Xavier Leleu, MD, PhD
Dr. Leleu indicated no relevant conflicts of interest.
Mateos MV, Oriol A, Martínez-López 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;11:934-941.
The treatment of elderly patients with newly diagnosed symptomatic multiple myeloma has improved since the era of melphalan plus prednisone, the standard treatment for more than 30 years. Current regimens still include melphalan plus prednisone as a backbone for combination regimens that contain newer agents, such as bortezomib, lenalidomide, or thalidomide therapy. Despite remarkable response rates and survival benefits, none of these combinations has freed patients and physicians from the anxiety of various side effects. Aside from constipation and somnolence, thalidomide shares thromboembolic events and fatigue with lenalidomide, and peripheral neuropathy with bortezomib. Bortezomib is also marked by gastrointestinal symptoms, most notably diarrhea. In the VISTA study [Velcade as Initial Standard Therapy in Multiple Myeloma] that supported the approval of bortezomib in newly diagnosed elderly patients with multiple myeloma, grade 3 or worse peripheral neuropathy was described in 13 percent of patients and grade 3 or worse gastrointestinal symptoms in 19 percent.1 Still, patients must receive some kind of treatment without delay, since myeloma can rapidly lead to renal failure, bone lytic lesions and fracture, severe bone pain, and spinal cord compression, among other complications.
Mateos et al. from the Spanish Myeloma Group reported the results of a phase III trial in which 260 patients with untreated multiple myeloma, 65 years of age and older, were randomly assigned to receive six cycles of bortezomib plus melphalan and prednisone (VMP) or bortezomib plus thalidomide and prednisone (VTP) as induction therapy. The first cycle of bortezomib was given at maximum intensity per cycle (twice per week for six weeks) followed by five cycles of reduced intensity bortezomib (once per week for five weeks). Patients were then randomized to maintenance therapy.
This approach was associated with similar response rates and slightly better progression-free survival than VISTA, although the two approaches were never directly compared in a randomized study. More importantly, this approach was associated with a reduction in the incidence of grade 3 or worse peripheral neuropathy (8% of patients) and gastrointestinal symptoms (4%). The frequency of peripheral neuropathy might be further decreased if the dose of bortezomib was reduced to 1.0 mg/m². This study reported use of a novel and less intensive bortezomib-based treatment regimen with two objectives: to maintain efficacy and reduce toxic effects compared with the regimen used in VISTA.
This study shows that bortezomib-based regimens using an intensive dosing schedule of bortezomib twice per week in the first cycle to obtain rapid debulking activity, followed by less intensive weekly dosing, are not only well-tolerated but are also an active approach for elderly populations. These changes could not only provide a more safe and convenient treatment for patients, but may also reduce early discontinuations, which eventually lead to decreased efficacy. In the present study, 28 infusions of bortezomib within 31 weeks were as good as 32 infusions within 24 weeks in the VISTA study. Similar results were confirmed in other studies published and ongoing. For example, low-dose dexamethasone was as good as high-dose dexamethasone because it was less toxic.2 The race to develop the most effective novel agents and to determine the most intensive regimens has escalated since 2000, and yet the most striking observation in recent years has been that “more is better” only in a less intensive manner in elderly patients with multiple myeloma.
- San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917.
- 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.