Double-Drug Combos Equivalent to Triple-Drug Regimens in Multiple Myeloma

For patients with transplant-ineligible multiple myeloma (MM), a two-drug combination of bortezomib plus dexamethasone resulted in a similar duration of progression-free survival (PFS) as two different three-drug combinations, according to a study published in the Journal of Clinical Oncology that reported on the phase IIIb UPFRONT trial.

The community-based UPFRONT trial compared three bortezomib-based treatment options for patients with transplant-ineligible MM: bortezomib-dexamethasone (VD), bortezomib-thalidomide-dexamethasone (VTD), and bortezomib-melphalan-prednisone (VMP). A total of 502 patients were randomly assigned to 24 weeks of induction therapy:

  • 168 to VD, intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 plus oral dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 [cycles 1 to 4], or 1, 2, 4, and 5 [cycles 5 to 8)
  • 167 to VTD, bortezomib and dexamethasone (same as VD regimen) plus oral thalidomide 100 mg on days 1 to 21
  • 167 to VMP, bortezomib (same as previous regimens) plus oral melphalan 9 mg/m2 and oral prednisone 60 mg/m2 on days 1 to 4, every other cycle, followed by 25 weeks (five 35-day cycles) of bortezomib maintenance (1.6 mg/m2 on days 1, 8, 15, and 22)

Ruben Niesvizky, MD, of Weill Cornell Medical College in New York, and colleagues compared median PFS (the study’s main endpoint), overall survival, and overall response rates among the three treatment groups. Investigators at the participating centers assessed patient responses using International Myeloma Working Group criteria.

“The initial hypothesis that the efficacy of VD would be inferior to that of VTD and VMP was not confirmed, highlighting a less-than-expected difference between doublet and triplet therapy,” Dr. Niesvizky and co-authors wrote.

The mean dose intensity of bortezomib (the dose received compared with the dose planned) was 72 percent, 63 percent, and 68 percent in the VD, VTD, and VMP groups, respectively, during induction, and 75 percent, 81 percent, and 87 percent during maintenance.

After a median follow-up of 42.7 months, the median PFS was 14.7 months for the VD cohort, 15.4 months for the VTD cohort, and 17.3 months for the VMP cohort. When compared with the other groups, none of the differences was significant.

Length of median overall survival was also similar among the three groups: 49.8 months for VD, 51.5 months for VTD, and 53.1 months for VMP. Overall response rates for VD, VTD, and VMP were 73 percent, 80 percent, and 70 percent, respectively. The median duration of response was comparable among all three groups, as well: 18.3, 22.4, and 19.8 months for VD, VTD, and VMP.

In terms of safety, adverse events (AEs) related to treatment were more common with VTD than with VD or VMP: In the VD group, 74 percent and 9 percent of patients experienced at least one grade ≥3 AE during induction and maintenance therapy, respectively; 82 percent and 3 percent in the VMP group; and 84 percent and 8 percent in the VTD group. Peripheral neuropathy was the most commonly reported AE in all three treatment groups.

Bortezomib maintenance therapy was feasible and did not produce more toxicity, the researchers noted. “Less-intensive bortezomib dosing and/or subcutaneous bortezomib may be beneficial for reducing the toxicities (particularly the high rates of peripheral neuropathy) associated with these regimens while maintaining efficacy, an important consideration in elderly persons,” they added. “Although all bortezomib-containing regimens produced good outcomes,” the authors concluded, “VTD and VMP did not appear to offer an advantage over VD in transplantation-ineligible patients with myeloma treated in U.S. community practice.”


Niesvizky R, Flinn IW, Rifkin R, et al. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Jun 8. [Epub ahead of print]