Discussants: Matt Kalaycio, MD¹; Sagar Lonial, MD²

From Cleveland Clinic, Cleveland, OH¹; Emory University, Atlanta, GA²

Address for correspondence: Matt Kalaycio, MD, Cleveland Clinic Main Campus, Mail Code R32, 9500 Euclid Avenue, Cleveland, OH 44195

E-mail: kalaycm@ccf.org

Biographical sketch:

Matt Kalaycio, MD, FACP, is Chairman of the Department of Hematologic Oncology and Blood Disorders at Cleveland Clinic Taussig Cancer Institute. Dr. Kalaycio holds a joint appointment in Cleveland Clinic's Transplant Center and is a Professor in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Board-certified in hematology and medical oncology, Dr. Kalaycio's clinical interests are in leukemia and stem cell transplantation.

Dr. Kalaycio has been published in numerous scientific publications including Bone Marrow Transplantation, Journal of Clinical Oncology, and Leukemia. He also is the editor of a book on leukemia and co-editor of a book on clinical malignant hematology. His research interests focus on testing new treatments for leukemia.

Dr. Kalaycio received his degree from West Virginia University School of Medicine in Morgantown. He completed his residency in internal medicine at Mercy Hospital of Pittsburgh and fellowships in hematology and medical oncology and bone marrow transplantation at Cleveland Clinic.

Sagar Lonial, MD, FACP, is internationally recognized as a leading authority in multiple myeloma treatment and research. As a medical oncologist at the Winship Cancer Institute, Dr. Lonial treats patients with multiple myeloma and is a lead member of the bone marrow transplantation team and clinical trials team. He is board certified in hematology, oncology and internal medicine.

Dr. Lonial is involved in numerous professional organizations including the American Society of Clinical Oncology, American Society of Hematology, and the American Society for Blood and Marrow Transplantation. He serves as Vice Chair of the Myeloma Committee in the Eastern Cooperative Oncology Group and as Chair of the Steering Committee for the Multiple Myeloma Research Consortium. Additionally, he is on the board of directors for the International Myeloma Society, and on the scientific Advisory Board for the International Myeloma Foundation.

Transplant Eligibility

Dr. Kalaycio: Sagar, I have this question, and I go over it more than once with my colleagues. I'm interested in your take on it. Many papers and many protocols distinguish between the transplant eligible and the nontransplant eligible patient.

I hear different definitions about that. As a stem cell transplanter myself, I tend to think people are more eligible than others might think. I wonder if in your practice, you make that distinction between transplant eligible and nontransplant eligible. If you do, how so?

Dr. Lonial: That’s a really good question. I think It's a really confusing area because we are being held hostage to the European definition of transplant eligible and non-eligible, which is basically, age 65.^1,2We know that in the United States we'll transplant people much older than they will in Europe, we just use a reduced dose of melphalan. My way of categorizing people here is actually different from the simple eligible/non-eligible dichotomy. I break down patients into three categories.

The first category is the young fit patient, which is usually the patient who is under age 65. The second category is the older fit patient, which is probably between 65 and 75, and may even go a little bit older than that, depending upon fitness. The third category is the frail patient. The frail category actually has no age definition, because I've said no to 55 year olds for transplant, and I’ve said yes to 77 year olds for transplant. The frail category is defined now using the frailty index, published by Palumbo et al.³ In general for me it tends to be people between ages 75 and 78 at the lower end, and then above that.

I think about people who are in the frail category as not being able to tolerate a transplant, and so I'm going to treat them with a different treatment approach in a much more gentle way, with the same goal of trying to achieve a complete response. With the other two categories, the young fit and the older fit patient, I'm going to try to induce with a three-drug regimen, and use that as their stress test to see whether they can go forward to the next step in terms of collection of stem cells and transplant.

Dr. Kalaycio: I'm familiar with Palumbo's article and his frailty index. We've not applied it in the clinic. It sounds like you have.

Dr. Lonial: Yes, I think it's not so straightforward in the sense that it is not just a bunch of laboratory values. It really does require you to do a little bit of work in terms of activities of daily living, and things along those lines. It is a pretty good validated tool for identifying patients who are at higher risk of toxicity from treatment. It's going to be used increasingly now in clinical trials for phase III patients, as well as for the International Myeloma Working Group description about how to approach treatment.³ It really is a nice objective tool for how to evaluate that.

Dr. Kalaycio: I think that's an important point. I do not think the Hematopoietic Cell Transplantation-Comorbidity Index⁴ is reliable in distinguishing patients who are good candidates for high-dose melphalan versus those who are not.

Dr. Lonial: I completely agree. It's interesting, because I actually completed a consent yesterday afternoon with a patient for transplant. He read our book on transplant on what to expect. As he was going through his concerns, it struck me that most of the toxicity we talk about with an autotransplant is really related to lymphoma transplant in which they’re getting three or four drugs as part of the conditioning. Most people get pretty sick with the lymphoma transplant, whereas most myeloma transplant patients report fewer problems. It’s an unusual patient who has a lot of toxicity associated with an autotransplant from myeloma, as opposed to a lymphoma patient.

Dr. Kalaycio: Agreed. We do not typically use cytogenetic analysis, or even molecular analysis, to determine whether a patient gets transplanted or not. Do you use those biologic stratification techniques?

Dr. Lonial: We do, and we use them on the front end to determine how we're going to maintain patients. Our approach now is not the risk adapted under-treatment of patients with good risk genetics, versus more aggressive treatment for patients with poor risk genetics in the induction setting as is recommended by other centers. We think everybody should get the absolute best induction therapy there is regardless of genetic risk. In our opinion, that’s an immunomodulatory drug (IMiD) proteasome inhibitor (PI) combination. We recommend that most patients proceed with transplant in the absence of a clinical trial.

We use that genetic information and diagnosis to base how we maintain them. For a standard-risk patient we would recommend lenalidomide maintenance. For a high-risk patient we would actually recommend lenalidomide, bortezomib and dexamethasone (RVD)-based maintenance. That is based on some data we published about 18 months ago where high risk patients, 17p deletion, t(14;16) are hypodiploid, actually have a much better progression-free survival, and overall survival by using triplet maintenance post-transplant.⁵ Then for the t(4;14), which is an intermediate group, we end up using just a PI as maintenance. We get the information and we use it to inform the maintenance approach.

Dr. Kalaycio: All right, now that article that you referenced is prospectively derived, but not a randomized trial, correct?

Dr. Lonial: That's absolutely correct.

Dr. Kalaycio: On a more practical note, talking about patients who you're thinking about transplanting—by whatever stratification algorithm you use—are you collecting stem cells on everybody regardless, or reserving them for future transplants? Or are you just collecting at the time you're actually doing the transplant?

Dr. Lonial: We collect on everybody after cycle 4. We collect enough for a couple of transplants so that we've got backup products available down the road, if we ever need them. The challenge with waiting until you’re ready to transplant is that if you get beyond cycle 4, it often gets more challenging to collect stem cells. Our approach is not dissimilar from the current Blood and Marrow Transplant Clinical Trials Network DETERMINATION trial, which is asking the question of early versus delayed transplant, but that everybody gets collected after four cycles of therapy.

Dr. Kalaycio: Lots of large centers adhere to that approach, but we have not. We have not found any trouble in our own experience, even with lenalidomide, when we collect stem cells at the time we need to do the procedure, assuming the lenalidomide has been stopped for a period of time.

With plerixafor, we found that we've been able to collect just about everybody regardless of prior exposure as long as there has been a time frame stopping lenalidomide before we actually try to collect. That goes for second remissions too. We don't seem to have any problem collecting in a second chemo-sensitive remission, or even a third. I guess we have not reached the point where we think it necessary to collect and cryopreserve. We wonder about that because there are costs involved. Insurance companies, we find, often are reluctant to pay for cryopreservation if you're not planning on using them right away.

Dr. Lonial: We've not run into that challenge as of yet. Truth be told, the cost of cryopreservation is a fixed cost. I know that there are centers that charge annually for cryopreservation—we don't do that. It’s a one-time fixed cost. I think that’s an interesting concept. For the collection of second and third autographs, your experience is not what I think is typically reported by many centers. These would be very interesting data to see, and to get out there in the literature, because that's a different model than I think many of us have approached. It would be good to get that information out.

Dr. Kalaycio: Yes, it turns out that we don't do that many second transplants, so we don't have a large experience yet to report. For the few that we have done, we haven't had any trouble. We manage it like we would lymphoma.

Dr. Lonial: Interesting.

Read Part 3 of the 3-Part Series.

Medical Roundtable: Multiple Myeloma & Transplant Eligibility