Collaborations C: Discovery and Success

102:22 - Segment 09: The Challenge of Defining “Cure” in Oncology; Views of Research Approval Processes

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Partial Transcript: "So I say, well, someone’s got to come up with a definition of cure. What will it be? So I says, “I think I’ll do it. So let’s call ‘cure’ someone who has not relapsed after twelve years,” and that’s the definition. It may change."

Segment Synopsis: In this segment, Dr. Alexanian talks about the difficulty in defining “cure” when discussing cancer, and notes his own publication on the topic: Alexanian R, Delasalle K, Wang M, Thomas S, Weber D. Curability of multiple myeloma. Bone Marrow Res 2012:916479, 2012. e-Pub 5/2012. PMCID: PMC3366198.

[The recorder is paused for about 3 minutes.]

Dr. Alexanian talks about how MD Anderson’s research approval processes get in the way of research and addressing patient needs. He admits, “I’m a bit of a rebel.” He tells an anecdote about providing drugs to patients.

Keywords:

Subjects: 1. Segment Code – B: Overview 2. Story Codes – A: The Researcher A: The Clinician B: Critical Perspectives on MD Anderson D: The History of Health Care, Patient Care D: Understanding Cancer, the History of Science, Cancer Research

0:00

 ROSOLOWSKI:

All right. So now we are recording, and I am Tacey Ann Rosolowski, and today is May 15, 2014, and the time is 9:47 a.m. I'm in the Reading Room of the Historical Resources Center on the twenty-first floor of Pickens Tower, the Research Medical Library, and I am interviewing Dr. Raymond Alexanian for the Making Cancer History Voices Oral History Project run by the Historical Resources Center at MD Anderson Cancer Center in Houston, Texas. Dr. Alexanian joined MD Anderson in 1964 as an assistant professor of medicine, and you were in the Department of Hematology at the time. Is that correct?

ALEXANIAN:

That's correct.

ROSOLOWSKI:

Okay. And he served many roles during his time at MD Anderson, including deputy head of the Division of Cancer Medicine and deputy head of the Department of Hematology. And you retired in 2004, is that correct?

ALEXANIAN:

I believe that's correct, but then I have been part-time until last year.

ROSOLOWSKI:

Oh, okay. Wow. I didn't realize that. And you hold emeritus status now.

ALEXANIAN:

Yes.

ROSOLOWSKI:

Okay. I'm just taking a few notes on that. This is the first interview session together, and I already gave the time, so we are ready to roll. All right. Well, thank you so much for agreeing to participate in the project. I'm glad we could find the time.

ALEXANIAN:

Yes.

ROSOLOWSKI:

And let me just take down the time so I've got my notes all straight here. All right.

ROSOLOWSKI: +

So why don't we just start with some general background, and let me ask you when you were born and where, and where you grew up.

ALEXANIAN:

Yes. Well, I was born in Queens in New York in 1932.

ROSOLOWSKI:

What's your birth date?

ALEXANIAN:

June 8, 1932. My father was a grocer, and we moved to different—as a child I was moved with my family to different neighborhoods in Manhattan and the Bronx, and I was raised in the Bronx in a, you could say, lower-middle-class neighborhood and went to public high school, DeWitt Clinton High School, which was a large boys' high school. I was successful there so that I was also fairly active in high school, volunteering for many jobs, and I was also a member of the Honor Society and secretary of the Honor Society and then—

ROSOLOWSKI:

Was anyone else in your family interested in the sciences?

ALEXANIAN:

Yes. My mother's father, my grandfather, was a physician who was of Armenian extraction, born in Turkey, but was chosen to be among a small group of young men who were educated in the United States to some degree, so that he returned to Turkey as a specialist in obstetrics, and was drafted into the Turkish Army in the First World War and spared from the persecution of the Armenians because of his status as a surgeon, and managed to save his family from the genocide of Armenians by just fortuitous circumstances, so that my mother, who was then about thirteen, and her family were saved and then eventually immigrated to Philadelphia, where my grandfather was a physician and then—

ROSOLOWSKI:

That's an amazing story to have in your background.

ALEXANIAN:

Yes.

ROSOLOWSKI:

Was that inspiring for you, and did that influence your decision—

ALEXANIAN:

I think it did. Let's see. I think perhaps also at the age of three I developed polio and so had some handicap and was unable to be as physically active as my peers, but I was able to be somewhat active in terms of being swim team and other kind of non-running activities.

My mother was also very motivated toward education of her children as a way of moving up in our society, so that I was a good student and volunteer, and so found myself at Dartmouth College, which was a, I guess—

ROSOLOWSKI:

How did you end up going there?

ALEXANIAN:

A leap forward from a public high school in the Bronx, as you can imagine.

ROSOLOWSKI:

Yeah, no kidding. How did you make the decision to go there? How did that work out?

ALEXANIAN:

Well, in those days you applied to a mixture of colleges, as you do now, I assume, and I guess I had a good record and good recommendations.

ROSOLOWSKI:

Were there any teachers who helped you along the way or kind of mentored you?

ALEXANIAN:

Well, I think almost all. I had very good teachers, because in our Honor Society cadre at this large public high school we had some of the best teachers in the school, who were all New York bred and raised, so that we were encouraged to apply to the best colleges if possible.

ROSOLOWSKI:

Did they identify you as a person—I mean, did you have an intention when you went to college that you were going to become a physician? When did that interest start?

ALEXANIAN:

Yes. I think that interest started very early in high school.

ROSOLOWSKI:

Did it? Okay. Why?

ALEXANIAN:

Well, I had been exposed to my own personal illness that required regular doctor visits and physical therapy, and I guess my mother's motivation to emulate her father. I also had a great-uncle who was a somewhat famous dental surgeon. His name was Kazanjian, K-a-z-a-n-j-i-a-n, who was a First World War pioneer in reconstructive maxillofacial surgery and was given an award by the king of England—

ROSOLOWSKI:

Oh, wow.

ALEXANIAN:

—and other things at that time, because he was based at a British military facility and there all kinds of horrible face traumas that were sent to him for working out methods to make a new face. I'm not that familiar with his work, but there have been books written about his work and activity.

ROSOLOWSKI:

So those are two pretty amazing figures from your past, your grandfather and your great-uncle.

ALEXANIAN:

Yes. Right.

ROSOLOWSKI:

And your grandfather's name is?

ALEXANIAN:

His name was Bynderian, B-y-n-d-e-r-i-a-n.

ROSOLOWSKI:

And his first name?

ALEXANIAN:

Nishan, N-i-s-h-a-n.

ROSOLOWSKI:

Great. Thank you.

ALEXANIAN:

As you can recognize, they're Armenian names, because they end in i-a-n.

ROSOLOWSKI:

Yes. Do you have a strong sense of yourself as an Armenian American?

ALEXANIAN:

Not so much. Not as much as my parents. My mother and father were very—it was very important to them to have assimilation in American society, so that she contradicted my father's preference to study Armenian at the school and says, "Well, we don't have time for that. He has to learn his English and other things," and so on. So—

ROSOLOWSKI:

Yeah, it's interesting how different immigrant families sort of dealt with that whole issue differently.

ALEXANIAN:

Yeah. So I think a lot of that was inspiring and—

ROSOLOWSKI:

So you said when you went to college you had the intention of becoming a physician.

ALEXANIAN:

Yes

ROSOLOWSKI:

So tell me about your college experience.

ALEXANIAN:

Well, I think I had a full experience. A college like Dartmouth is a very absorbing place where everyone is part of an academic and social kind of environment which has all kinds of sports and social life and academics, in a small village in New Hampshire, as you may know. I don't know if you visited there. You're somewhat isolated, and in those days, there were all men, and so it was also a very important growth experience, which you might call—what do they call that when teenagers develop, go through an initiation into adulthood? I forget the term. So it was a very good experience.

ROSOLOWSKI:

What were the classes that you took that began to make you feel you were evolving into the person that you would become professionally?

ALEXANIAN:

Well, from the very beginning, I felt it was very important to have a broad liberal arts education, so I was very happy that there were requirements for English, social studies, language, history, in addition to the scientific requirements.

ROSOLOWSKI:

Why did you believe that?

ALEXANIAN:

I guess in high school I was imbued with the idea that the well-educated person should be educated in as many areas as possible as he's able to absorb, in terms of music, philosophy, literature, history, so that I sort of was motivated that way and throughout my life have continued to study and read. I read books and history and things like that. I feel I guess I was maybe somewhat old-fashioned, but that the well-educated physician is a well-educated person and sensitive to society and has to contribute to society in more ways than his medical work, that we live in an imperfect world that will always be imperfect, and that we should do whatever we can to improve it. So that has been sort of my creed. (laughs)

ROSOLOWSKI:

No, that's lovely. (laughs)

ALEXANIAN:

Well, it's kept me comfortable. My wife puts up with it and she helps me with it. (laughter) She volunteers with the homeless and all that, so it's something to do.

ROSOLOWSKI:

Yeah. Well, it's interesting, because, I mean, in the course of interviewing people, I discover, you know, sort of pockets of interesting—there are a number of physicians who create art, for example. They have different dimensions of their lives that round out the science, the science focus. Others are very uniformly focused on science or clinical work, so that there are different ways of constructing that way of being.

ALEXANIAN:

That's right. Sure.

ROSOLOWSKI:

Yeah. So tell me about the balance. So you created this liberal education for yourself. What were the classes that helped you develop your interests in the direction that they would go in, in terms of your research or your understanding of yourself as a doctor focused on patients?

ALEXANIAN:

Well, as I mentioned, even as I began high school, I intended to become a doctor or try to become a doctor, so that I followed the requirements to do that, which were in many ways interesting and challenging, but also part of my overall educational goals, so that many times the requirements were just secondary. I did not like all my science subjects.

ROSOLOWSKI:

What were your favorites?

ALEXANIAN:

Well, I think in college I liked comparative anatomy, where the anatomy of different creatures, birds, reptiles, snakes, and all that are evaluated. I found that challenging. I didn't like botany. I found that boring. And I think botany was probably required because of the ancient requirements to understand all the plants and chemicals that they were the only source of in the old days, that my faculty advisors felt were important but really not important. (laughs)

ROSOLOWSKI:

Mm-hmm, yeah, so it was kind of a holdover. (laughter) Interesting.

So tell me about going to medical school, when, how did you decide? So you ended up going to—you continued at Dartmouth for your MD.

ALEXANIAN:

Yes, at Dartmouth, Dartmouth had a two-year medical school in those days—

ROSOLOWSKI:

Oh, really?

ALEXANIAN:

—so that you could enter in your fourth year of undergraduate. So as a senior in college, it was combined with my first year in medical school. Now, we had had a small medical school class of twenty-four, twenty-four men, boys, and after two years, we were all required to transfer to a four-year medical school that would absorb us into their third year.

ROSOLOWSKI:

Why did they set it up that way?

ALEXANIAN:

In the history of medical education in this country, there was a more or less major change in medical school standards at the turn of the century, where several hundred medical schools were evaluated and many of them were considered to be well short of the standards required for medical school education, and so they—

ROSOLOWSKI:

Is this the Flexner Report?

ALEXANIAN:

The Flexner Report. So many of those were dropped from the roster of medical schools, but a small number, approximately six, were retained as two-year schools because they were usually in rural areas without access to a large clinical population, and their undergraduate students were well qualified for medical education. Since all my classmates were Dartmouth graduates, usually above-average graduates, they qualified as students almost anywhere in the country, so that for many years between maybe 19—I'm guessing now—1920 and 1955, that was a two-year medical school.

Then as the facilities expanded and patients—the problem was that there weren't sufficient numbers of patients with a broad range of disorders to fulfill the requirements for third- and fourth-year medical education. You had to have a lot of sick people—

ROSOLOWSKI:

Right.

ALEXANIAN:

—to show students.

ROSOLOWSKI:

Strange needs, but— (laughs)

ALEXANIAN:

There was a Veterans Hospital in a nearby town, but that was not sufficient.

ROSOLOWSKI:

So you ended up transferring to—

ALEXANIAN:

To Harvard.

ROSOLOWSKI:

And just for the record, you left Dartmouth in '53, and then in 1955, received your MD from Harvard Medical School.

Raymond Alexanian, PhD

Harvard, yes.

ROSOLOWSKI:

So was there a big difference between the two schools? Tell me about your training. What was your evaluation of your training through those programs?

ALEXANIAN:

Well, as you can imagine, the medical school training is kind of in stages for basic science and then clinical training so that, of course, the environment from a rural, small agricultural area in New Hampshire to a big city was a geographic change, but I don't think the scholastic demands were any different. I think the clinical rotations through multiple teaching hospitals required a different schedule. Harvard in those days—I'm not sure now—every day there was a morning lecture, and then in the morning and afternoons you had rotations through the different clinical facilities in the different specialties: pediatrics, surgery, medicines, so on and so on.

ROSOLOWSKI:

What did you gravitate toward during that time as a specialty?

ALEXANIAN:

At that time I had the notion, with my friends, that it was important to become a well-rounded physician, so I thought at that time that I would be the best possible general practitioner that could be attained. And within a few years, it was obvious that that was not logical, because as you—even through my internship, I felt that that was a good idea, because I—in those days you could elect a rotating internship, which would mean you rotated among the different specialties, you know, gynecology, obstetrics, surgery, medicine, so on, and that's what I did at the University of Washington in Seattle, the King County Hospital.

In those days, choices of internships were as random as they are now, I think, but you had a wider choice. You could have rotating internships or specialty internships. Most of them at that time were rotating internships because there was still the notion that primary care, rather than specialty care, was the dominant future for physicians. But shortly after I began my internship, I also wanted to do something constructive in medicine, so I then proceeded into a medical residency.

ALEXANIAN: +

I also spent two years in the army. In those days, there was a required draft of physicians, so that I was classified as an obligated volunteer, if you can see the kind of inconsistency there. (Rosolowski laughs.) That was the designation.

ROSOLOWSKI:

Really? An obligated volunteer. And this was 1956 to 1958.

ALEXANIAN:

Right.

ROSOLOWSKI:

Yes. And you were a captain.

ALEXANIAN:

Yes. It was important to do that because there were no residency programs that would accept you if there was a risk of being drafted—

ROSOLOWSKI:

Oh, how interesting.

ALEXANIAN:

—during the program.

ROSOLOWSKI:

Right.

ALEXANIAN:

So any of the selective residencies made it clear that, "You'd better get this behind you, or else we're not interested."

ROSOLOWSKI:

Did that military service develop any skills for you that were important later?

ALEXANIAN:

After I was drafted and sent to the what they call U.S. Army Physician Training Center at San Antonio, which I think still is active—all physicians went through a six-week program there—they made it clear that they were seeking volunteers in certain specialties which were in short supply in the army, and they were in short supply because there were military bases all over the world in the Cold War period, and there large numbers of dependents at many of these bases.

So the choices were in areas such as pediatrics, anesthesia, radiology, ear, nose, and throat, areas that were meant to provide coverage for dependents in a greater way than their normal draft could do. So I elected to have training in anesthesia for somewhat selfish reasons, because I felt it might be interesting and useful, but also I knew for certain that I would be based at a large hospital in a comfortable area, because there was a rumor that you might have potential assignments to Greenland, Alaska, or the Eniwetok Atoll and isolated places like that if you did not having something special. So, in a way, I was lucky so that I had anesthesia training at Fort Benning, Georgia, which was a large military facility, and was assigned to a hospital in Japan, which was my first trip abroad and opened up a whole new society of interest. Of course, it was approximately ten years after the war, so that there was not the society that we know of today.

ROSOLOWSKI:

Right. A very different attitude towards Americans, too, I imagine.

ALEXANIAN:

Well, actually, by then, the public was very receptive. As you probably know, General MacArthur had a very enlightened rule. He retained the Emperor and many of the customs as the old military hierarchy was disbanded. So it was a pleasant time. It wasn't very challenging, but it was a time I had to pass over.

ROSOLOWSKI:

So when you finished that, you came back and went to a clinical residency at the University of Washington in Seattle.

ALEXANIAN:

University of Washington, in medicine.

ROSOLOWSKI:

Yeah.

ALEXANIAN:

And I returned to the place I had my internship because I liked the atmosphere and was impressed with the training program, and I thought this would be a way to begin my career, and went through the normal rotations in internal medicine for two years and then elected a specialty in hematology for two more years.

ROSOLOWSKI:

And that was your research fellowship from '60 to '62.

ALEXANIAN:

Yes. I met my wife, which was certainly a very important event. (laughs)

ROSOLOWSKI:

And her name is?

ALEXANIAN:

Lois. We're still married; same lady.

ROSOLOWSKI:

Yeah, that's an achievement these days. (laughter)

ALEXANIAN:

Right. And have one daughter.

ROSOLOWSKI:

And her name is?

ALEXANIAN:

Is Jane, J-a-n-e, who has her own family, and whom we visit.

ROSOLOWSKI:

So tell me about your hematology residency, because that, of course, ended up being—

ALEXANIAN:

Well, the hematology residency was a clinical hematology program for the first two years and then a research program in the third year, and that was followed by another year of research in Manchester, England, with a research leader in the field where I did my first research and wrote my first papers. His name was Lajtha, L-a-j-t-h-a.

ROSOLOWSKI:

Yeah, Laszlo, the first name.

ALEXANIAN:

Yes.

ROSOLOWSKI:

You very kindly put all these names on your CV, so I have them down, which is great. (laughs)

ALEXANIAN:

Well, good.

ROSOLOWSKI:

And that was from 1962 to 1963, the Christie Hospital and Holt Radium Institute in Manchester, England.

ALEXANIAN:

Yes. He had been based at Oxford, and I thought when I applied for the program that I would be at Oxford, I thought that was really neat, and then after I was accepted in his program, he made it clear that he was moving to what was considered a better position for him in Manchester. And so therefore, I trailed along to Manchester.

ROSOLOWSKI:

So how did these residencies develop your interests in hematology? And, you know, because, of course, the question is coming, when did you become very interested in cancer.

ALEXANIAN:

A lot of that are byproducts of the opportunities for academic positions. When one is embarking on a hematology training program, you really don't know where you're going to end up, whether you're going to be in some group practice in hematology or you might get an appointment at some medical school or move on to another training or research program, so that the opportunities were not clear, and so you progressed from year to year hoping for the best, you might say.

ROSOLOWSKI:

Interesting. Now, am I correct in assuming that you were directing yourself more toward an academic career than private practice?

ALEXANIAN:

Yes. Well, it seemed that whatever exposure I had in my education in a way sort of appealed to me as a potential career, and I never knew what was going to happen. So in high school, I thought, "Well, it might be nice to be a teacher," and then in college I said, "Well, maybe I could learn to become a professor of something." Then in medical school I said, "Well, I'm going to become a doctor. I'll become a general practitioner somewhere and see what happens."

ROSOLOWSKI:

Yeah, you're a bring-it-on kind of guy. (laughs)

ALEXANIAN:

Bring it on. (laughs) Then as you go on and on, and you say, "Well, I like the people, so maybe I'll become a professor in a medical school," after you see all the—I said, "Well, how are you going to do that unless you make yourself known somehow?" So I said, "Well, maybe I'll do some research and maybe I'll find a way to do that." So from year to year, as you can imagine, I was always packing my suitcase going somewhere.

ROSOLOWSKI:

I'm starting to feel sorry for Lois. (laughs)

ALEXANIAN:

Well, and I'm sure you've interviewed others, so that between the ages of sixteen and thirty-two, I was packing my suitcase every year or two, going from one thing, place, to another. And I wasn't very good at packing, my wife will tell you. She said, "How did you manage to pack?" One of her favorite questions. And I said, "I don't know how to pack." So I always had many of my personal things stashed with my mother somewhere, wherever she was with my father, so I never regained my boyhood things until I settled into some place, like my stamp collection or my baseball cards or all this stuff.

ROSOLOWSKI:

Well, you kind of made up for it when you came to Houston, because you stayed here for—

ALEXANIAN:

Comic books.

ROSOLOWSKI:

Your comic books. (laughs)

ALEXANIAN:

You can't do without those.

ROSOLOWSKI:

Oh, you had a big collection of comic books?

ALEXANIAN:

Not big, but my mother was very fast to get rid of them.

ROSOLOWSKI:

What was your favorite comic, or did you have a bunch of them?

ALEXANIAN:

I had some of the first Batman and Superman comics.

ROSOLOWSKI:

Oh, my gosh.

ALEXANIAN:

I never knew that they were going to be useful or valuable. (laughter)

ROSOLOWSKI:

That's funny.

ALEXANIAN:

So can I ask, I'm sure many of these itineraries are similar to what—you've heard others like this?

ROSOLOWSKI:

You know, it's amazing, some people are incredibly focused, "I'm going to do this. This is what—."

ALEXANIAN:

Do this in one place.

ROSOLOWSKI:

And others are more, you know, open to opportunities and things that fall very organically. It's all about what opportunities and mentors come your way.

ALEXANIAN:

Right. That's right.

ROSOLOWSKI:

So the stories can be very, very different.

ALEXANIAN:

I'm sort of in the latter category.

ROSOLOWSKI:

Yeah. Well, it's very interesting. So tell me how did the cancer focus start. Tell me about that.

ALEXANIAN:

When I was in Manchester, it's obvious that I had no job after that, so my previous mentor, Dr. Finch, F-i-n-c-h, in Seattle said, "When you're finished in Manchester, you're welcome to come back here, and we'll get started on a program for you."

So that was my intention until Dr. Lajtha, my Manchester mentor, who was often a visiting lecturer throughout the world and had given a lecture and was invited at a program at MD Anderson Hospital in 1963, came back and said, "Ray, I've got a job for you."

I said, "What do you mean, Dr. Lajtha?"

He said, "Well, they're looking for somebody like you down at Houston."

I said, "Well, that's interesting, because I don't have a job unless I go back to Seattle." So I sent in my résumé, which was virtually nonexistent, just my school program, and I had a couple of papers in Manchester, but it was very—and so had an interview here in transit back to Seattle.

ROSOLOWSKI:

Who did you interview with?

ALEXANIAN:

In transit back, my wife and daughter went on to Seattle, and I detoured for an interview with Dr.—

[interruption]

ALEXANIAN:

So, Dr. Bergsagel, B-e-r-g-s-a-g-e-l, Bergsagel, I had an interview here, and that was followed by—let's see. That was in July of 196—

ROSOLOWSKI:

Let's see. It must have been 1963?

ALEXANIAN:

Sixty-three. Followed by a second interview in December of 1963 at a hematology meeting where I presented a paper and—

ROSOLOWSKI:

Now, when Dr. Lajtha said, "They're looking for somebody like you," what did he mean? I mean, what were you doing at the time?

ALEXANIAN:

I had finished the two years in hematology and was finishing—no, two years in hematology, one more year of research in Seattle and one more year with him.

ROSOLOWSKI:

What was the research that you were doing?

ALEXANIAN:

With Dr. Lajtha?

ROSOLOWSKI:

Mm-hmm.

ALEXANIAN:

Well, it's an area called stem cell kinetics. It has to do with the primordial cells in the bone marrow that lead to other cells, normal cells. What are the normal—is there some grandfather cell that accounts for all the different red cells, white cells, and platelets? It's called the stem cell, and it had to do with that primordial cell that he had an interest in and that if they could understand that cell, that might eventually lead to an understanding of leukemia and other diseases like that.

ROSOLOWSKI:

What did you find most intriguing about that research? Because you stuck with it.

ALEXANIAN:

Well, first of all, with Dr. Finch, who was also a research scientist of some renown in red-cell disorders, like anemias and conditions like that, had been a very good teacher in terms of approaching research problems related to red cells and how to understand anemias and the processes and causes and diagnoses and so on. All of these areas were in their different phases of evolution. So he was a very good person to teach his students how to approach these diseases from not only a clinical way but a research way.

Then with my time in Manchester, this was a similar process of where one can—I worked with hundreds of experimental mice, literally hundreds of mice, and where one could apply techniques of transfusion into mice, believe it or not, exposing them to low oxygen and injecting animals and radiating mice and work out answers to certain questions related to stem cells.

So with those two consecutive years added to the clinical hematology, I was prepared to work this out and also have the qualifications, with help from Dr. Finch, to apply for a research grant so that I would be developing my own projects, at first with his supervision and then with my own. And that's, as you can imagine, a fairly intense one-on-one, "What are you doing this week?" And, "Report to me what's the progress, and are you writing this up? Are you presenting this, or what are you doing?"

ROSOLOWSKI:

It's like really intense mentoring.

ALEXANIAN:

And then when you write something, he said, "Well, send me a draft of what you're writing." So I would write something, which I thought I was good at writing, but I was not really as good as he was, of course, and so he would edit everything I wrote in great detail. He was a terrific, superb editor of science-writing. He says, "Are you saying something that's clear here? That's not clear to me."

ROSOLOWSKI:

Is this Dr. Lajtha?

ALEXANIAN:

Dr. Finch first, and then Dr. Lajtha, the same thing, a double-barreled sequence. And he said, "Well, if you can't write clearly, then you can't think clearly." So I didn't quite agree with that, but still you can think up to a point but maybe expressing it is different, so I was drilled heavily for two years on this.

ROSOLOWSKI:

So with both problem solving and kind of basic knowledge and—yeah.

ALEXANIAN:

So I was in a good position to come here, and so I had my own research project here.

ROSOLOWSKI:

And what was that?

ALEXANIAN:

Well, at that time, I carried the program I had begun in Seattle. You see, there was another year in Seattle in '63, as I was—

ROSOLOWSKI:

So you began your own research project during that year?

ALEXANIAN:

During that year with Dr.—that dealt with the hormone called erythropoietin. It's sort of spelled out in the writing. And this substance is, as you know, widely used now for treating anemia and—

ROSOLOWSKI:

And what was the project? What were you working on with it?

ALEXANIAN:

Well, it's hard to believe, but I was the first one to detect or measure normal levels in human beings, which everyone knew that it was there, but no one could quantify it, so I was able to quantify it in human urine. So my project dealt with large twenty-four-hour collections of urine from patients and normal people, and we would take the urine and concentrate it into a tiny amount by essentially drying it up, dry up the urine by allowing the water to flow through a cellophane filter over a period of time, and you're left with a small amount, say a cupful, that represents a twenty-four-hour collection, or even less. And you can take those small amounts and inject it into mice and measure their erythropoietin. There's more to it than that, but that's essentially the process.

ROSOLOWSKI:

Now, what does erythropoietin do in the body?

ALEXANIAN:

As human beings become more anemic due to blood loss or due to disease, they build up a normal response with high levels of erythropoietin, which is a hormone, to make more red cells. It's a compensating feature for anemia, and it's also a compensating feature for people at high altitude, so as you get low in oxygen, it helps you adjust. It's part of a normal adaptation, I guess similar to many other hormones like insulin. When the sugar levels are high, we make more of our insulin to bring it down. And other hormones.

ROSOLOWSKI:

Interesting. So, coming to MD Anderson.

ALEXANIAN:

So I began with this project, but also began to see patients and—

ROSOLOWSKI:

So when you were hired here, what was your—

ALEXANIAN:

I had very limited experience, very limited in oncology. I had my two-year training in hematology, the fundamental two years, the first two years. So I did see some patients, a few patients, with leukemia or lymphoma or myeloma, very few, but I did see some. Dr. Finch was a teacher in all of these areas, and so I had some—and, of course, I had studied the textbooks and articles of these different diseases, but I had not seen a large number of patients.

ROSOLOWSKI:

So why did they bring you here? What was your [unclear]?

ALEXANIAN:

Well, the goal was to—at that time Dr. Bergsagel's ambition was to develop a department that combined basic with clinical research, so that in those days, Dr. Clark, who was the president, felt that it was important to shorten the time between the laboratory and the bedside. That was part of the philosophy of research in those days and still is now. So if one could shorten the time, one could help more patients.

But as soon as I arrived, Dr. Bergsagel, who was then going to be my mentor, my new mentor—you remember I've had a number of mentors along—

ROSOLOWSKI:

Yeah, very lucky too.

ALEXANIAN:

—said that he was moving to Toronto and that I'm more or less on my own. But I also had other colleagues here, Dr. Schullenberger, who was head of hematology then, Dr. Gamble, who was head of medicine then, but they had less focus on research than Dr. Bergsagel.

So Dr. Bergsagel invited me to join him in Toronto, and so I did go for an interview, and I and my wife said, "Hell, no, I'm not going up to Canada." (laughter) I just came from Seattle. We just had moved after a series of moves, and I was not ready. So here I am.

ROSOLOWSKI:

So here you are. Right. So that meant, wow, suddenly you're here at MD Anderson having research going without a mentor for the first time, really.

ALEXANIAN:

Without a mentor, but that was quickly partially resolved in different ways. First of all, as soon as I arrived, there was a Southwest Oncology Group that MD Anderson was part of with other academic centers in the Southwest, and I inherited Dr. Bergsagel's myeloma program that he had begun here. This is clinical trials in myeloma.

However, there were also programs in lymphoma and leukemia, and Dr. Clark very rapidly then hired other leaders in these fields, like Dr. Frei and Dr. Freireich, who began their own department, who had a major influence on my research, because even though I was not physically in their department, they were major mentors in the area of clinical trials and studying disease and so on.

ROSOLOWSKI:

And just for the record, the department that Dr. Frei and Freireich were part of was Developmental Therapeutics.

ALEXANIAN:

Developmental Therapeutics. And since I was hired in hematology, I chose to stay in hematology since I felt it improper to change departments so soon after I had—

ROSOLOWSKI:

But you considered it?

ALEXANIAN:

No, I didn't.

ROSOLOWSKI:

Oh, you didn't consider it. Okay.

ALEXANIAN:

I was invited to, and I made it clear that it was just too fast, too quick for me, and I'd just as soon learn from Dr. Frei and Freireich, who were very helpful and constructive, teaching me a lot. I went to all of their conferences and so on. So I had a new set of mentors, you might say.

ROSOLOWSKI:

We have just a few minutes remaining today because I know you have something else to do after this.

ALEXANIAN:

[unclear].

ROSOLOWSKI:

Yes, we have. It's almost quarter of.

ALEXANIAN:

Well, I can do eleven—until twelve.

ROSOLOWSKI:

Oh, you can?

ALEXANIAN:

You want to keep going?

ROSOLOWSKI:

Oh, great. Sure. That would be fine.

ALEXANIAN:

Let's keep going.

ROSOLOWSKI:

Okay. Terrific.

ALEXANIAN:

Because the more we can do today, the better.

ROSOLOWSKI:

Yeah, that's great.

ALEXANIAN:

Are you tired yet?

ROSOLOWSKI:

No, I'm good. (laughter) I just didn't want to make you late if you had something you had to do.

ALEXANIAN:

Am I covering the kind of ground you're looking for?

ROSOLOWSKI:

Mm-hmm, yeah, and I'll certainly ask a question to direct focus if we need to do that. O

One thing I wanted to ask you about is kind of your impressions of MD Anderson at the time when you arrived. I mean, it's a very different institution than it was by the time you left.

ALEXANIAN:

Yes. Well, by then, as you can imagine, I had already been at so many institutions, both in my education, including army hospitals and centers in England, because even in my training, it was customary in those days of more difficult travel that if you're going on a trip, by the way, stop off at this center and give a little talk or see what they're doing. So there was a kind of a custom to visit different centers in transit.

So, going to England back, I must have visited ten different centers in transit to give talks and learn from them in different areas like Salt Lake City and Brookhaven and places at Cambridge and Paris, different places all over, who wee doing research similar to my area of study, so that I would present my data and they would critique it, which is good, and say, "Maybe you could do this better this way," or that way, and they would tell me their project. As a younger person, I wasn't as competent as they were in helping me as suggesting to them. So it was a very good experience. I don't know, I don't think that's done anymore in that way. It was more of a family of people in your field whom you engaged with.

So where were we?

ROSOLOWSKI:

You were contrasting—

ALEXANIAN:

Oh, my impressions of MD Anderson.

ROSOLOWSKI:

Yeah, mm-hmm.

ALEXANIAN:

Well, first of all, I was kind of happy that I had a job that I could say was my permanent job at least for a period and that I had a direction and project. I had my erythropoietin project and also clinical trials projects and myeloma or any other related cancers that would be of interest, and I was part of a team that was focusing on these different areas related to cancer so that there was more of a cancer-focus orientation.

It was apparent very early that MD Anderson was a leading center for cancer research. There were only three at the time: there was Sloan-Kettering, MD Anderson, and Roswell Park. So I was at one of the three leading cancer centers. At this center, there was also a clear desire to develop in the field, to expand and move up, to build more, become bigger, more people, and so on, so that I was part of an ambitious program.

Dr. Clark was a very, in a way, inspiring type of person. Even though he was a surgeon, he had kind of grand view of the future that was interesting. Of course, many of the people you hear in my training, college presidents and medical school deans, they all have a grand view for their own future, and so he was in that vogue of future. So it was different from what I had been exposed to before because it was cancer-focused and it was an institution-focused.

ROSOLOWSKI:

So tell me about how your research evolved once you came here, because you obviously had expanded the array of research you had done.

ALEXANIAN:

I felt I was successful in my erythropoietin program for a number of years. I can't remember when my last paper in that field was written. It probably ran for maybe eight or ten years, something like that. And then as—

ROSOLOWSKI:

Can I ask you, what was the significance of that research vis-à-vis cancer?

ALEXANIAN:

Well, at the time, patients with hematologic cancers usually had developed anemia, and anemia was due to bone marrow failure, usually, or infiltration of some sort. So there was the idea that maybe one could learn to help the anemia in some way. And as it turned out, some of my research both in Seattle and here was incorporated into the later development of commercially produced erythropoietin by Amgen Company, and they were based in Seattle [unclear], because that was an anemia red-cell center. As I say, Dr Finch was interested in that. So that evolved. I think that's the connection. There could have been another reason why they're based in Seattle.

So they developed commercial erythropoietin for treating patients with anemia, at first with kidney failure, where they cannot make erythropoietin, so they have an inability to make any erythropoietin. Then it was applied to other causes of anemia, including cancer-related anemia. There was not a direct, thoughtful plan in that on my part. It just happened to evolve that way, and I was kind of pleased to see that some of my earlier work sort of contributed to this later therapeutic process.

So by then, though, after a number of years, it was evident that myeloma as a clinical problem was becoming more important to me, and there were many more patients, and it was evident that with the resources available with the number of patients and the variety and the clinical trials, that there was a major potential for research and understanding what the disease was and how it developed and what could be done to control it and whether one could reach a point where one could cure it eventually.

ROSOLOWSKI:

Now, when I was doing some background work on this, it seemed as though myeloma was actually a pretty—I mean, there wasn't a huge incidence of it. Is that correct?

ALEXANIAN:

That's correct. However, it's all in proportion. Compared to the three common diseases, leukemia, lymphoma, myeloma, each of these, leukemia has a dozen varieties or more, maybe, lymphoma the same dozen varieties, myeloma has just myeloma. There are attempts to break down varieties. And the number of patients in the country with myeloma who are diagnosed are more common than, say, from Hodgkin's Disease, which is a common lymphoma, but only one of a variety of lymphomas, and it's more common than the most common acute leukemia, but there are a whole bunch of varieties. So leukemia has a variety of diseases. So—

ROSOLOWSKI:

I guess the reason I said that was because it sounds as though MD Anderson, since it saw so many patients, gave you an opportunity to see more cases of this relatively rare condition.

ALEXANIAN:

More cases, but it's not about the cases. You want to—I look on each patient as not only a project to do the best for that patient, but to learn the most from that patient for future patients. So every patient is—I don't want to use the word "experiment." Maybe that's something I should seal for fifteen years. (laughs) Each patient is a model, is a sample of what dozens of future patients will become with time, who have not been diagnosed yet, but will develop. You and I could develop. So it was important to document each patient as best as possible, the nature of his disease, how he fits into the spectrum of myeloma, what features he had that were different from others, how one could control it, which drugs, which combinations, and so on and so on and so on, so that every patient became a research subject. Every patient I saw was a research subject.

ROSOLOWSKI:

Why did myeloma become so important rather than you focusing on lymphoma or [unclear] leukemia?

ALEXANIAN:

Well, as this center evolved, as you heard, when Dr. Frei and Dr. Freireich came, the division of patients was a controversial area. I'm sure others have spoken to this. And there was a de facto scheme that evolved with time over a period of several years that leukemias would be primarily with developmental therapeutics. Myeloma would be with Dr. Alexanian. Since it was an uncommon disease, let him take care of it. And lymphomas became kind of a battleground, you might say. As time developed, I don't think the lymphoma issue was ever finally settled. The leukemias and myeloma were settled, and lymphoma's remained a battleground for many years, in part—well, I'm not sure of some of this, but my understanding was in part because the radiation therapy was an important part of the lymphoma treatment and radiation therapy such as with Dr. Fuller—have you interviewed her?

ROSOLOWSKI:

No.

ALEXANIAN:

She would be interesting to interview.

ROSOLOWSKI:

Her first name?

ALEXANIAN:

Lillian Fuller. She's getting older, but I think she's clear. Sort of sided with hematology on that issue. I tried to stay out of this battle. It was sometimes acrimonious and—

ROSOLOWSKI:

I get the picture of some pretty intense personalities at the time.

ALEXANIAN:

Yeah, intense personalities, but, you know, the referral pattern automatically, in a way, neutralized some of the tension, because when patients are referred to an individual doctor or a group, that is the pathway that patient would follow. So the control of the referral pattern was there was no specific control. Dr. Clark made it clear that the referral pattern was a referral pattern, that if a doctor outside wanted to send a patient to a doctor here, there's nothing anyone's going to do to change that. So after a number of years, this conflict became more settled. Maybe it took ten years, though.

ROSOLOWSKI:

Wow. ALEXANIAN:

I think I'd be interested in hearing what Dr. Freireich says to this, because he was a major factor in this tension.

ROSOLOWSKI:

Interesting. Wow. Well, I kind of derailed you on this from talking about the progress of your research on myeloma, so let's [unclear].

ALEXANIAN:

Well, when I first came here for an interview, there was no effective treatment for myeloma. None. Dr. Bergsagel was one of the very first to discover a drug that was effective in controlling myeloma. In 1962, he wrote his paper. So at that time, there was only one effective drug, and there were clinical trials in the Southwest Oncology Group with that drug that led to this discovery.

Then when Dr. Frei influenced me as my mentor in clinical trials, along with Dr. Bergsagel, there was the effort to evaluate combinations of drugs. So combinations of drugs were developed for treating leukemia, lymphoma, myeloma, and so combinations of drugs were developed for myeloma that were better than the single drug. Then as the years elapsed, other techniques such as high-dose therapy supported by bone marrow transplant, were developed—that's some years later—as another modality.

ROSOLOWSKI:

Now, is the first kind of big landmark—because I have 1969 as the date when you were able to show that Melphalan with Prednisone—

ALEXANIAN:

Melphalan with Prednisone. Yes, that was an important study that showed that, the first combination, and that was then the worldwide standard of care for many years, and you can say that was my first major discovery, but that was developed by a number of many people in the Southwest Group with Dr. Frei and Dr. Bergsagel's influence.

ROSOLOWSKI:

So what was the reasoning to combine those particular drugs? What's the logic of trying the combinations?

ALEXANIAN:

You know, it's very empiric. Dr. Frei, when I met with him, says, "Ray, what drugs are useful in myeloma? What might be useful?"

And I said, "Well, we have Melphalan."

"Okay. Well, what else is there? Is there anything out there?"

So I said, "Well, we use Prednisone to treat high blood calcium in myeloma, and when we give Prednisone, it makes people feel better when they're taking it, and it seems to alleviate nausea sometimes, but I don't know if it will kill myeloma."

So he said, "What else?"

I said, "Well, the bones are soft in myeloma, and there's some people that think that fluoride," fluoride like for your teeth, fluoride, "might help myeloma, help with the bones."

"Okay. Let's put that down. Fluoride. What else?"

I said, "Well, in patients with anemia, I'm giving a male hormone to boost up erythropoietin levels to help with anemia in some patients." And at that time, male hormone injections were a common treatment for anemia. And I worked out that it was through erythropoietin, the improvement, but that's a different story, but still.

So he said, "Let's put that on the list. Anything else?"

So I said, "Well, that's all I can think of. Maybe something will come to me."

So he said, "Well, let's put together a cocktail and let's give it some people." You know, in those days, research protocols did not have to go through the scrutiny they do now. I'm sure we couldn't have done any of these trials with our current standards requirements.

ROSOLOWSKI:

Right.

ALEXANIAN:

So we put this combination together and brought it to the Southwest Group as a proposal. At that time, MD Anderson registered maybe half the patients with myeloma. The other half came from all the others together, so we could double the pace of it. And we found that the combination of the four drugs worked better in inducing remissions and building up the hemoglobin and maybe helping the bones and so on.

Then as time went on, it became evident, well, maybe we don't need the fluoride and the male hormone. Maybe we just do the Prednisone and so on. That's why we focused on that. Then with the Prednisone, as you can imagine, there are side effects from a drug like that. If you take it daily for a long period, you get bloated and irritable and so on. So I worked it out so that the Prednisone would only be given for a short burst in high dose with the Melphalan, so that the side effects would be markedly reduced, although for a few days you might have insomnia that you could also neutralize with some, in those days, barbiturate. Now there are other sedatives now.

So a lot of this was trial and error and working out the details, and then from then there were long gaps in our progress, but then every so often new drugs and new programs—and the two main programs would be the transplant-supported program, which we began here with Dr.—get my bibliography. (laughter)

ROSOLOWSKI:

I don't know if I have a complete one. This is the advantage of being able to go back and correct.

ALEXANIAN:

[unclear].

ROSOLOWSKI:

No, no, it's quite all right. Also, as you'll notice, I'm taking a lot of notes, and I can send you the notes and you'll probably be able to supply the name at a later date.

ALEXANIAN:

These only have the recent papers.

ROSOLOWSKI:

That's okay. We can fill it in later. Not to worry.

ALEXANIAN:

Anyway, but also that doctor—the major influence then, the next thing was when Dr. Barlogie joined me. Dr. Barlogie was a very important scientist who worked in Dr. Freireich's department in the laboratory, but he was also interested in clinical matters and was a very inspiring person to work with, who thought of a number of imaginative things and felt that if we could exploit a—there was an Englishman named McElvain, M-c-E-l-v-a-i-n, who presented a paper that showed that if you gave Melphalan in very high dose, very high toxic dose, severely toxic doses, you could recontrol the myeloma in patients who would otherwise be dying of myeloma, but with a high mortality of about 25, 30 percent.

So Dr. Barlogie said, "There's something there that we need to look into."

And I said, "Great."

So he said, "Why don't we just see if we can use the high doses and rescue the patient with a transplant so they would survive the procedure." So he then persuaded our transplant service. The gentleman's name I'm thinking is from Holland. Why can't I think of his name?

So we decided, "Okay, let's find some patients who would otherwise be dead in a few months, and let's do the same procedure on them."

So I said, "Well, you can't do it on them, because their marrow is filled with tumor, and how are you going to get your stem cells?" Remember stem cells, that's my old field. (laughs)

ROSOLOWSKI:

Mm-hmm.

ALEXANIAN:

"How are you going to get your stem cells?" So I said, "Well, maybe there are enough in there that we can use, or maybe we can work out a way of purifying it or something like that."

Well, to make a long story short, there were enough even in patients—enough stem cells.

ROSOLOWSKI:

Oh, really?

ALEXANIAN:

But at the time you drew the marrow, then there weren't enough in everybody. In other words, you couldn't tell who had enough stem cells to save them and who didn't. So we could collect the marrow, calculate if we had enough, give them the high-dose therapy, give them their marrow back, and hope for the best.

ROSOLOWSKI:

My god.

ALEXANIAN:

They're otherwise dying, though, so they sign consents.

ROSOLOWSKI:

Sure.

ALEXANIAN:

So it turned out that more than 90 percent had enough stem cells, but in the early phases, we did lose a small number because what we thought were sufficient were not, and it turned out to be effective in half of the 90, half of those. In other words, we were able to do what McElvain had done without the transplant with the transplant and pull 90 percent of them through it successfully.

So then it was apparent pretty early on that even though it worked, it only worked for a few months, six months. So I said, "Well, this doesn't make sense. We've got to do this earlier in the disease, before they relapse." So then we said we have to take patients who are in remission, who are healthy and not relapsing, and who could be healthy for five years, and then take their stem cells, hope we had enough, and hit them hard then. Of course, no one had done these things before. (laughs)

ROSOLOWSKI:

Right, right.

ALEXANIAN:

So then we started to do that, and it turned out that we began to see instead of what we call partial remissions, which is where you have remission but you still have residual disease left, from the tests that we do, we began to see a higher number of so-called complete remissions, there was no sign of disease, that we rarely ever saw with just Melphalan and Prednisone. Melphalan and Prednisone may have a 5 percent complete remission rate, but with the transplant-supportive therapy, it had become 25 percent or 30 percent. So I said, "Something's happening here, and maybe that'll last longer." Well, it does last. Complete remissions do last a lot longer, but then there was, again, recurrence.

ROSOLOWSKI:

How long did those remissions last?

ALEXANIAN:

Partial remissions lasted, on the average, two years, and complete remissions lasted, on the average, four years.

ROSOLOWSKI:

Now, let me ask a question. Here you have a patient who's in remission, they've gone through, you know, a very arduous treatment process. Was it difficult to convince patients to undertake another trial, to go through this kind of thing again?

Raymond Alexanian, PhD

Well, one of the things about a center like this, which, even before the patient comes here, has a big, strong reputation, and when they've come to see a specialist in that center such as myself, who has probably a lot more experience than their oncologist does in this disease, and I explain to them that, "This is where we are in our knowledge of your disease and that your likelihood of relapse is such-and-such after so many years, based on previous natural history." As I mentioned, every patient I see is a study, so I'm collecting all of this, hundreds and hundreds of patients in my database, that I can tell them with some accuracy, "This is what's going to happen if we don't do this with certain ranges, you know. And we're developing this new program, which involves this, this, and so on, and I can tell you, sir, that if it were me or my family, I would do it, because we have maybe done it ten and you may be the eleventh, and so far it's working out and they're getting through it. It's not easy, and you don't have to do this if you don't want to, but I think it's worth it. Plus it's going to cost you a lot," because insurance had not approved these procedures, "but we can cover some of it at a center like ours." It's curious, we can cover the indigents, but we can't cover those with money. You know that.

ROSOLOWSKI:

Mm-hmm, mm-hmm.

ALEXANIAN:

So the indigents who come here get more—in those times, got more expert professional attention than those with resources, because they couldn't afford it, which is a sort of, I guess, kind of an irony, you might say. However, very quickly on, we lobbied hard to get Medicare approval, and then once they got Medicare approval, we got insurance approval, and this took a couple of years.

ROSOLOWSKI:

What years are we talking about here for this process?

ALEXANIAN:

Oh, gosh, I'd have to look at my—can I see this?

ROSOLOWSKI:

Yeah, sure. Let's see. I didn't have a date for those bone marrow transplants. I hadn't done a complete review of your—

ALEXANIAN:

I would say in the 1980s, somewhere in there. And Dr. Barlogie was very instrumental in working this out too.

ROSOLOWSKI:

Oh, really.

ALEXANIAN:

So then it's become the standard of treatment now so that—

ROSOLOWSKI:

And it's still the standard treatment?

ALEXANIAN:

Standard treatment.

ROSOLOWSKI:

Wow.

ALEXANIAN:

However, only about 80 percent of patients qualify for it. There are certain physical health requirements. You can't have severe heart disease or emphysema, and the transplant service likes to have people who are fit-looking. By that they mean if they can at least walk to the bathroom. And there are some patients who come from abroad who are unable to stay or you have to be physically here. So about 20 percent who might qualify don't receive that for various reasons, but almost all of them do, 80 percent.

Then there were more complexities. [unclear] says, "Well, if one transplant is good, maybe two transplants are better." And that's what Dr. Barlogie developed when he moved to Arkansas. So the people who I work with always move on somewhere else, right?

ROSOLOWSKI:

Why did Dr. Barlogie leave?

ALEXANIAN:

He wanted to set up a Myeloma Center, which—I think he could have stayed here, and I begged him to stay and try to do it here, but I don't know the full—are you going to interview him some day?

ROSOLOWSKI:

I don't know. I haven't heard his name before, so I don't know.

ALEXANIAN:

Well, the University of Arkansas were willing to commit huge resources, a whole building, staff, money, multimillions, to develop a Myeloma Center in Arkansas. So it is called the Myeloma Cancer Center, and you could look up his résumé. It's very impressive.

ROSOLOWSKI:

Interesting.

ALEXANIAN:

And it turns out that his Center was so successful that he had some conflict with his Division of Medicine head, who wanted some of the money drained to his services that were coming into the Myeloma Center.

ROSOLOWSKI:

Very interesting.

ALEXANIAN:

So that's the reason he moved.

ALEXANIAN: +

So anyway, but still we carried on here. It turns out that the double transplants were not any better than the single transplant. Then the notion was, well, how about giving a double transplant with the first transplant your own cells and the second transplant from a matched sibling donor, so you can get a graft versus tumor effect. There are all kinds of variations on that, and that didn't turn out to be successful.

The next big breakthrough came with the two drugs, the Thalidomide group of drugs and the Velcade or Bortezomib group. Now, you should probably read a little bit on how Thalidomide became discovered. Have you heard of that?

ROSOLOWSKI:

Tell the story for the record. (laughs)

ALEXANIAN:

Dr. Barlogie had a patient who was otherwise dying and wanted to offer a new drug to try something on him, so he asked a specialist in—let's see. What is the research area? And I can't remember his name either. Oh, my memory. Anyway, a specialist at Harvard who was doing work related to small-capillary development around tumors, and he found that Thalidomide, which is a drug that caused birth defects, could inhibit the development of this vascular network, and why don't you give it a try? Of course, Thalidomide had become an orphan drug, but it was still available through sources in Europe and other places, and it was available because it was effective in treating a group of patients with HIV who got various skin ulcers, and I cannot recall the details of that, but it was an effective drug in healing.

So Dr. Barlogie gave a patient Thalidomide. It didn't work in the first one, and he gave it to a next one. One of these first two patients had—there was an article in New York Times about the evolution. I should bring that clipping to you, because it was such an interesting journalistic story. The wife of the patient begged him to try anything on her husband, and so he found the Thalidomide and gave it, and I don't know if it was to her husband or the next patient, it was effective in controlling the myeloma—

ROSOLOWSKI:

Wow.

ALEXANIAN:

—just out of the blue. And a whole new development of Thalidomide and analogs of Thalidomide developed, and there were very rigorous controls in terms of avoiding pregnancy and so on. So the Celgene company, that was virtually nonexistent and operating out of a closet, you might say, sort of had manufactured this for the HIV patients and became a huge profit-making company because of this single drug and other drugs to follow and then—

ROSOLOWSKI:

So were there difficulties with dosage? I mean, how—were you involved in this as well?

ALEXANIAN:

So once it was effective, I said, "Well, what do we do next?" We put it in combinations, right?

ROSOLOWSKI:

Yeah, yeah. Right. Mm-hmm.

ALEXANIAN:

So, therefore, we were first to do a combination of—I forget the first combination, Thalidomide with Dexamethasone, and somewhere in here Dr. Weber has a paper on that.

Then the next drug that came was Valcade that Dr. Orlowski was instrumental, who is now head of myeloma, developed when he was at North Carolina, and this drug was also, as it was being evaluated in Phase 1 trials in cancer, different cancers, found to be effective in myeloma, one patient or two patients, and says, "Oop, we got another one." So, the next round of combinations.

So the current standard of care is a combination of Velcade first with Thalidomide and Dexamethasone, and then with its analog, R_____ and Dexamethasone, followed by transplant. So that over a period of forty years we have evolved from no remissions and an average survival of a year and a half in myeloma to a combination of drugs that can control and transplant that induces remission in 95 percent of patients, of whom 40 percent are complete remissions and where the average survival is six years, median survival, with about 3 percent probably being cured. I have a paper on curability in here, the last paper—

ROSOLOWSKI:

Mm-hmm. That's the most recent one.

ALEXANIAN:

—where we followed patients for up to twenty years. This is from the old file, carried on, that about 3 percent of patients have not relapsed. They're in complete remission beyond twelve years. In other words, between twelve and twenty years, still in complete remission.

ALEXANIAN: +

So I say, well, someone's got to come up with a definition of cure. What will it be? So I says, "I think I'll do it. So let's call 'cure' someone who has not relapsed after twelve years," and that's the definition. It may change.

ROSOLOWSKI:

Interesting. Yeah, I mean, I hadn't really thought about that question, but it is a question. How do you know when you cure somebody?

ALEXANIAN:

How do you know when you're cured of any disease?

ROSOLOWSKI:

Yeah, yeah.

ALEXANIAN:

And I think, now, you can quibble. What do you call somebody who's in, like, complete remission for twelve years and dies of something else? Is he cured? How about if he's in complete remission for five years and dies of something else? Okay. So you can get into little word games and semantics. So I say if you've gone in complete remission twelve years and die of something else, then you're cured, because no one else has died of myeloma after twelve years. But at five years, the prospect of dying from myeloma is higher because you haven't reached that milestone.

ROSOLOWSKI:

That milestone, yeah.

ALEXANIAN:

And I think the same thought processes have gone for leukemia and lymphoma and other conditions.

ROSOLOWSKI:

Right.

ALEXANIAN:

I'm going to stretch for a minute.

ROSOLOWSKI:

Sure.

ALEXANIAN:

How are we doing?

ROSOLOWSKI:

We're doing fine. I'll pause the recorder. It is exactly 11:30.

[recorder is paused] (end of first audio file)

ALEXANIAN:

—is that there's no design. You've got to get away from that, and I think you've seen that with others.

ROSOLOWSKI:

Yeah, yeah.

ALEXANIAN:

All of this is just by chance, and the individuals have to have a certain minimum of ambition for their own careers and also kind of commitment to humanity to some extent—to a big extent, I think. You can't just say, "I'll do it and maybe it'll help somebody." You have to have some commitment to humanity.

ROSOLOWSKI:

Well, just the way that you've told the stories, you know, that the patient need drives—

ALEXANIAN:

It drives, right.

ROSOLOWSKI:

—drives what the researcher's is doing.

ALEXANIAN:

There are many circumstances I faced where there's a—and this is what troubles me even now. There are effective programs that could be applied to a difficult patient, but, "Well, we don't have the approvals, we don't the protocols, we don't have the drugs. We can get all these if you wanted to work on it right now."

And I say, "Look. This man's in the room here," or woman. "We've got to deal with this now. We can't wait for a year." So I'm a little bit of a rebel in the sense that I will bypass, deliberately bypass requirements I think I can get away with if I'm going to help a patient, that if I can get a drug somewhere, somehow, and I have this drug, "Sir, I'm putting this on the table here."

And the nurse said, "Look. You haven't heard anything here."

"I'm leaving the room. If you want to steal this, I don't know anything about it. But take it in this way. Watch for this side effect."

So that's why I've broken a lot of rules here. Do you like to hear that? I mean, you can—

ROSOLOWSKI:

Yeah.

ALEXANIAN:

You can put it in now and you don't have to save it for fifteen years.

ROSOLOWSKI:

You can decide. You can decide.

ALEXANIAN:

No, no.

ROSOLOWSKI:

You want to stretch your legs a little bit or do you—

ALEXANIAN:

I tell you what. I think I'd better go, because I have to get some copies done. Do you know how to make copies here of anything in the library? I have an office, a secretary who can do it.

ROSOLOWSKI:

I'll turn off the recorder. So we're finishing up with our interview session now, and the time is 11:36. Thank you, Dr. Alexanian.

ALEXANIAN:

Yes, thank you. 21