Thalidomide improves response in three-drug regimen for multiple myeloma

The use of thalidomide, bortezomib and dexamethasone may improve response rates compared with cyclophosphamide, bortezomib and dexamethasone prior to autologous stem cell transplantation for multiple myeloma, according to results of a randomized, open-label phase 3 trial.

A previous analysis showed bortezomib (Velcade, Millennium Pharmaceuticals) induction resulted in improved PFS and OS compared with non-bortezomib induction in transplant-eligible patients with previously untreated multiple myeloma prior to autologous stem cell transplantation (ASCT).

“The goal of induction treatment before ASCT is the achievement of the highest possible response rate while avoiding an impairment of stem cell collection and significant toxicity that may preclude intensive therapy,” Philippe Moreau, MD, head of the hematology department at the University Hospital of Nantes, France, and colleagues wrote.

Phase 2 and 3 studies demonstrated that the most commonly used three-drug combinations — bortezomib–thalidomide (Thalomid, Celgene)–dexamethasone (VTD) and bortezomib–cyclophosphamide–dexamethasone (VCD) — demonstrated high response rates prior to ASCT and have become the standard of care in practice. However, these combinations have never been prospectively compared.

“The quality of response to the induction treatment prior to ASCT, as well as the response achieved following high-dose melphalan, are important prognostic factors and are predictive of PFS following ASCT. Therefore, it is important to optimize this first sequence of therapy,” the researchers added.

Moreau and colleagues randomly assigned 338 patients with newly diagnosed multiple myeloma 1:1 to receive four cycles of VTD or four cycles of VCD as induction before high-dose therapy and ASCT.

Both groups received four 3-week cycles of 1.3 mg/m² of bortezomib subcutaneously on days 1, 4, 8 and 11, as well as 40 mg of dexamethasone on days 1 through 4 and days 9 through 12. In addition, clinicians administered 100 mg/day of thalidomide orally to the VTD group and four 3-week cycles of 500 mg/m² of cyclophosphamide orally on days 1, 8 and 15 to the VCD group.

Post-induction very good partial response (VGPR) rate served as the primary endpoint. Secondary endpoints included complete response and overall response rates (ORR), safety of the induction regimen and stem cell harvest.

The intent-to-treat and safety analyses included all patients who received one dose of therapy. The per-protocol analysis included all patients who completed four cycles of treatment (VTD, n = 157; VCD, n = 154).

More patients who received VTD induction achieved VGPR compared with patients who received VCD induction in the intent-to-treat analysis (66.3% vs. 56.2%; 95% CI, 1%-18%, P = .05) and the per protocol analysis (70.7% vs. 60.4%; 95% CI, 2%-21%, P = .05).

The ORR also was higher in the VTD arm in the intent-to-treat analysis (92.3% vs. 83.4%; 95% CI, 2%-16%, P = .01) and the per protocol analysis (98.7% vs. 90.3%; 95% CI, 3.4%-13.5%, P = .001).

“Our results are of major importance since the quality of response to induction, and

especially the achievement of at least VGPR, clearly correlates with the outcome following ASCT,” Moreau and colleagues wrote.

Patients in both arms experienced similar rates of severe adverse events (VCD, 68.2%; VTD, 63.9%); however, hematologic toxicity was higher in the VCD arm, with increased rates of grade 3 and grade 4 anemia (9.5% vs. 4.1%), thrombocytopenia (10.6% vs. 4.7%) and neutropenia (33.1% vs. 19.9%). The rate of grade 3 to grade 4 peripheral neuropathy was increased in the VTD arm (7.7% vs. 2.9%).

Overall, 93% of patients — 159 in the VTD arm and 155 in the VCD arm — underwent stem cell mobilization. VTD induction demonstrated a superior stem cell yield compared with VCD induction (median number of CD34-positive cell/kg, 10.7 x 10⁶ vs. 9.2 x 10⁶; P = .05).

The researchers acknowledged that a study limitation includes that subsequent consolidation and maintenance treatments were at the discretion of the treating physician and PFS or OS data were not collected.

In this setting, VCD is less costly than VTD; however, the researchers expect price to become an important issue.

“The cost of thalidomide and cyclophosphamide is highly variable from one country to the other, but these two combinations are considered affordable for the majority of centers performing ASCT all over the world,” Moreau and colleagues wrote. – by Kristie L. Kahl

Disclosure: Moreau received honoraria from Celgene and Janssen-Cilag. Please see the full study for a list of all other researchers’ relevant financial disclosures.