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Improved Survival With Four-Drug Induction Regimen Followed by Maintenance in Initial Treatment of Transplant-Ineligible Multiple Myeloma

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Key Points

  • Bortezomib, melphalan, prednisone, and thalidomide (VMPT) induction followed by bortezomib plus thalidomide (VT) maintenance significantly improved progression-free and overall survival and time to next treatment vs bortezomib, melphalan, and prednisone without maintenance in patients with multiple myeloma ineligible for stem cell transplantation.
  • VMPT-VT was associated with higher rates of grade 3 or 4 neutropenia, cardiologic events, sensory neuropathy, and vascular events and a higher rate of treatment discontinuation.

In an updated analysis of an Italian phase III trial reported in the Journal of Clinical Oncology, Palumbo et al found that induction with bortezomib (Velcade), melphalan, prednisone, and thalidomide (Thalomid) followed by bortezomib plus thalidomide maintenance (VMPT-VT) significantly improved progression-free and overall survival vs bortezomib, melphalan, and prednisone (VMP) without maintenance as first-line treatment in patients with multiple myeloma who were ineligible for stem cell transplantation.

Study Details

In the trial, 511 patients ineligible for transplantation due to age (≥ 65 years) or coexisting morbidities were randomly assigned to receive VMPT-VT as nine 5-week cycles of VMPT followed by 2 years of VT maintenance (n = 254) or VMP as nine 5-week cycles without maintenance (n = 257). Patients had a median age of 71 years and 27% were aged > 75 years.

In the initial report from this trial at median follow-up of 23 months, VMPT-VT was associated with greater response rate (38% vs 24%) and 3-year progression-free survival (56% vs 41%). The current report provided 4-year follow-up.

Improved Progression-Free and Overall Survival

After median follow-up of 54 months. median progression-free survival was 35.3 months in the VMPT-VT group vs 24.8 months in the VMP group (hazard ratio [HR] = 0.58, P < .001). The median time to next therapy was 46.6 vs 27.8 months (HR = 0.52, P < .001). Five-year overall survival was 61% vs 51% (HR = 0.70, P = .01). Median survival from relapse did not differ between groups (HR = 0.92, P = .63).

On multivariate analysis, treatment with VMPT-VT (HR = 0.69, P = .02), age < 75 years (HR = 0.58, P = .002), female sex (HR = 0.62, P = .003), and International Staging System stage I to II (HR = 0.69, P = .04) were significantly associated with prolonged overall survival.

Therapy after first relapse consisted of bortezomib in 4%, thalidomide or lenalidomide (Revlimid) in 25%, conventional chemotherapy in 11%, and radiotherapy in 1% of the VMPT-VT group; and bortezomib in 11%, thalidomide or lenalidomide in 39%, conventional chemotherapy in 8%, and radiotherapy in 1% of the VMP group.

Increased Adverse Events

Grade 3 or 4 hematologic adverse events occurred in 48% of VMPT-VT patients vs 41% of VMP patients (P = .13) and grade 3 or 4 nonhematologic adverse events occurred in 54% vs 33% (P < .001). Grade 3 or 4 adverse events that were more common with VMPT-VT were neutropenia (38% vs 28%, P = .01), cardiologic events (11% vs 5%, P = .02), sensory neuropathy (11% vs 5%, P = .02), and vascular events (5% vs 2%, P = .05).

During the maintenance phase with VT, the incidence of new or worsened grade 3 or 4 adverse events was < 5%. Adverse events led to treatment discontinuation in 28% vs 16% of patients (P = .001), including 25% vs 15% of patients aged < 75 years and 35% vs 16% of those aged > 75 years.

The investigators concluded, “Bortezomib and thalidomide significantly improved [overall survival] in multiple myeloma patients not eligible for transplantation.”

Antonio Palumbo, MD, of Azienda Ospedaliera Città della Salute e della Scienza di Torino, Italy, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by the Italian Medicines Agency. For full disclosures of the study authors, visit jco.ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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