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

Summary

Background

Bortezomib plus melphalan and prednisone (VMP) is significantly better than melphalan plus prednisone alone for elderly patients with untreated multiple myeloma; however, toxic effects are high. We investigated a novel and less intensive bortezomib-based regimen to maintain efficacy and to reduce toxic effects.

Methods

Between March, 2006, and October, 2008, 260 patients with untreated multiple myeloma, 65 years and older, from 63 Spanish centres, were randomly assigned to receive six cycles of VMP (n=130) or bortezomib plus thalidomide and prednisone (VTP; n=130) as induction therapy, consisting of one cycle of bortezomib twice per week for 6 weeks (1·3 mg/m² on days 1, 4, 8, 11, 22, 25, 29, and 32), plus either melphalan (9 mg/m² on days 1–4) or daily thalidomide (100 mg), and prednisone (60 mg/m² on days 1–4). The first cycle was followed by five cycles of bortezomib once per week for 5 weeks (1·3 mg/m² on days 1, 8, 15, and 22) plus the same doses of melphalan plus prednisone and thalidomide plus prednisone. 178 patients completed the six induction cycles and were randomly assigned to maintenance therapy with bortezomib plus prednisone (n=87) or bortezomib plus thalidomide (n=91), consisting of one conventional cycle of bortezomib for 3 weeks (1·3 mg/m² on days 1, 4, 8, and 11) every 3 months, plus either prednisone (50 mg every other day) or thalidomide (50 mg per day), for up to 3 years. Treatment codes were generated with a computerised random number generator, and neither participants nor study personnel were masked to treatment. The primary endpoint was response rate in induction and maintenance phases. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00443235.

Findings

In the induction phase, 105 (81%) patients in the VTP group and 104 (80%) in the VMP group achieved partial responses or better (p=0·9), including 36 (28%) and 26 (20%) complete remissions, respectively (p=0·2). Treatment with VTP resulted in more serious adverse events (40 [31%] vs 20 [15%], p=0·01) and discontinuations (22 [17%] vs 15 [12%], p=0·03) than did treatment with VMP. The most common toxicities (grade 3 or worse) were infections (one [1%] in the VTP group vs nine [7%] in the VMP group), cardiac events (11 [8%] vs 0), and peripheral neuropathy (nine [7%] vs 12 [9%]). After maintenance therapy, the complete remission rate was 42% (40 [44%] patients in complete remission in the bortezomib plus thalidomide group, 34 [39%] in the bortezomib plus prednisone group). No grade 3 or worse haematological toxicities were recorded during maintenance therapy; two (2%) patients in the bortezomib plus prednisone group and six (7%) in the bortezomib plus thalidomide group developed peripheral neuropathy.

Interpretation

Reduced-intensity induction with a bortezomib-based regimen, followed by maintenance, is a safe and effective treatment for elderly patients with multiple myeloma.

Funding

Pethema (Spanish Program for the Treatment of Hematologic Diseases).

Introduction

Melphalan plus prednisone has been the standard treatment for elderly patients with newly diagnosed multiple myeloma for more than 30 years.¹ It is regarded as an appropriate backbone for combination regimens containing novel agents. Findings from five randomised trials2, 3, 4, 5, 6 have shown that melphalan, prednisone, and thalidomide (MPT) is better than melphalan plus prednisone in terms of response rate and progression-free survival (PFS), with increased overall survival reported in three trials.3, 5, 6 Preliminary results from a randomised trial of melphalan and prednisone plus lenalidomide, with or without lenalidomide maintenance, versus standard melphalan plus prednisone have shown that the lenalidomide-containing regimen induces higher response rates than does melphalan plus prednisone alone, and that addition of maintenance translates into longer PFS; no differences in overall survival have yet been recorded.⁷

Melphalan plus prednisone has also been combined with bortezomib (VMP). In a large randomised study (VISTA [Velcade as Initial Standard Therapy in Multiple Myeloma]),⁸ VMP was better than was melphalan plus prednisone alone for all efficacy endpoints, including response rates (30% vs 4% complete responses), and PFS and overall survival. The basis for the VISTA trial was a pilot study by the Spanish Myeloma Group (PETHEMA/GEM),⁹ the efficacy results from which were closely reproduced in VISTA. In both studies important toxic effects were recorded, particularly peripheral neuropathy (grade 3 or worse in 13% of patients in the VISTA study and in 17% in the pilot study) and gastrointestinal symptoms (19% grade 3 or worse in VISTA). Accordingly, we planned 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. We designed a two-stage randomised trial. In the first stage, patients received induction therapy based mainly on a once per week dosing of bortezomib, rather than twice a week as in VISTA, in combination with prednisone plus either melphalan (an alkylating agent) or thalidomide (an immunomodulatory drug). This stage was followed by a second randomisation to maintenance therapy with bortezomib plus either thalidomide or prednisone.