The Treatment of Elderly Patients With Multiple Myeloma: Is More Better?

The variety of treatment options available to patients of all ages who have multiple myeloma has improved considerably in the past decade. However, elderly patients have benefited more than patients of other ages. Because elderly patients, as a group, are usually not offered autologous stem cell transplant (ASCT) as a treatment option, they have been unable to benefit from the wide application of this technique, first introduced in the late 1980s. In the past 8 years, however, thalidomide, bortezomib, and very recently lenalidomide, when combined with conventional doses of alkylators and corticosteroids, have produced marked improvements in progression-free survival (PFS) and overall survival (OS) in elderly patients. Harousseau has thoroughly reviewed the important studies documenting these benefits for this population.

A point that is made well in this article and that cannot be overemphasized is the importance of the dosage and schedule of all these drug combinations to successful treatment outcomes. In elderly patients, more is not necessarily better. Appropriate dosing in elderly patients allows them to remain on therapy for sufficient time to achieve a response. Thus, in the melphalan, prednisone and thalidomide (MPT) trials, the higher doses of melphalan and thalidomide used in the Nordic trial[1] (median age, 78 years) were not associated with improved PFS or OS. The French trial,[2] which had a similar median age but used lower doses of melphalan and the lowest dose of thalidomide, demonstrated significant improvements in both PFS and OS. The lesson here is the value of compliance with the prescribed regimen: in the Nordic trial, the rate of dropouts resulting from toxicities was significantly higher than that reported in the French trial. A recent meta-analysis of six trials involving 1682 elderly patients demonstrated a 5-month improvement in PFS and a 7-month improvement in OS for MPT compared with melphalan and prednisone (MP).[3] This meta-analysis suggests that, as a group, patients over the ages of 65 to 70 will derive significant benefit from treatment with MPT, as long as the doses are not excessive.

A similar trial comparing MP without lenalidomide to MP with lenalidomide (MPR) has generated more questions than answers. This trial compared MP to MPR for induction for nine 4-week cycles; however, there was also a third arm, in which MPR was followed by lenalidomide maintenance until progression occurred.[4] MPR with maintenance was the clear winner in terms of PFS. Despite a superior overall response rate of 67% with MPR (versus 49% with MP), PFS was identical (13 months) in the MP and MPR arms that did not include maintenance. Although questions regarding the role of lenalidomide maintenance were not directly addressed in this trial, its results suggest that maintenance with lenalidomide is a helpful addition after induction with MP but that MPR for induction may be unnecessary.

The importance of the dose and schedule of dexamethasone when this agent is combined with immunomodulatory drugs for the treatment of older patients has been underscored by 2 recently reported trials. Thalidomide combined with intermediate-dose dexamethasone (TD; 320 mg of dexamethasone per cycle) was compared to MP; there was no difference in PFS in the two arms, but OS was significantly shorter in the TD arm because of toxicities and a high dropout rate.[5] The OS in the TD arm was shorter despite a higher overall response rate with TD. The Eastern Cooperative Oncology Group (ECOG) trial compared lenalidomide given with high-dose dexamethasone (480 mg/cycle) to lenalidomide with low-dose dexamethasone (160 mg/cycle).[6] Despite a higher response rate, the lenalidomide and high-dose dexamethasone arm was associated with far greater toxicities and a higher death rate in the first 4 months of treatment: 12 deaths in the high-dose dexamethasone arm compared with 1 death in the low-dose arm. The outcome of this trial was influenced primarily by the results in patients older than 65 years, who had a significantly higher death rate from complications and from progressive myeloma (due to the higher dropout rate among patients receiving lenalidomide and high-dose dexamethasone). In patients younger than 65 years, there were no differences in early outcomes between the high- and low-dose dexamethasone groups.

In the Spanish cooperative trial (Velcade as Initial Standard Therapy in Multiple Myeloma [VISTA]), the addition of bortezomib to MP twice weekly for 2 weeks out of 3, given for 8 cycles and followed by weekly maintenance with bortezomib, demonstrated a remarkable major response rate and significantly improved PFS and OS in all age groups.[7] While the development of neuropathy was significantly greater with MP plus bortezomib (MPV), this did not result in a higher rate of drug discontinuation (15% with MPV versus 14% with MP) and thus had no adverse effect on outcomes. The lack of effect of neuropathy on discontinuation rates was likely due to an aggressive, proactive dose reduction algorithm that allowed most patients to continue to receive therapy.

Another approach to ensuring disease control-maintenance therapy-has had more limited testing. After MPT induction, thalidomide maintenance has not clearly been shown to provide a survival advantage; trial results have been conflicting. As previously noted, MPR plus lenalidomide maintenance improves PFS but has not yet shown a survival advantage.[4] Bortezomib plus thalidomide maintenance improved PFS in one study; however, the trial was confusing since the maintenance arm followed a 4-drug induction regimen but was compared to a 3-drug induction regimen without maintenance.[8]

The role of ASCT in older patients remains controversial. Although at least one trial has demonstrated survival advantages for tandem, reduced–melphalan-dose transplants,[9] another trial did not show such a benefit.[10] At present, the role of ASCT in the elderly remains unresolved, and ASCT should not be routinely offered to elderly patients. This is not necessarily a disadvantage for this population, since outcomes with combinations of novel drugs and older drugs, used at appropriate dosages, have greatly improved.

Financial Disclosure:Dr. Bensinger has conducted clinical research studies for Celgene and Millenium, and he serves on the advisory board of Millenium and on the speakers’ bureau of Celgene.

References:

References

1. 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.

2. 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.

3. Waage A, Palumbo A, Hulin C, et al. MP versus MPT for previously untreated elderly patients with multiple myeloma [abstract]. Haematologica. 2010;95 Suppl 2:567.

4. Palumbo A, Dimopoulos M, Delforge MA. Phase 3 study to determine the efficacy and safety of lenalidomide combined with melphalan and prednisone in patients ≥ 65 years with newly diagnosed myeloma [abstract]. Hematologica. 2010;95 Suppl 2:566.

5. Ludwig H, Hajek R, Tóthová E, et al. Thalidomide-dexamethasone compared to melphalan-prednisolone in elderly patients with multiple myeloma. Blood. 2008;113:3435-42.

6. 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.

7. Mateos MV, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28:2259-66.

8. Boccadoro M, Bringhen S, Gaidano G, et al. Bortezomib, melphalan, prednisone and thalidomide (VMPT) followed by maintenance with bortezomib thalidomide (VT) for initial treatment of elderly multiple myeloma patients. J Clin Oncol. 2010;28:576s (Abstract 8013).

9. Palumbo A, Triolo S, Argentino C, et al. Dose-intensive melphalan with stem cell support (Mel 100) is superior to standard treatment in elderly myeloma patients. Blood. 1999;94:1248-53.

10. Facon T, Mary JY, Hulin C, et al. Intergroupe Francophone du Myélome. 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. 2007;370:1209-18.