Bortezomib/dexamethasone versus VAD as Induction Prior to Autologous Stem Cell Transplant (ASCT) in Previously Untreated Multiple Myeloma (MM): Updated Data from IFM 2005/01 Trial

Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 31 de mayo del 2008

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Presenter: Harousseau J.L.
Presenter's Affiliation: Hoteldieu Hospital, Nantes, France
Type of Session: Scientific

Background

  • Multiple Myeloma (MM) remains an incurable condition, with a median survival of 48-68 months.
  • Autologous stem cell transplant (ASCT) is the standard of care for MM patients aged ≤65 years old and is associated with a high complete response (CR) rate as well as a high very good partial response (VGPR) rate.
  • There are numerous strategies which have been used to try and improve outcomes. Strategies include intensification of therapy, such as with the use of tandem transplants; improvements in maintenance therapy; and use of new induction regimens (prior to ASCT).
  • The preclinical rationale for the combined use of bortezomib with dexamethasone is based on the ability of both agents to inhibit NF kappa B activity, which will hopefully lead to an additive effect. Additionally, bortezomib appears to activate caspase 8, whereas dexamethasone has weak activity on caspase 8 but has stronger activity on caspase 9. This combined activity may increase apoptosis, or programmed cell death, of the myeloma cells. 
  • Prior Phase II studies have demonstrated that bortezomib and dexamethasone (BD) are an effective induction therapy combination.
  • The present study compares the use of induction BD versus vincristine, doxorubicin, and dexamethasone (VAD) prior to ASCT in the treatment of MM.

Materials and Methods

  • Patients who were enrolled in this study were ≤65 years old with previously untreated MM.
  • The present study is a phase III trial comparing BD and VAD as induction therapy regimens prior to ASCT. The present study also examined the role of consolidation therapy with dexamethasone, cyclophosphamide, etoposide, and platinum (DCEP) in both BD and VAD therapy.
    • This was done as a four-armed trial, with the four arms as follows:
      • BD alone
      • VAD alone
      • BD followed by DCEP
      • and VAD followed by DCEP
    • BD was given in four cycles: bortezomib was given on days 1, 4, 8 and 11. Two cycles of dexamethasone were given.
    • VAD was given in four cycles
    • Consolidation with DCEP was given in two cycles.
  • The primary end point of this study was CR rates and near-complete response (n-CR) rates. These rates were defined based on negative immunofixation.
  • Planned enrollment was 480 patients based on a power of 80% to detect a 10% difference (10% versus 20%) in CR and n-CR rates between the treatment arms. Patients were evaluated using intent-to-treat analysis (ITT).

Results

  • A total of 482 patients were enrolled from July 2005 to January 2007: 
    • There were 121 patients in the VAD arm, 121 patients in the VAD+DCEP arm, 121 in the BD arm, and 119 patients in the BP-DCEP arm.
    • A total of 442 patients were evaluable at the time of this analysis.
    • Patients were stratified by high risk factors ( > 3mg/L versus ≤3 mg/L beta2 microglobulin and patients with and without deletion of chromosome 13).
  • Results of the ITT analysis of CR+nCR and ≥ VGPR after induction was as follows:
  VAD BD p-value
CR+nCR 8.3% 21.3% p=0.0023
≥VGPR 18.6% 46.7% p<0.0001
  • BD had superior response rates in low-, intermediate-, and high-risk patients. Patients with high and low levels of beta2 microglobulin and patients with and without deletion of chromosome 13 all benefited from BD therapy.
  • The significant differences between the 2 arms in both the CR+nCR rates as well as the ≥VGPR were maintained after ASCT both in the treated and ITT analyses. 
  VAD/ASCT BD/ASCT p-value
CR+nCR 28.8% 40.8% p=0.0089
≥VGPR 51% 71.8% P<0.0001

  

  VAD/ITT BD/ITT p-value
CR+nCR 23.6% 35% P=0.0056
≥VGPR 41.7% 61.7% P<0.0001
  • Consolidation with DCEP was not found to increase response rates.
  • There were fewer patients treated with BD who needed an additional transplant (28% versus 47%). 
  • However, the change in response rate was not associated with an increase in overall survival (OS) or progression free survival (PFS):
    • OS at 18 months was 89.3% for the VAD group as compared to 92.4%, and this was not statistically significant (p=0.45).
    • PFS at 18 months was 85.1% for the VAD group as compared to the 89.5% for the BD group, and this difference was not found to be statistically significant.
  • Toxicity:
    • Overall toxicity:
      • Grade 3 toxicity was similar between the two treatment arms, with 38.2% of patients in the BD arm and 40.6% of patients in the VAD arm having grade 3 toxicity. 
      • There was a lower rate of adverse event in the BD arm (25.2%) compared with the VAD arm (31.0%). 
      • There was a lower rate of adverse events leading to death in the BD arm (0.8%) as compared to the VAD arm (2.9%).
      • Neuropathy (all grades) was higher in the BD arm (35.3%) compared with the VAD arm (22.6%). 
    • Hematologic toxicity: 
      • There were higher rates of anemia and neutropenia in the VAD arm, with higher rates of infection. 
      • Thrombocytopenia was higher in the BD arm.
      • Stem cell collection was done with colony stimulating factor (CSF) alone without chemotherapy. There was a slightly higher rate of adequate stem cell collection (defined as >2.0x106 CD34+ cells/kg) in the VAD arm (99%) as compared to the BD arm (97%), and more patients in the BD arm required a second collection.

Author's Conclusions

  • BD increases CR and nCR rates compared with VAD in all groups of patients.
  • The higher post-induction response rates translated into better response rates after ASCT.
  • There was no benefit in OS or PFS in patients treated with BD versus those treated with VAD; however, there was short follow-up.
  • Given the results of this study, BD should be considered the standard of care for induction prior to ASCT.
  • The authors are now in the process of starting a trial investigating BD combined with thalidomide compared with linezolid and dexamethasone as induction therapy, to see if there is any improvement in response rates or survival.

Clinical/Scientific Implications

  • Prior to making conclusions regarding how the improvement in response rate seen with BD affects OS, longer follow up is needed. It is also possible that a larger difference in response rates is needed to see an effect on OS, and adding more therapeutic agents may be a way to do this. It is also possible that we need a better way of determining which patients may benefit the most from these new agents. Pharamcogenomics may help in defining these patient populations. These therapies may also be of more benefit in high-risk patients, and prior studies have suggested this. This may be a population to focus on in future studies. 
  • Although this study does suggest great potential for this induction therapy regimen, it is not yet the standard of care. Longer follow-up is needed, and there should ideally be a true improvement in quality of life, overall survival, or cost of treatment (with equivalence of effect) prior to accepting this regimen as the standard of care for induction prior to ASCT.

Patient Summary

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