Melphalan or No Melphalan: That Is the Question

Clinical outcomes data for all of oncology include those from trial after trial demonstrating poor outcomes in older patients with cancer. Whether these are the result of limited biologic reserve, poor performance status, or inherently worse biological disease at the time of diagnosis, such age-based disparities have continued unabated for decades. However, for the first time, older patients with multiple myeloma (MM) are starting to enjoy the kinds of remission durations and overall survival (OS) seen in younger patients. In this review by Dr. Harousseau, we see that through the use of regimens such as MPV (melphalan and prednisone plus bortezomib), MPT (melphalan and prednisone plus thalidomide), MPR (melphalan and prednisone plus lenalidomide), VMPT (bortezomib, melphalan, prednisone, and thalidomide), and Rd (lenalidomide and low-dose dexamethasone), we can begin to provide older patients with MM with a median OS approaching the 4- to 5-year mark-a far cry from the median OS of 2.5 to 3 years seen with MP just 15 years ago. So what are the remaining hurdles and challenges to be addressed in the upcoming 10 years?

Depth of Response
There remains considerable disagreement regarding the importance of deep responses in older patients with MM; however, there are now several examples of instances in which complete remission (CR) in older patients correlated with improved progression-free survival (PFS) and OS.[1,2] This does not mean that all caution should be thrown to the wind in order to achieve CR. Tolerance considerations clearly are of supreme importance in older patients. Still, that should not prevent us from trying to maximize depth of response while minimizing toxicity. Decreasing the intensity of bortezomib therapy to weekly dosing in elderly patients has been shown by Mateos and colleagues to reduce the rate of peripheral neuropathy while still maintaining a high CR rate.[3] Weekly therapy likely also makes longer duration of therapy possible, because of better tolerance, thereby providing another approach to effective and well-tolerated therapy.[4,5] In several of the MPT studies and TD (thalidomide and dexamethasone) studies with negative outcomes, thalidomide-related toxicity was the chief reason for failure.[6,7] In the Intergroupe Francophone Mylome (IFM) trial conducted by Hulin and colleagues, thalidomide dosing was lower and patients were able to achieve a significant survival benefit with MPT.[8]

Age for High-Dose Therapy
European studies suggest that for patients older than 65 years, the effects of high-dose therapy (HDT) are simply too toxic to warrant the use of full-dose melphalan. Many US transplant centers routinely administer HDT to patients between the ages of 65 and 75 years without a significant increase in morbidity or mortality. Furthermore, data from Badros and colleagues suggest that for patients older than 70 years, reducing the melphalan dosage from 200 mg/m2 to 140 mg/m2 decreases the toxicity of the transplant process, making this an option for even semi-frail patients up to the age of 70 years.[9] Given the improvement in supportive care techniques used with HDT in transplant centers that have sufficient volume and experience, patient age greater than 65 years should no longer be considered a barrier to the use of HDT in selected patients. These types of patients should be referred to and discussed with an experienced myeloma/transplant physician before initiation of oral melphalan-based therapy, and in suitable patients HDT should be considered, even outside of clinical trials.

Maintenance Therapy
As questions regarding duration of therapy, benefits of treatment-free intervals, and chronic disease control versus intermittent pulses of therapy continue to be asked, emerging data from transplant trials suggest a benefit for maintenance therapy. Trials from Europe and the United States suggest that lenalidomide therapy post transplant improves response duration,[10,11] although additional data on survival benefit are not currently available. In the population of non–transplant-eligible patients, three trials have now tested maintenance therapy in the post-induction phase; to date, these have also demonstrated a significant benefit in terms of PFS for patients receiving either lenalidomide-based,[12] or bortezomib-based maintenance therapy.[13,14] Bortezomib maintenance in combination with either low-dose prednisone or low-dose thalidomide was given on an every-2-weeks schedule or with a standard cycle (days 1, 4, 8, and 11) every 3 months[13,14] after induction therapy in these studies in older patients. In light of data suggesting that older patients may not receive salvage therapy if their performance status declines in the setting of relapsed disease, it is appropriate to consider maintenance therapy with less of an emphasis on the survival benefit for this subset of patients. Is it time to consider maintenance therapy for all older patients, assuming it is tolerable?

Melphalan Required?
While MPT, MPV, and MPR are active regimens, the non–melphalan-containing regimen of lenalidomide plus low-dose dexamethasone (40 mg once per week; Rd) is also a treatment option.[15] This recommendation is based primarily on encouraging survival data from the Eastern Cooperative Oncology Group trial in patients with newly diagnosed MM (E4A03). However, can we ultimately maintain and possibly improve outcomes by eliminating melphalan altogether? Can these non–melphalan-containing approaches maintain efficacy? In the RVD (lenalidomide, bortezomib, and dexamethasone) trial conducted by Richardson and colleagues,[16] the oldest patient in the study was 86 years old. For younger transplant-eligible patients, the use of upfront high-dose melphalan is being re-evaluated in clinical trials. Trials testing the use of low-dose melphalan in older patients are currently in progress or being initiated with the intent of prolonging remission duration, improving OS, and avoiding the use of alkylating agents. These new regimens will have to be tested against the current standards of MP plus a new agent before they can be established as standard approaches for older patients.

Treatment options and outcomes for patients with MM have never looked better. For our older patients, there is finally cause for celebration as the benefits enjoyed by younger patients become accessible to non–transplant-eligible patients through the use of new combinations. It is now more important than ever that we hold ourselves to evidence-based approaches when treating patients outside of clinical trials, since the use of regimens such as MPT, MPV, and Rd clearly improve survival for older patients and should be the standards against which new approaches are tested.

Financial Disclosure: Dr. Kaufman serves as a consultant for Celgene, Millenium, and Keryx, and he provides research support for Celgene and Merck. Dr. Lonial serves as a consultant for Celgene, Novartis, Millenium, and Bristol-Myers Squibb.

References:

References

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2. Harousseau JL, Palumbo A, Richardson PG, et al. Superior outcomes associated with complete response in newly diagnosed multiple myeloma patients treated with non-intensive therapy: analysis of the phase 3 VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone. Blood. 2010 Jul 13. [Epub ahead of print]

3. Mateos MV, Oriol A, Martinez-Lopez J, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Aug 23. [Epub ahead of print]

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6. Waage A, Gimsing P, Fayers P, et al. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010;116:1405-12.

7. Ludwig H, Hajek R, Tothova E, et al. Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood. 2009;113:3435-42.

8. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009;27:3664-70.

9. Badros A, Barlogie B, Siegel E, et al. Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years. Br J Haematol. 2001;114:600-07.

10. McCarthy PL, Owzar K, Anderson KC, et al. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant (ASCT) for multiple myeloma (MM): CALGB 100104. J Clin Oncol (Meeting Abstracts);28:8017.

11. Attal M, Cristini C, Marit G, et al. Lenalidomide maintenance after transplantation for myeloma. J Clin Oncol (Meeting Abstracts);28:8018.

12. Palumbo A, Dimopoulos MA, Delforge M, et al. A phase III study to determine the efficacy and safety of lenalidomide in combination with melphalan and prednisone (MPR) in elderly patients with newly diagnosed multiple myeloma. ASH Annual Meeting Abstracts. 2009;114:613.

13. Mateos M-V, Oriol A, Martinez J, et al. A prospective, multicenter, randomized, trial of bortezomib/melphalan/prednisone (VMP) versus bortezomib/thalidomide/prednisone (VTP) as induction therapy followed by maintenance treatment with bortezomib/thalidomide (VT) versus bortezomib/prednisone (VP) in elderly untreated patients with multiple myeloma older than 65 years. ASH Annual Meeting Abstracts. 2009;114:3.

14. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib, melphalan, prednisone and thalidomide (VMPT) followed by maintenance with bortezomib and thalidomide for initial treatment of elderly multiple myeloma patients. ASH Annual Meeting Abstracts. 2009;114:128.

15. 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. 2010;11:29-37.

16. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-86.