Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone compared with no intensification in patients with newly diagnosed multiple myeloma: subgroup analysis of the Myeloma XI trial

At diagnosis of myeloma, there can be significant intraclonal heterogeneity due to the accumulation of a variety of genetic lesions.¹ In order to maximize the effect of induction therapy, and avoid selecting resistant tumor cell clones, the use of combination therapies has become the norm.² In order to further deepen response, there are multi-step treatment strategies that may include induction followed by hematopoietic stem cell transplantation (HSCT) and then a post-transplantation consolidation step. The Myeloma IX study found that patients with a complete response (CR) before HSCT demonstrated better progression-free survival (PFS) and overall survival (OS) than those without a CR. This demonstrates that perhaps there should be a pre-transplant treatment intensification rather than the more standard post-transplant consolidation.^{3, 4}

Graham Jackson, Newcastle University, UK, and colleagues have just published their results from the Myeloma XI trial (NCT01554852). This open label, randomized, adaptive design, phase III trial was undertaken at 110 hospitals around the UK and included three randomizations: at induction, intensification, and at maintenance treatment. The publication in Lancet Haematology covers the randomization to intensification treatment part of the study.² A total of 583 patients with newly diagnosed multiple myeloma (NDMM), who had a suboptimal response to initial standard triplet induction treatment, were randomized to the intensification treatment and received either cyclophosphamide (C), bortezomib (V), and dexamethasone (d; CVd; n=289) or no treatment (n=294).

Dosing schedule

Patients in the CVd group received:

• Oral C: 500mg (Days 1, 8, and 15)
• Subcutaneous or intravenous V: 1.3mg/m² (Days 1, 4, 8, and 11)
• Oral d: 20mg (Days 1, 2, 4, 5, 8, 9, 11, and 12) for a maximum of 8 x 21-day cycles

Efficacy

All data shown is CVd vs no treatment.

• Median follow-up after randomization: 29.7 months (interquartile range [IQR], 17.0–5)
• Patients who had disease progression or died during the study: 131/289 (45%) vs 170/294 (58%)
  • Patients who died during the study: 54/289 (18%) vs 54/294 (19%)
• Median PFS: 30 months (95% confidence interval [CI], 25–36) vs 20 months (95% CI, 15–28), hazard ratio (HR) = 0.60 (95% CI, 0.48–0.75), p< 0.0001
• Median PFS in transplantation-eligible patients: 48 months (95% CI, 35–not reached [NR]) vs 28 months (95% CI, 22–33), HR = 0.50 (95% CI, 0.36–0.68), p< 0.0001
• Median PFS in transplantation-ineligible patients: 20 months (95% CI, 15–23.7) vs 9 months (95% CI, 6–15), HR = 0.73 (95% CI, 0.52–1.02), p= 0.061
• Median OS was NR
• Three-year OS: 77.3% (95% CI, 71·0–83·5) vs 78·5% (95% CI, 72·3–84·6), HR = 0·98 (95% CI, 0·67–1·43), p= 0·93
• At the time of randomization there were similar rates of minimal response, CR, very good partial response (VGPR), and stable or progressive disease across the two study groups
  • VGPR: 113/289 (39.1%) patients (95% CI, 33.4–44.9) vs 40/289 (33.6%) patients (25·2–42·9)
  • CR: 10/289 (3·5%) patients (95% CI, 1·7–6·3) vs 7/289 (5.9%) patients (2.4–11.7)
• Median PFS of CVd intensification treatment was also beneficial across cytogenetic risk groups: standard risk HR = 0·45 (95% CI, 0·28–0·73), high-risk HR = 0·40 (95% CI, 0·21–0·76), and ultra­-high-risk HR = 0·18 (95% CI, 0·06–0·49)

Safety

• Median number of CVd cycles: four (range 3–5)
  • There were 144/289 (50%) of patients in the CVd arm who had a dose modification:
    • Modified C: 58/289 (20%)
    • Modified V: 115/289 (40%)
    • Modified d: 74/289 (26%)
  • Serious adverse events were reported in 103/289 (37%) patients in the CVd group, with the most common being infection (42/289 [59%])

Graham Jackson and team concluded that the use of CVd intensification treatment significantly improved PFS when compared to no intensification in patients with NDMM who had a suboptimal response to the standard induction therapy. There was no improvement in OS.

There have been a number of other analyses from the Myeloma XI trial which have been summarized on the Multiple Myeloma Hub. They can be found here:

• EHA 2019 | Molecular subgroup analysis of the Myeloma XI phase III trial
• Lenalidomide maintenance compared to observation in patients with newly diagnosed multiple myeloma: sub-group results from the Myeloma XI trial
• ESH MM 2018 | Continuous or fixed-duration therapy in multiple myeloma?
• Patients with multiple myeloma with a high sub-clonal fraction of 17p deletion have poor prognosis