Myeloma: Stem Cell Transplant Up Front or After Progression?
2008; Wolters Kluwer; Volume: 30; Issue: 24 Linguagem: Inglês
10.1097/01.cot.0000343802.99857.07
ISSN1548-4688
Autores Tópico(s)Chronic Lymphocytic Leukemia Research
ResumoCHICAGO—Standard treatment for newly diagnosed patients with multiple myeloma has been induction chemotherapy until the patient is in remission and then an autologous stem cell transplant. But the introduction in recent years of novel agents associated with high response rates begs the question of whether transplant might wait until after the disease progresses. The answer appears to hang on data from clinical trials not yet conducted. Two experts in a session here at the “Great Debates and Updates in Hematology” meeting, sponsored by the American School of Oncology, basically agreed that delaying stem cell transplant can be preferable, saying that data supporting upfront stem cell transplant are from older trials using older chemotherapy regimens. Both speakers suggested that patients who achieve an immunofixation-negative complete response with modern novel frontline therapy could have the same chance of staying in remission whether they have a stem cell transplant upfront or not, and thus be spared the rigors of transplant until relapse. The co-chairs of the meeting—Hagop Kantarjian, MD, James O. Armitage, MD, and Robert Z. Orlowski, MD, PhD—chose the speakers and their respective positions. The “yes” position, that stem cell transplant should be delayed, was taken by Dr. Orlowski, Director of the Myeloma Section and Associate Professor of Lymphoma/ Myeloma and Experimental Therapeutics at the University of Texas M. D. Anderson Cancer Center.Figure: ROBERT Z. ORLOWSKI, MD, PhD, said that complete remission after initial therapy appears to be key to good long-term outcome, that today's novel agents increase CR rates, and that the durability of CR after novel up-front therapy seems to be equal to CR after SCT.Rafael Fonseca, MD, Professor of Medicine in the Departments of Hematology/Oncology and Transplantation and Deputy Director of Mayo Clinic Cancer Center in Scottsdale, Arizona, managed to take the same “delay stem cell transplant” position even while answering “no,” by stating the question as to whether patients in complete remission should undergo transplant upfront. Delaying Dr. Orlowski's main points were that complete response after initial therapy appears to be key to good long-term outcome, that today's novel agents increase complete response, and that the durability of complete response after novel upfront therapy seems to be equal to complete response (CR) after stem cell transplant. “Maybe we really need to get to CR with better induction therapy, and it doesn't matter that much how it happens,” he said. Dr. Orlowski said a problem with early studies supporting transplant during first remission used inferior induction regimens and that very few patients actually achieved a complete remission on those regimens. Out of eight randomized trials where patients received stem cell transplantation during remission, two used historical controls. And of the other six, only three showed a statistically significant survival benefit for stem cell transplant over use of chemotherapy alone. “With ongoing studies we will be able to show that complete response is a good marker for overall survival, and it's very possible that we don't need to add anything else for patients in complete response from induction,” he said. “It may be reasonable to just collect stem cells in those patients, store them away, and use transplant at the time of first relapse.” Dr. Orlowski cited a 2006 study presented at that year's American Society of Hematology Annual Meeting by Michael Wang, MD, showing that complete response is the major surrogate marker of long survival in multiple myeloma. In the retrospective analysis, 748 patients with newly diagnosed disease received dexamethasone-based induction with or without high-dose therapy within one year. The two survival curves matched very closely after complete response, and suggested that “it doesn't matter how you get into CR,” he said. Also of note, he said, was a more recent trial by Martha Q. Lacy, MD, and colleagues that used a modern regimen of lenalidomide-dexamethasone as induction therapy in patients with multiple myeloma (Mayo Clin Proc 2007;82:1179–1184). After four cycles of chemotherapy, 13 of the 34 patients chose to discontinue treatment to undergo stem cell transplant. The overall survival rate at two years for those patients was 92%, compared with 90% for patients receiving lenalidomide-dexamethasone alone. The three-year overall survival rates were 92% and 85%, respectively. This again indicates that lenalidomide-dexamethasone is highly active whether combined with stem cell transplant or not, Dr. Orlowski said, concluding that for most patients with an immunofixation-negative complete response, there is no evidence that adding transplant is of benefit.Figure: RAFAEL FONSECA, MD, noted that the cost of transplant is not insignificant and that it means time away from home and carries serious and long-lasting side effects. “There is no way to tell now whether transplant is better or not, but these are very important considerations. If we can find a treatment that's going to achieve similar results without having to go through transplant, that would be important.”But whether a patient not in complete remission should receive transplant has not been answered, he added, although he said that at his institution stem cell transplant is usually recommended in that case. Value to Adding Transplant Dr. Fonseca began his presentation by saying that there is no clear answer about whether stem cell transplant adds value to a patient in remission after modern first-line systemic therapy, and that in general, he believes it reasonable to delay transplant for some patients. He did, though, review some studies that appear to support stem cell transplant in the upfront setting. There is no doubt, Dr. Fonseca said, that the road to cure of myeloma starts with a complete response, and recent studies by Jean-Luc Harousseau, MD, of University Hospital in Nantes, France, as well as by Michele Cavo, MD, of Seragnoli Institute of Hematology of the University of Bologna show that getting better induction translates to better post-transplant control. He also cited a study reported at last year's American Society of Hematology Annual Meeting showing good outcomes following stem cell transplant during remission. In that study, presented by Craig B. Reeder, MD, of Mayo Clinic Scottsdale, patients received the cyclophosphamide-bortezomib-dexamethasone regimen called Cybor-D, and of the 33 patients, 23 had a transplant after the chemotherapy, and so far 13 of 18 patients who have completed treatment had gone into a complete or near complete remission. “It's hard not to be optimistic when one sees results like this with a combination of induction plus autologous stem cell transplant,” Dr. Fonseca said. “But the following question applies: Is there another way we can achieve similar results with the use of transplant?” Dr. Fonseca then pointed to the landmark analysis by Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, MN, of the Eastern Cooperative Oncology Group E4A03 Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in patients with newly diagnosed multiple myeloma, presented at the most recent ASCO Annual Meeting. The main findings were an 88% two-year overall survival rate for lenalidomide plus low-dose dexamethasone, and a similar 78% two-year overall survival rate for lenalidomide plus high-dose dexamethasone. More relevant to the debate here, Dr. Rajkumar's report showed a two-year survival rate of 93% for patients who continued lenalidomide plus low-dose dexamethasone therapy beyond four cycles, and an identical 93% for those who went on to transplant. While the decision to transplant early or not depends greatly on the patient's response to initial therapy, Dr. Fonseca asked the audience to consider other factors. He pointed out that the cost of transplant is not insignificant (although that is now also true for some of the novel agents); that transplant means a significant time away from the patient's family and job; and that transplant carries some significant and long-lasting side effects. “There is no way to tell now whether transplant is better or not, but these are very important considerations,” Dr. Fonseca said. “If we can find a treatment that's going to achieve similar results without having to go through transplant, that would be important.” Audience Response Despite the fact that both Dr. Orlowski and Dr. Fonseca supported delay of transplant, very few of the physicians in the audience voting in favor of giving stem cell transplant during remission changed their minds by the end of the debate. On the other hand, two-thirds of those who had not made up their minds before the discussion switched their votes to “delay transplant.” Case Study The audience was presented with this case: A healthy 61-year-old man is diagnosed with IgG-kappa multiple myeloma. He has multiple lytic bone lesions, mild anemia, serum albumin of 3.3 gm/dl, and serum calcium of 10.4 gm/dl. Beta-2M is 3.6. Cytogenetics by FISH show a t(11;14) translocation. The patient is treated with lenalidomide plus low-dose dexamethasone and achieves a complete response by immunofixation. Stem cells are harvested after four cycles of therapy. He receives two more cycles of lenalidomide plus low-dose dexamethasone and is then considered for autologous stem cell transplant. The patient is feeling very good, has tolerated treatment well, and is uncertain if he wants to subject himself to stem cell transplant (SCT) at this time. Would you encourage him to undergo transplant now or wait until he demonstrates disease progression? The audience's answers by keypad vote were as follows: “I would strongly encourage SCT at this time”—Before the debate, 43% agreed with this; afterwards, 39% did. “I would strongly recommend that the patient receive maintenance lenalidomide plus low-dose dexamethasone and postpone SCT until disease progression”—Before, 23%; after, 50%. “I could go either way”—Before, 33%; after, 11%. Why Would Some Physicians Prefer Upfront SCT? After the meeting, Dr. Orlowski was asked for this article why he thought some physicians would prefer upfront stem cell transplant. “We do not have results from a current trial using modern induction therapy prior to stem cell transplant that proves that delaying transplantation would give you the same or a better benefit than doing the transplant right away,” he said. “The ideal trial today would give everyone the same induction therapy, such as velcade-revlimid-decadron, and then take those who get a complete remission and randomize them to either get transplant now or have stem cells stored for later and then transplant them at the time of first relapse.” He said a study of this kind is actually being planned but in the absence of such data, some practitioners prefer to follow older approaches until they are proven wrong—“and the tried-and-true method is to do transplant upfront.” Dr. Orlowski also pointed out that patients in complete remission after transplant can be followed without any chemotherapy, while even those who achieve a complete response after induction chemotherapy are typically advised to continue on maintenance therapy, with some lower dose of one or two of the drugs that they received as induction. “Since these drugs can still cause side effects, even at lower doses, patients often feel better being totally off therapy than on low-dose chemotherapy,” he explained. “Thus, practitioners often prefer to have patients do induction and then transplant because of quality-of-life considerations.”
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