Addition of Bortezomib to Thalidomide-Dexamethasone as Post-ASCT Consolidation Therapy Significantly Increases Response and PFS in Multiple Myeloma

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SAN DIEGO, CA—Patients with multiple myeloma (MM) had significantly increased rates of complete response (CR) and progression-free survival (PFS)—including superior PFS across poor prognosis subgroups—when postautologous stem cell transplantation (ASCT) consolidation therapy utilized bortezomib-thalidomide-dexamethasone compared with thalidomide-dexamethasone, investigators reported during the 53rd American Society of Hematology Annual Meeting and Exposition.

Michele Cavo, MD, Bologna University School of Medicine, Seràgnoli Institute of Hematology, Bologna, Italy, and colleagues sought to determine the specific impact of bortezomib-thalidomide-dexamethasone consolidation on improved clinical outcomes following a randomized Phase 3 study1 in 474 patients newly diagnosed with MM. They found bortezomib-thalidomide-dexamethasone as induction therapy prior to and consolidation therapy after double ASCT increased response rates and extended PFS when compared with thalidomide-dexamethasone.

As a follow-up, they performed a per-protocol analysis of 321 patients who received the entire treatment program, which comprised two preplanned cycles of consolidation therapy with either bortezomib-thalidomide-dexamethasone (160 of 236 patients, 68%) or thalidomide-dexamethasone (161 of 238 patients, 68%). By study design, two 35-day cycles of bortezomib 1.3mg/m2 Days 1, 8, 15, and 22; thalidomide 100mg/day Days 1–35; dexamethasone 40mg on day of and after each bortezomib administration; or thalidomide-dexamethasone (same doses as in bortezomib-thalidomide-dexamethasone) were given as consolidation therapy to patients randomly assigned to each of two respective induction regimens.

The two groups had comparable patient and disease characteristics at baseline. Median age was 57.4 years in the bortezomib-thalidomide-dexamethasone arm and 56.8 years in the thalidomide-dexamethasone arm; males comprised 60% and 59% of the patients and 61.2% and 61.5% had IgG myeloma subtype, respectively.

Rates of CR and CR/near CR (CR/nCR) were found to be significantly higher after consolidation therapy with bortezomib-thalidomide-dexamethasone compared with thalidomide-dexamethasone (CR: 60.6% vs 46.6%; P=0.012; CR/nCR: 73.1% vs 60.9%; P=0.02). The McNemar test confirmed bortezomib-thalidomide-dexamethasone consolidation post-ASCT enhanced CR and CR/nCR rates; CR: P=0.0009; CR/nCR: P=0.004; conversely, no significant increase in frequencies of CR (P=0.052) or CR/nCR (P=0.110) were demonstrated with thalidomide-dexamethasone consolidation therapy.

The absolute probability of upgrading from less than CR before consolidation to CR after consolidation was 30.4% with bortezomib-thalidomide-dexamethasone and 16.6% with thalidomide-dexamethasone (Pearson chi-square test P=0.03), the investigators found. Of patients who upgraded from less than CR to CR after bortezomib-thalidomide-dexamethasone consolidation, 96% were categorized as nCR (44%) or had a very good partial response (52%). A landmark analysis, in which the landmark was set as initiation of consolidation therapy, was performed to compare time to progression (TTP), PFS, and overall survival (OS) between treatment groups.

The estimated 3-year probability of relapse or progression at a median follow-up of 30 months was 39% with bortezomib-thalidomide-dexamethasone and 52% with thalidomide-dexamethasone (P=0.04 by Kaplan-Meier analysis; HR: 0.68, 95% CI: 0.48–0.98, P=0.041). For patients receiving bortezomib-thalidomide-dexamethasone consolidation, PFS was significantly longer than those treated with thalidomide-dexamethasone (3-year estimates: 60% vs 48%; P=0.042) (HR: 0.69, 95% CI: 0.48–0.99, P=0.043).

The investigators reported the superior PFS with bortezomib-thalidomide-dexamethasone consolidation compared with thalidomide-dexamethasone was retained across poor prognosis subgroups, including patients with t(4;14) and/or del(17p) (P=0.002), del(13q) (P=0.006), high serum β2-microglobulin >3.5 mg/L (P=0.022), lactate dehydrogenase >190 U/L (P=0.007), or ISS stage 2 and 3 (P=0.023). A multivariate regression analysis found the most important and independent variables to be positively correlated with PFS were bortezomib-thalidomide-dexamethasone consolidation therapy (HR 0.61, 95% CI: 0.42–0.89; P=0.01), β2-microglobulin <3.5 mg/L (HR 0.42, 95% CI: 0.29–0.61; P<0.0001), and absence of t(4;14) and del(17p) (HR 0.49, 95% CI: 0.34–0.73; P<0.0001).

Both bortezomib-thalidomide-dexamethasone and thalidomide-dexamethasone consolidation therapy were very well tolerated. Frequency of treatment-emergent Grade 3/4 adverse events was comparable, 10.6% in the bortezomib-thalidomide-dexamethasone group and 9.3% in thalidomide-dexamethasone group. In the bortezomib-thalidomide-dexamethasone group, 0.6% of patients reported peripheral neuropathy (one patient with non-severe pre-existing neuropathy that worsened during consolidation) vs. 0% in the thalidomide-dexamethasone group; in both groups, rates of skin rash and deep vein thrombosis were 0.6%. Patients treated with bortezomib-thalidomide-dexamethasone received 93%, 93%, and 96% of planned doses, respectively.

The investigators concluded that specific response and landmark analyses performed in this per-protocol population have shown consolidation therapy with bortezomib-thalidomide-dexamethasone significantly contributed to improved clinical outcomes previously observed for patients randomly assigned to the triplet as induction and consolidation therapy plus double ASCT.

Reference

1. Cavo M, Tacchetti P, Patriarca F, et al for the GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376(9758):2075-85. Epub 2010 Dec 9.

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