Chapter 06: Focusing on Myeloma and Perspectives on Myeloma Research and Treatment
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Description
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.
Identifier
Alexanian_R_20140415_S06
Publication Date
4-15-2014
Publisher
The Making Cancer History® Voices Oral History Collection, The University of Texas MD Anderson Cancer Center
City
Houston, Texas
Interview Session
Topics Covered
The Interview Subject's Story - The Researcher; The Researcher; Discovery and Success; Evolution of Career; Controversy; MD Anderson History; Professional Practice; The Professional at Work; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; Collaborations; Overview; Definitions, Explanations, Translations
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Disciplines
History of Science, Technology, and Medicine | Oncology | Oral History
Transcript
Tacey A. Rosolowski, Ph.D:
So tell me about how your research evolved once you came here, because you obviously had expanded the array of research you had done.
Raymond Alexanian, MD:
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"”
Tacey A. Rosolowski, Ph.D:
Can I ask you, what was the significance of that research vis-Ã -vis cancer?
Raymond Alexanian, MD:
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.
Tacey A. Rosolowski, Ph.D:
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?
Raymond Alexanian, MD:
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"”
Tacey A. Rosolowski, Ph.D:
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.
Raymond Alexanian, MD:
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.
Tacey A. Rosolowski, Ph.D:
Why did myeloma become so important rather than you focusing on lymphoma or [unclear] leukemia?
Raymond Alexanian, MD:
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?
Tacey A. Rosolowski, Ph.D:
No.
Raymond Alexanian, MD:
She would be interesting to interview.
Tacey A. Rosolowski, Ph.D:
Her first name?
Raymond Alexanian, MD:
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"”
Tacey A. Rosolowski, Ph.D:
I get the picture of some pretty intense personalities at the time.
Raymond Alexanian, MD:
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.
Tacey A. Rosolowski, Ph.D:
Wow.
Raymond Alexanian, MD:
I think I'd be interested in hearing what Dr. Freireich says to this, because he was a major factor in this tension.
Tacey A. Rosolowski, Ph.D:
Interesting. Wow. Well, I kind of derailed you on this from talking about the progress of your research on myeloma, so let's [unclear]. CLIP Research Innovations
Raymond Alexanian, MD:
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.
Tacey A. Rosolowski, Ph.D:
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"”
Raymond Alexanian, MD:
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.
Tacey A. Rosolowski, Ph.D:
So what was the reasoning to combine those particular drugs? What's the logic of trying the combinations?
Raymond Alexanian, MD:
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.
Tacey A. Rosolowski, Ph.D:
Right.
Raymond Alexanian, MD:
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)
Tacey A. Rosolowski, Ph.D:
I don't know if I have a complete one. This is the advantage of being able to go back and correct.
Raymond Alexanian, MD:
[unclear].
Tacey A. Rosolowski, Ph.D:
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.
Raymond Alexanian, MD:
These only have the recent papers.
Tacey A. Rosolowski, Ph.D:
That's okay. We can fill it in later. Not to worry. "
Recommended Citation
Alexanian, Raymond MD and Rosolowski, Tacey A. PhD, "Chapter 06: Focusing on Myeloma and Perspectives on Myeloma Research and Treatment" (2014). Interview Chapters. 96.
https://openworks.mdanderson.org/mchv_interviewchapters/96
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