In 2012, three randomized placebo-controlled trials reported a significant prolongation of progression-free survival with lenalidomide (Revlimid) as maintenance therapy for multiple myeloma.1-3 Two of these trials tested lenalidomide maintenance after stem cell transplantation, and one investigated maintenance following conventional melphalan-based therapy. One of the three trials, a post-transplant study conducted in the United States, found an improvement in overall survival, while in the others, no survival benefit was seen. All three trials showed a significant increase in the incidence of second cancers.
Following the publication of these trials, there has been some controversy on the implications of these findings. Some experts have endorsed routine maintenance, at least in the post-transplant setting, while others have argued that additional data are needed before such therapy might be recommended. Frequent updates of these study results at subsequent meetings have not clarified the issues, but rather, have given rise to new misconceptions. In this column, I will focus on those findings that apply to the post-transplant setting.
Why the Reservations?
When these studies were first published, I had pointed out reasons why caution is needed, and stated that we need more data to determine whether all patients should receive post-transplant maintenance with lenalidomide.4 I still feel that way. But why would someone like me who has worked with lenalidomide from the outset not recommend routine maintenance? What is it that I am worried about?
Let us first examine the setting: post-transplant maintenance therapy. Autologous stem cell transplantation is not curative in myeloma but prolongs overall survival. Subsequently, three randomized trials found that the timing of stem cell transplantation (early vs transplant at first relapse) does not affect overall survival, but we generally favor early stem cell transplant since it provides a longer time without therapy or toxicity. Routine maintenance, even with an orally administered, well-tolerated drug, threatens the concept of “time without therapy,” which in fact is the major allure of early autologous stem cell transplantation.
In fact, indefinite maintenance until disease progression virtually ensures continuous lifelong drug therapy for myeloma patients, at a time when median survival for younger standard-risk patients is approaching > 10 years. A clear overall survival benefit will still justify this approach, particularly if therapy is reasonably well tolerated. Chronic myelogenous leukemia is a good example in this situation. However, we simply do not have data that survival is convincingly prolonged, at least as of now. Even in the U.S. study that found a survival benefit, we know that not all subgroups derived an improvement in survival. And we do know that some patients can be harmed.
Major Misconception
Next, let us examine a major misconception. We have two fairly similar trials, one done in the United States and one in France by the Intergroupe Francophone du Myélome (IFM), but a survival improvement was seen only in the U.S. trial. Why?
A common explanation is that the French trial stopped maintenance after 2 years, whereas the U.S. trial continued maintenance until progression. This is an incorrect interpretation. The U.S. trial found a survival benefit at a time when the median duration of maintenance in the study was several months short of 2 years, and much less than the median duration of therapy that had already been administered in the French trial!
While it is true that the IFM trial decided to cap maintenance after a median duration of 2 years once a risk of second cancers was identified, that was not the reason for the lack of survival benefit. Patients in the IFM trial, which accrued and closed faster than the U.S. trial, at that point had already received almost an extra year of therapy (lenalidomide or placebo) but were simply not seeing the survival difference that the U.S. trial observed.
In fact, since the U.S. trial recommended a crossover when the median duration of maintenance was approximately 12 months—a point from which comparisons between the two arms becomes difficult to interpret—it is impossible to determine the specific benefit gained by prolonging the maintenance duration beyond that point other than to confirm that differences persist despite crossover. At this point, the 4-year overall survival is 80% to 82% in both arms of the IFM trial and the lenalidomide arm of the U.S. trial; it is approximately 10% lower in the placebo arm of the U.S. trial.
Possible Explanations
What could possibly be the reason for the differences in survival between the two trials? There are many possible reasons,4 but at least two are worth discussing in detail. One is that 35% of patients in the U.S. trial had received lenalidomide as induction, and these were the patients who contributed to the significant survival benefit. No significant survival differences were seen in patients not receiving lenalidomide induction. How does this affect interpretation?
Since the response and toxicity to lenalidomide use was known a priori in a substantial subset of patients screened for enrollment in the U.S. trial, patients who did not respond and those with undue toxicity with lenalidomide induction were naturally less likely to have been enrolled. On the other hand, patients in whom a clear survival benefit was observed were those who received prior lenalidomide, and were most likely already known to be responsive and tolerating such therapy well at the time of randomization.
A second stated reason for the lack of survival benefit in the IFM trial is that 2 months of consolidation with lenalidomide was given to all patients following autologous stem cell transplantation. While some may view this as a problem in the French trial, I do not. A more reasonable interpretation is that if 2 months of consolidation can provide all of the improved survival that comes with 4 years of maintenance, why not go with that? After all, 2 months’ consolidation is less toxic, carries little risk of second cancers, and is much less expensive!
Risk of Second Cancers
A major concern is the increased risk of second cancers in all three trials of lenalidomide maintenance—approximately 7% in the lenalidomide group vs 3% in the placebo group (P < .01). This risk is related to the fact that lenalidomide is given shortly after high-dose melphalan–based therapy in the transplant setting, as it is not seen in the front-line settting, where lenalidomide can be given until progression without an apparent increase in the risk of second cancers.5
The risk of second cancers can be negated by a clear survival benefit, but not by merely showing a delay in time to progression.6 Although the risk of progression of myeloma is much higher than the risk of second cancers, this is not a relevant comparison in this setting since “progression” is largely a biochemical definition in myeloma that can be treated upon detection, while a lethal second cancer is far more serious.
Recommendations
It is likely that many remaining questions will be resolved by longer follow-up of these trials, and also by final results of a separate Italian trial that tested this question. We will also gain insight from an ongoing randomized trial by the Eastern Cooperative Oncology Group that is testing duration of maintenance: for 2 years vs until progression.
Meanwhile, we have to make some judgments based on available incomplete data. At the Mayo Clinic, after a careful assessment of risks and benefits, we have the following recommendations (www.msmart.org).7
For standard-risk patients, we recommend 2 months of lenalidomide consolidation following autologous stem cell transplantation. The French results show that with this strategy, overall survival is similar with and without lenalidomide maintenance. After 2 months of consolidation, if patients are known to be lenalidomide-responsive and are not in very good partial response or complete response, we recommend lenalidomide maintenance. These are the specific subsets where the U.S. trial found a survival benefit.
As far as duration of therapy, we recommend capping maintenance at approximately 2 years. Beyond this point, we do not have randomized comparative data on the value of prolonged maintenance, but we do know risks of second cancers increase in the French trial where the integrity of the random assignment has been preserved.
For intermediate- and high-risk patients, we prefer bortezomib (Velcade)-based maintenance based on the results of several recent trials. Myeloma is a cytogenetically heterogenous complext entity, and we should try to indivualize therapy to maximize benefit and limit harm to patients. ■
Disclosure: Dr. Rajkumar reported no potential conflicts of interest.
Dr. Rajkumar is a hematologist at Mayo Clinic College of Medicine, Rochester, Minnesota.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.
References
1. McCarthy PL, Owzar K, Hofmeister CC, et al: Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1770-1781, 2012.
2. Attal M, Lauwers-Cances V, Marit G, et al: Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1782-1791, 2012.
3. Palumbo A, Hajek R, Delforge M, et al: Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 366:1759-1769, 2012.
4. Rajkumar SV: Haematological cancer: Lenalidomide maintenance—perils of a premature denouement. Nat Rev Clin Oncol 9:372-374, 2012.
5. Facon T, Dimopoulos MA, Dispenzieri A, et al: Initial phase 3 results of the FIRST (Frontline Investigation Of Lenalidomide + Dexamethasone Versus Standard Thalidomide) trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma (NDMM) patients (Pts) ineligible for stem cell transplantation (SCT). 2013 ASH Annual Meeting. Abstract 2. Presented December 8, 2013.
6. Rajkumar SV, Gahrton G, Bergsagel PL: Approach to the treatment of multiple myeloma: A clash of philosophies. Blood 118:3205-3211, 2011.
7. Mikhael JR, Dingli D, Roy V, et al: Management of newly diagnosed symptomatic multiple myeloma: Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc 88:360-376, 2013.
