High-dose Therapy with Single Autologous Transplantation versus Chemotherapy for Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Abstract

Myeloablative high-dose therapy and single autologous stem cell transplantation (HDT) is frequently performed early in the course of multiple myeloma, supported by some randomized controlled trials (RCTs) indicating overall survival (OS) and progression-free survival (PFS) benefit compared with nonmyeloablative standard-dose therapy (SDT). Other RCTs, however, suggest variable benefit. We therefore undertook a systematic review and meta-analysis of all RCTs evaluating upfront HDT versus SDT in myeloma. The primary objective was to quantify OS benefit with HDT, with PFS benefit a secondary objective. Anticipating heterogeneity, sensitivity and subgroup analyses were undertaken to assess robustness of results. Assessment of harms (treatment-related mortality) was also undertaken. We searched the PubMed, Embase, and Cochrane Collection of Controlled Trials databases using the terms myeloma combined with autologous or transplant or myeloablative or stem cell. In total, 3407 articles were accessed, and 10 RCTs prospectively comparing upfront HDT with SDT, with > or =2-year follow-up, and reporting OS benefit on an intent-to-treat basis were identified. Two reviewers independently extracted study characteristics, interventions, and outcomes. Hazard ratios (with 95% confidence interval) were determined. Nine studies comprising 2411 patients were fully analyzed. Significant heterogeneity was present. The combined hazard of death with HDT was 0.92 (95% confidence interval, 0.74-1.13). The combined hazard of progression with HDT was 0.75 (95% confidence interval, 0.59-0.96). The totality of the randomized data indicates PFS benefit but not OS benefit for HDT with single autologous transplantation performed early in multiple myeloma. Sensitivity and subgroup analyses supported the findings and indicated that, contrary to current reimbursement criteria, PFS benefit with upfront HDT is not restricted to chemoresponsive myeloma. However, the overall risk of developing treatment-related mortality with HDT was increased significantly (odds ratio, 3.01; 95% confidence interval, 1.64-5.50). Hence, evaluating alternative therapeutic options upfront may also be reasonable.

International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100)

“…This paradigm is supported by the results of multiple randomized trials demonstrating a higher complete remission rate and longer event-free survival in high-dose therapy recipients. 41 With the advent of novel induction therapies containing either bortezomib, lenalidomide or combinations that result in complete remission rates of up to 30% and VGPR rates of over 50%, the role of both single and tandem high-dose therapy consolidation for transplant eligible patients needs to be reexplored in the context of well designed clinical trials. An important aspect of new trials will be the role of planned up front transplant versus transplant at the time of subsequent relapse.…”

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma

“…Auto-HCT was associated with superior PFS and OS in two large randomized studies while a meta-analysis showed superior PFS. [1][2][3] Incorporation of auto-HCT and the introduction of the immunomodulatory drugs (ImiDs; thalidomide, lenalidomide and pomalidomide) and proteasome inhibitors (bortezomib and carfilzomib) have led to significant improvement in clinical outcomes, but cure has remained elusive. Allogeneic HCT (allo-HCT) studies demonstrated a plateau in OS with long-term follow-up, indicating a potential cure fraction.…”

G-CSF plus preemptive plerixafor vs hyperfractionated CY plus G-CSF for autologous stem cell mobilization in multiple myeloma: effectiveness, safety and cost analysis

“…1 MM remains incurable and the aim of treatment in non-elderly patients, in general o65 years, is to prolong survival using chemotherapy, corticosteroids and/or novel agents such as bortezomib or lenalidomide followed by high-dose chemotherapy and auto-SCT, which has been shown to be superior to conventional chemotherapy alone. [2][3][4] The optimal regimen to mobilize stem cells in patients with MM is still controversial and has not been clearly defined. The mobilization strategies implemented by most transplant centers consist of G-CSF alone (steady-state strategy) or CY followed by G-CSF (chemo-mobilizing strategy).…”