We want to provide patients with treatment that has the best long-term maximum benefit against their disease, but without potential toxicities that could possibly affect them for many years beyond treatment.
—Paul G. Richardson, MD
Although high-dose chemotherapy plus autologous transplantation has been a standard of care in the treatment of younger patients with newly diagnosed multiple myeloma, the advent of effective novel agents for the cancer over the past 15 years has raised the question of whether transplantation, with its myriad toxicities, is still necessary. The findings from a phase III study1 presented at the 2015 American Society of Hematology Annual Meeting and Exposition suggest that it probably is—at least for now.
The randomized study, a joint effort between the Intergroupe Francophone du Myelome (IFM) trialists group and Dana-Farber Cancer Institute (DFCI), compared a triplet combination of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVD) with the triplet plus transplantation conditioned with melphalan in 700 previously untreated French and Belgian patients with a median age of 58 years. Patients in both arms of the study also received 1 year of maintenance therapy with lenalidomide.
The results showed that although significantly more patients in the transplant arm achieved complete response than did patients in the triplet-only arm (58% vs 46%, respectively) and there was a progression-free survival advantage of 8.8 months, the 3-year post-randomization overall survival rate of 88% was similar between the two groups. Further, there were five deaths due to toxicities in the transplant arm, and more transplant patients than patients in the RVD arm experienced second primary malignancies, 23 vs 18, respectively, including secondary acute myeloid leukemia.
Paul G. Richardson, MD
A parallel trial2 using a similar design but includes continuous administration of maintenance lenalidomide until disease progression in both arms is being conducted in the United States and is being led by Paul G. Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute; and R.J. Corman Professor of Medicine, Harvard Medical School. Currently, the study has accrued more than 560 patients and is moving closer to the target number of 660 randomized patients.
The ASCO Post talked with Dr. Richardson about the results so far from the two studies, what clues are emerging about the future use of transplantation compared with novel therapies and which patients might benefit most from either approach, and the potential of turning myeloma into a chronic disease.
‘Unique Opportunity to Compare Data’
The purpose of the IFM/DFCI trial is to determine whether autologous transplantation is still required in the initial management of myeloma in younger patients in the era of effective targeted drugs. Please talk about the findings thus far from both the French and American trials.
In essence, both our study and the French trial are exploring the advantage of early vs late transplant in healthy patients aged 65 and younger and asking where transplantation belongs in the new therapeutic paradigm for multiple myeloma. To do this, we wanted to evaluate the use of RVD-based treatment both as induction and consolidation as well as the role of lenalidomide maintenance therapy.
A key point is that the French trial stopped lenalidomide maintenance after just 1 year as a regulatory requirement from the French authorities. However, in the United States, we pursued a trial design that was driven by data from the Alliance/CALGB 100-104 study, which showed a survival benefit with the use of continuous lenalidomide maintenance in the post-transplant setting. The U.S. trial is thus importantly different from that of our French partners.
The French study has shown an 8.8-month progression-free survival advantage in favor of the transplant arm vs the triplet arm with transplant kept in reserve, but no overall survival difference is seen. An important point of context to consider is that if maintenance therapy is given until disease progression, the progression-free survival benefit seen is of the order of 2.5 years; so if transplant generates 8.8 months of benefit, and continuous maintenance derives 2.5 years in other studies, answering the question in the U.S. trial of continuous maintenance therapy until disease progression becomes critically important.
Another important question is whether transplant is worth the potential toxicities. In the French study, there were both acute and long-term treatment-related toxicities that lead to death, which were numerically higher in the transplant arm than in the nontransplant arm, including a number of patients in the transplant arm who died of secondary leukemia. The numbers were fortunately very small overall, but they give us clues about why answering this question is so important for our patients in the longer term.
The U.S. trial is running parallel to the French study, and so far, our study has not shown any significant difference in outcome between the two arms, with a low event rate overall and excellent safety, which is very good news for our patients.
We know that the use of continuous therapy with effective immunomodulatory drugs has been shown repeatedly to be positive in terms of clinical benefit. So, answering the question of continuous therapy is vital, and Michel Attal, MD [of the Institut Universitaire du Cancer de Toulouse-Oncopole, in Toulouse, France, and lead author of the French study] was very clear at the ASH Annual Meeting about the necessity of this, and these two studies actually provide us with a unique opportunity to compare data from the two parallel experiences.
Transplantation for Younger Patients
With more targeted drugs for myeloma being developed, do you envision a time when transplantation might become obsolete?
Transplant provides a platform for rebooting the immune system, and the question is now how best to achieve it. Do you need high-dose melphalan for transplant conditioning, with its toxicity and side effects, which can be both short- and long-term, or can we achieve the same immunologic platform with fewer side effects and less risk in a different way?
I think transplantation is clearly an important option for younger patients, but I do not believe that one size fits all. In other words, does every myeloma patient need a transplant, and in whom should it be given early, rather than later? These are key questions for which we do not yet have answers.
Do we think every younger patient needs a transplant at some point in his or her disease course? Probably in the majority of cases, yes, but there are a number of patients who may not need a transplant, and then the question that arises is, if patients are living 10, 15, or 20 years with their disease, why would we accept an early toxicity risk if we don’t need to?
The importance of the U.S. trial is also that it is the first of its kind on this scale and reflects a new model, where we are trying to answer as many reasonable questions as we can within a large cooperative group trial setting to improve clinical practice. It also reflects a remarkable degree of collaboration among academia, the intergroups—specifically the National Cancer Institute Clinical Trials Network and the Alliance for Clinical Trials— our pharma partners, and the U.S. Food and Drug Administration.
A Chronic Illness for Many
The newer therapies are probably allowing myeloma to be converted into a chronic disease but still not a curable one. Is that correct?
For an increasing proportion of patients, the disease is becoming a chronic illness, in which we are able to control their myeloma for up to 10 or 15 years, whereas in the past, survivorship was measured at a median of 2 to 3 years in older patients and 3 to 5 years in younger patients. So this reflects truly dramatic progress.
It is in this context that the results from the French and American studies matter so much, because, obviously, we want to provide patients with treatment that has the best long-term maximum benefit against their disease, but without potential toxicities that could possibly affect them for many years beyond treatment. Moreover, we have a wealth of new agents and emerging immuno-oncologic options that will make yet further improvements in outcome a reality. ■
Disclosure: Dr. Richardson has served on advisory committees for Celgene, Johnson & Johnson, Millennium, Takeda, Bristol-Myers Squibb, and Novartis.
1. Attal M, Lauwers-Cances V, Hulin C, et al: Autologous transplantation for multiple myeloma in the era of new drugs: A phase III study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 trial). 2015 ASH Annual Meeting. Abstract 391.
2. Richardson PG: Randomized trial of lenalidomide, bortezomib, dexamethasone vs high-dose treatment with SCT in MM patients up to age 65 (DFCI 10-106). Available at https://clinicaltrials.gov/ct2/show/NCT01208662?term=Richardson&rank=2. Accessed February 23, 2016.