Review and meta-analysis of phase III RCTs assessing the role of HDT/ASCT in NDMM

In the past two decades, the standard treatment for Newly Diagnosed patients with Multiple Myeloma (NDMM) consists of a high-dose therapy with melphalan (HDT) followed by autologous stem cell transplant (ASCT). Prior to the use of novel agents, several studies confirmed an improvement in the response rate (RR), progression-free survival (PFS), and overall survival (OS) with the administration of HDT/ASCT.

Binod Dhakal, from the division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, US, and colleagues, sought to re-evaluate the efficacy of HDT/ASCT in light of the new treatments available to NDMM patients. The details of this meta-analysis using previously published randomized clinical trials (RCTs) were published in JAMA Oncology in January 2018.

Key Highlights:

• Material used included: MEDLINE (PubMed), Scopus, and Cochrane Collection of Controlled Trial databases; 2480 relevant articles published after 1 January 2000, and congress abstracts from ASCO, ASH, and EHA congresses during the last 4 years
• Studies were included if they met the following criteria: ‘1) use of phase III randomized clinical trial (RCT) design; (2) enrolled and reported outcomes for patients with NDMM undergoing HDT/ASCT; (3) directly compared combination chemotherapy with novel agents followed by consolidation with HDT/ASCT vs standard-dose therapy (SDT) alone; and (4) directly compared single HDT/ASCT (HDT1) vs tandem HDT/ASCT (HDT2) (for network meta-analysis only)’
• Four RCTs were used for the conventional meta-analysis
  • Complete response (CR) achieved by a higher proportion of pts receiving HDT/ASCT vs STD
  • CR: HR for HDT/ASCT vs STD = 1.27 (95% CI, 0.98–1.65; P = 0.07)
  • Statistically significant PFS benefit with HDT/ASCT; HR = 0.55 (95% CI, 0.41–0.74; P = 0.004
  • Significant beneficial effect of HDT on PFS associated with longer median follow-up (HR/mo = 0.98; 95%CI, 0.96–0.99; P = 0.03) and the use of HDT2 (HR for all HDT2 vs none = 0.61; 95%CI, 0.39–0.93; P = 0.02)
  • OS (reported in three studies): combined HR = 0.76 (95% CI, 0.42–1.36; P = 0.20)
  • Significant beneficial effect of HDT on OS, associated with longer median follow-up (HR/mo = 0.90; 95% CI, 0.84–0.96; P = 0.002) and the use of HDT2 (HDT2 vs none, HR = 0.41 ; 95%CI, 0.23–0.71; P = 0.002)
• Findings from the network meta-analysis:
  • Higher PFS for HDT/ASCT vs SDT, although not statistically significant:
    • HDT2 vs SDT; HR = 0.49; 95%CI, 0.37–0.65
    • HDT1 plus bortezomib-lenalidomide-dexamethasone (VRD) vs SDT; HR = 0.53; 95%CI, 0.37–0.76
  • Statistically significant increase in PFS for HDT2 and HDT1:
    • HDT2 vs HDT1; HR = 0.79, 95%CI, 0.55–0.92; P < 0.001
    • HDT1 plus VRD vs HDT1; HR = 0.78; 95% CI, 0.54–1.00; P = 0.02
  • No difference in OS between HDT2 vs HDT1

This is the first meta-analysis evaluating the role of HDT/ASCT in the light of novel agents with a comparison of the differential role of HDT2 vs HDT1 and SDT, using all the relevant RCTs. This study showed a statistically significant increase in PFS when NDMM patients are treated with HDT2 or HDT1 plus VRD, in comparison to treatment with HDT1 alone. Regardless of the lack of OS benefit, NDMM patients treated with HDT/ASCT treatment display a significant PFS benefit, low treatment-related mortality (TRM), and potential high MRD-negative rates, which justifies the use of HDT/ASCT as an up-front treatment strategy in NDMM patients. Future studies will include following up on quality of life, patient-reported outcomes, and pharmacoeconomics related to the use of HDT/ASCT along with novel agents.

For an interview with Binod Dhakal on this topic recorded during the 2017 ASCO Annual Meeting, click here.