NEW YORK—After a data-filled debate between two hematology experts on whether newly diagnosed multiple myeloma patients should be treated with transplantation right away or later on, the audience voted. And the results, when shown on the slide screen, brought a loud round of applause: a tie between upfront and delayed transplant.
The debate, “Is There a Role for Upfront Transplant in the Current Management of Symptomatic Multiple Myeloma?” took place here during the National Comprehensive Cancer Network's Annual Congress on Hematologic Malignancies, in front of an audience of about 650 attendees.
Sergio A. Giralt, MD, Chief of the Adult Bone Marrow Transplantation Service Chief and the Melvin Berlin Family Chair in Multiple Myeloma at Memorial Sloan Kettering Cancer Center, defended the “pro” position; Kenneth C. Anderson, MD, Program Director of the Jerome Lipper Multiple Myeloma Center and the LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute and Kraft Family Professor of Medicine at Harvard Medical School, took the “con” position.
Giralt began with some self-deprecating humor. He showed a slide quoting his wife as saying “How can you even think of winning a debate with Ken Anderson? He'll devour you with kindness and honesty. Even if you're right he'll make you look wrong. Just say you got abducted by aliens.”
Knowing the personalities of the debaters, the audience was highly amused.
Sergio Giralt: ‘Rip-Roaring Yes’
Getting down to business, Giralt asked rhetorically, “When we're having the debate of early versus late transplant, the core question is, does intense therapy with high-dose melphalan supported by autologous peripheral blood make a difference?
“I believe the preponderance of evidence would suggest that the answer is a rip-roaring yes.”
The first premise to accept, he said, is that achievement of a complete remission is an important surrogate for long-term disease control and survival in myeloma.
“And with more than 20 years of experience, we have patients who are long-term survivors, who are without disease, and who are potentially curable—and what they have in common is that most, if not all, had transplants as part of their upfront therapy,” he said.
Giralt discussed induction regimens before transplant, citing the landmark meta-analysis by the Eastern Cooperative Oncology Group, E4A03, which had a median follow-up of 36 months (Rajkumar et al: Lancet Oncology 2010;1:29-37).
“The meta-analysis shows that lenalidomide with low-dose dexamethasone should be part of the induction regimen before transplant,” he said. “While that was not a randomized trial, people have compared the transplant group with those who continued therapy, and patients who had transplant did better.”
This was true even for patients age 65 to 70. Although that finding was not statistically significant, he said it again appeared that “going to transplant upfront did not hurt, and if anything, the burden of therapy was significantly less.”
What about Bortezomib?
How about adding bortezomib to the mix? He cited a meta-analysis presented at last year's American Society of Hematology Annual Meeting of four Phase III studies in which patients underwent autologous stem cell transplant after induction with either a bortezomib-based or non-bortezomib-containing regimen (Cavo et al: ASH 2013, Abstract 767).
The trials were IFM 2005-1, HOVON-65/GMMG-HD4, GIMEMA MM-BO2005, and PETHEMA GEM05MENOS65.
“Lo and behold, the meta-analysis showed a benefit, not only for progression-free survival but also for overall survival,” Giralt said. He noted that while none of the individual studies showed a survival benefit for bortezomib, “they did show a progression-free survival benefit. And when all four were put together in a meta-analysis, you start seeing a big difference in overall survival.”
In those four randomized trials, with more than 1,000 patients, the more intense treatment a patient could get, the better they did, he said.
Offering some valuable advice, Giralt said, “For those of you who have to take the boards, we are saying that in the context of modern therapy, particularly in transplant-eligible patients, bortezomib should be a component of the induction therapy.”
In another study at the ASH 2013 meeting, CALGB 100104, with 27,987 patients in the analysis, far more patients achieved an overall survival time of double the median of 26.7 months and up to 10 years and more if they had autologous hematopoietic cell transplant as initial therapy (Raghavendra et al: ASH 2013, Abstract 760).
Giralt said that patients achieving a complete response to induction therapy are a particularly challenging group because many can have good outcomes without receiving high-dose melphalan. Still, even in those patients, high-dose therapy seems to be associated with high rates of prolonged disease control, he said.
“The preponderance of evidence supports the use of high-dose melphalan and autologous stem cell transplant as upfront consolidation therapy for myeloma. Until the results of future randomized trials come out, high-dose melphalan consolidation should still be considered the standard of care for all eligible patients with myeloma.”
Giralt concluded by saying that new surrogate markers of myeloma activity, such as minimal residual disease (MRD), may soon become helpful in risk-stratifying patients.
Kenneth Anderson: Not All Newly Diagnosed Patients Need Early Transplantation
Anderson began by pointing out that he is not an impartial observer, having taken part in the trials that established transplantation as a practice in myeloma and having carried out several thousand of them in his career.
“Transplant is the standard, but clearly we can do better. We're trying to understand how to look at the data and perhaps interpret it a little bit differently.”
He said many of the transplant trials conducted before novel therapies were early versus late transplant comparisons, but now those novel therapies have been integrated into the transplant paradigm either as induction, consolidation, or maintenance.
He said data show that transplant with novel therapies has continued to improve survival (Kumar et al: Leukemia 2014;239-240). “The question then is, do we really need the transplant component? There's no solid answer to that yet, but with novel drugs, including newly approved carfilzomib, it's clearly an unprecedented time in multiple myeloma.”
He cited a Phase I/II trial from the 2011 ASH Annual Meeting of carfilzomib-lenalidomide-dexamethasone (CRd) in which virtually all patients had a response and a very good partial response, with 85 percent of patients achieving a complete or near complete response, all with manageable side effects (Jakubowiak et al: ASH 2011, Abstract 631).
And data from another trial at last year's ASH Annual Meeting, with CRd therapy in which 27 patients had a complete response after eight cycles showed that all 27 were MRD negative (Korde et al: ASH 2013, Abstract 538)—“That's an unprecedented extent of response, and there's no sign of transplant in any of those slides,” Anderson said.
Another promising agent, ixazomib (MLN9708), an oral proteosome inhibitor, can be taken once per week, he noted. In a dose-response study treating newly diagnosed patients with ixazomib-lenalidomide-dexamethasone but not transplant, 48 percent of patients achieved a 100 percent reduction in M-protein with the all-oral regimen (Kumar et al: ASH 2012, Abstract 332).
“This may mean patients can get to an MRD-negative status with an all-oral regimen,” he said.
And in a separate trial of ixazomib twice weekly with lenalidomide and dexamethasone, 82 percent of patients achieved MRD-negative status (Richardson et al: ASH 2013, Abstract 535). “We're catching up with CML, but now we're worried about minimal residual disease,” Anderson said. “While we need to define what MRD really means in multiple myeloma, we can now achieve it in the absence of a transplant. It's up to us as a community to determine what the relevance of MRD is.”
Anderson concluded that in the absence of a transplant, patients can still achieve an unprecedented response. His key points:
- Optimal induction with triplets of novel agents achieves a high extent and depth of response;
- Novel agents can achieve MRD, with or without transplant;
- Maintenance therapy can prolong progression-free survival and overall survival with or without transplant;
- Early versus late transplant outcomes are similar in the eras of both conventional and novel agents; and
- The ongoing randomized Phase III IMF/DFCI 2009 “Determination” trial will hopefully define the added value and role of timing in stem cell transplant for multiple myeloma.
The audience was asked after the debate to vote on how they would treat a 50-year-old woman newly diagnosed with multiple myeloma who presents with anemia and fatigue, hematocrit 30, creatinine 1, 65 percent involvement by plasma cells, hyperdiploidy, IgA kappa 5 grams per liter, and multiple lytic lesions. After treatment with lenalidomide-bortezomib-dexamethasone therapy (RVd) and zoledronic acid, she achieved a molecular complete response.
The audience had these five choices, and these were the percentage of votes:
- Harvest stem cells with autologous stem cell rescue—six percent;
- Harvest stem cells, give melphalan and stem cell rescue with lenalidomide maintenance—42 percent;
- Harvest stem cells—two percent;
- Harvest stem cells, give lenalidomide maintenance but wait for high-dose therapy—43 percent;
- Continue RVd—six percent.
After the applause for the 42-43 votes, Anderson noted that at least everyone who voted had prepared for transplant, and the two options receiving the most votes had used lenalidomide maintenance. “We really need to highlight the concept of continuous therapy,” he said. “If we discontinue therapy in this patient, relapse would be inevitable.”
In an interview after the session, the meeting Chair, Andrew D. Zelenetz, MD, Vice Chair for Medical Informatics and Attending Physician in the Lymphoma Service of Memorial Sloan Kettering Cancer Center, said the question he wanted to emphasize in this debate was whether there are adequate data to make the upfront-versus-delayed transplant decision today: “A lot of the data that says ‘upfront transplant is the right thing to do’ is from an era when we didn't have some of these novel agents, and when we didn't have high-quality remissions. We need to understand what a high-quality molecular remission means and how does it impact the role of transplant.”
Ten years ago there was no question, he continued—upfront transplant was the best way to get to a complete remission and have a durable response.
“But today with some of the triplet combinations, particularly carfilzomib-lenalidomide-dexamethasone, we're seeing high-quality molecular remissions that may change our thinking about the role of upfront transplant. It might be just as good to do it at a subsequent time, as we do with large cell lymphoma.”
Another speaker here, Ola Landgren, MD, PhD, also at MSKCC, where he is Chief of the Myeloma Service, said: “Right now we are leaning on preliminary data, but it does seem that some patients may not need upfront transplant.”
He said in an interview that ongoing clinical trials are addressing transplant timing and progression-free and overall survival. “Until those studies are done, there is no formal evidence, but given the preliminary data it seems that among patients who receive the best drugs we have, there could be patients obtaining very good deep responses, even with MRD negativity, without a transplant.
“This suggests that there could be a subset of patients who do not need an upfront transplant, although there are also patients who don't have deep responses and who do need a transplant.”
In the future, patients may have to be stratified by who would or would not benefit from an upfront transplant, he said. “Right now we don't have those markers, but I do envision that we may treat with a few cycles to determine their response, and that could be the way to guide patients.”
Landgren noted that although carfilzomib is not currently approved by the Food and Drug Administration for newly diagnosed multiple myeloma patients, combined carfilzomib-lenalidomide-dexamethasone is part of the NCCN guidelines—“not with the highest evidence but with the same level of evidence as Velcade-Revlimid-dexamethasone,” he said.