The FIRST trial—reported by Benboubker and colleagues in The New England Journal of Medicine and summarized in this issue of The ASCO Post (page 93)—is a landmark study.1 It is one of the largest randomized trials in multiple myeloma ever conducted. More importantly, it is a well-designed trial that answers important questions in myeloma. The issues addressed include the role of melphalan in an era of new drugs and the value of continuous suppressive therapy vs treatment delivered for a fixed period of time. Remarkably, the trial also provides reassuring information on the association of second primary malignancies with lenalidomide (Revlimid) maintenance, an issue that was not recognized as a consideration when the trial was initially designed.2
Widely Used Regimen
The Rd (lenalidomide plus low-dose dexamethasone) regimen was developed first in the Eastern Cooperative Oncology Group (ECOG) E4A03 clinical trial.3 In that trial, Rd had the best 1-year survival rate of any published regimen at the time (96%), virtually eliminating early deaths from toxicity that plagued many other regimens. I am, therefore, not surprised that this well-tolerated, highly effective doublet administered until disease progression was found to improve overall survival compared with the previous standard of MPT (melphalan, prednisone, thalidomide [Thalomid]).
It took over 40 years for a regimen (ie, MPT) to beat MP (melphalan/prednisone) in overall survival.4 It took only 7 years for us to get a regimen (ie, Rd) to beat MPT in overall survival!1 Rd is widely used in the United States (and elsewhere) as initial therapy for both transplant-eligible and transplant-ineligible patients. It is also the backbone on which numerous other regimens are built (eg, bortezomib [Velcade]/Rd, carfilzomib [Kyprolis]/Rd, ixazomib/Rd, elotuzumab/Rd, etc).
Unresolved Question
A major unresolved question in the minds of many is that although progression-free survival is markedly better with Rd administered until progression compared with Rd given for 18 months, overall survival did not significanlty differ between these two arms. I think that superiority of continuous Rd will be seen, but will take more follow-up to demonstrate.
Nevertheless, in this case, given that progression occurred within a median of 2 to 4 months after stopping Rd in the fixed-duration arm, I recommend that if clinicians use Rd as initial therapy, they continue therapy until progression. This recommendation is made easier by the fact that Rd is convenient and well tolerated.
In my practice, I usually reduce the dose of dexamethasone as much as possible, and even try and stop it after the first 1 to 2 years.5 In some patients, we may need to re-increase the dose of dexamethasone, but in many patients, one can continue suppressive therapy with lenalidomide alone. I also try to reduce the dose of lenalidomide if needed to reduce side effects. One should be aware of some long-term problems—ie, diarrhea, fatigue, and leg cramps. Diarrhea occurs in only a small subset of these patients but can be particularly difficult to treat.
One of the unexpected benefits of this study is that it addressed whether lenalidomide maintenance given without melphalan exposure would increase the risk of second primary malignancies. In other trials so far, the risk of second primary malignancies has been found only when lenalidomide maintenance has been given following standard-dose or high-dose melphalan therapy. Thankfully, this study found no difference in the incidence of second primary malignancies with long-term Rd compared with either MPT or, more importantly, fixed-duration Rd. These are very reassuring data.
Economic Considerations
I will conclude by pointing out some economic considerations that must be kept in mind. Rd is not an inexpensive regimen. And, in many countries, there is considerable out-of-pocket cost for the therapy. Thus, Rd given for many years may not be a financially viable option for some, even though it is such a well-tolerated oral regimen and ideal for elderly patients.
Therefore, in some settings, it may be better to use a bortezomib-based regimen such as VCD (bortezomib/cyclophosphamide/dexamethasone), which can be given for a limited duration. VCD is a better-tolerated version of VMP (bortezomib/melphalan/prednisone), another regimen that has been shown to improve survival compared with MP.6
VCD and other bortezomib-based regimens are commonly used in the United States as an alternative to Rd. Unfortunately, no randomized trials have compared Rd to either VCD or VMP, so this is a judgment call we need to make based on economics, patient preferences, and certain disease characteristics. ■
Disclosure: Dr. Rajkumar reported no potential conflicts of interest.
References
1. Benboubker L, Dimopoulos MA, Dispenzieri A, et al: Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 371:906-917, 2014.
2. Dimopoulos MA, Richardson PG, Brandenburg N, et al: A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide. Blood 119:2764-2767, 2012.
3. Rajkumar SV, Jacobus S, Callander NS, et al: Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: An open-label randomised controlled trial. Lancet Oncol 11:29-37, 2010.
4. Facon T, Mary JY, Hulin C, et al: Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): A randomised trial. Lancet 370:1209-1218, 2007.
5. Rajkumar SV: Multiple myeloma: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol 89:998-1009, 2014.
6. San Miguel JF, Schlag R, Khuageva NK, et al: Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906-917, 2008.
Dr. Rajkumar is Professor of Medicine, Division of Hematology, Mayo Clinic College of Medicine, Rochester, Minnesota.
