Patients eligible for transplant

Results from a phase III trial evaluating autologous transplantation, consolidation and maintenance therapy in multiple myeloma

Progression-free survival (PFS) and overall survival (OS) advantages for transplant-eligible patients with multiple myeloma (MM) have been shown with single-cycle melphalan 200mg/m2 and autologous hematopoietic cell transplantation (AHCT) followed by lenalidomide (len) maintenance, which is the standard of care for patients in the United States (US).

Edward A. Stadtmauer, from Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA, Marcelo C. Pasquini from Medical College of Wisconsin, Wisconsin, US, and colleagues, conducted a randomized, three-arm, phase III trial (BMT CTN 0702; NCT01109004) across 54 transplantation centers in the US. The aim was to assess whether any further PFS and OS benefit can be provided from more intensive interventions such as second AHCT or consolidation with combinations of immunomodulatory agents, proteasome inhibitors or corticosteroids.

Study design and patient population
  • N = 758 symptomatic MM patients, median age: 56 years (range, 20–70)
    • Enrolment criteria: previous treatment with ≥2 cycles of any initial therapy regimen, without disease progression, within 212 months of first dose of therapy
    • At enrolment, 24% of patients had high-risk MM, 73% had a triple-drug regimen initially and 18% were in complete remission
  • Patients were randomly assigned 1:1:1 to one of three trial arms:
    • AHCT/AHCT + len (n = 247): high dose melphalan (200 mg/m2) followed by autologous peripheral-blood stem-cell infusion
    • AHCT + four cycles of len, bortezomib and dexamethasone (RVD; AHCT + RVD) + len (n = 254): four cycles of len 15 mg/d on days 1–14; bortezomib 1.3 mg/m2 on days 1,4, 8, and 11 of every 21-day cycle; and 40mg of dexamethasone per day on days 1, 8, and 15
    • AHCT + len (n = 257)
  • Primary endpoint: PFS measured until disease progression, nonprotocol systemic antimyeloma therapy or death
  • Secondary endpoints: OS, disease progression, disease response, conversion to complete response (CR) after initiation of maintenance, noncompliance with treatment, treatment related mortality (TRM), toxicities > grade 3 and infections
Key Findings

All data is given as AHCT/AHCT + len arm vs AHCT + RVD + len arm vs AHCT + len arm:

Efficacy
  • The 38-month PFS rates were: 58.5% (95% CI, 51.7%–64.6%) vs 57.8% (95% CI, 51.4%–63.7%) vs 53.9% (95% CI, 47.4%–60.0%)
  • OS rates: 81.8% (95% CI, 76.2%–86.2%) vs 85.4% (95% CI, 80.4%–89.3%) vs 83.7% (95% CI, 78.4%–87.8%)
  • Complete response rates at 1 year: 50.5% (n = 192) vs 58.4% (n = 209) vs 47.1% (n = 208)
  • Disease progression at 38 months: 39.8% (95% CI, 33.4%–46.1%) vs 41.0% (95% CI, 34.7%–47.0%) vs 45.6% (95% CI, 39.2%–51.8%)
Safety
  • TRM over 38 months occurred in: n = 4 vs n = 3 vs n = 1
  • The percentage of patients with ≥1 non-hematologic grade 3–5 toxicity in each arm were comparable at 49%, 47% and 48%, respectively
  • Cumulative incidences of SPM at 38 months: 5.6% (95% CI, 3.2%–9.1%) vs 5.7% (95% CI, 3.2%–9.0%) vs 4.1% (95% CI, 2.1%–7.1%)
  • Across all arms, toxicity profiles and development of secondary primary malignancies were similar

This phase III study has shown no additional benefit in PFS or OS over 38 months when more intensive treatment approaches, such as second AHCT or RVD + len maintenance cycles, are used. Therefore, in the transplant-eligible patient population, initial therapy of multidrug induction with AHCT consolidation and maintenance should remain as the standard approach.

References
  1. Stadtmauer EA.,  Pasquini MC. et al. Autologous transplantation, consolidation and maintenance therapy in multiple myeloma. J Clin Onc. 2019 Jan 17. DOI: 10.1200/JCO.18.00685. [Epub ahead of print].
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