Abstract

The introduction of novel agents and combination treatments in multiple myeloma (MM) has dramatically improved overall response rates and quality of responses including rates of complete and near complete response (CR/nCR) and very good partial response (VGPR). There is emerging evidence that achieving at least ≥90% disease reduction (≥ VGPR) at some point of treatment is associated with improved outcome and longer survival. Therefore, there is a need to identify patients who will likely achieve this level of reduction of disease and therefore who will have a higher likelihood of benefiting from the specific treatments. In the current study, we evaluated GEP of MM cells obtained from patients who were enrolled in a phase II clinical trial of the frontline therapy with a combination with bortezomib (Velcade), liposomal doxorubicin (Doxil) and dexamethasone (VDD). The primary objective of this research is to develop predictive biomarkers of response to VDD by identifying GEP of patient who achieve ≥ VGPR. Forty newly diagnosed patients were enrolled in the trial. The regimen was given for six 3-week cycles as follows: Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and dexamethasone at 40 mg on days 1–4 for the first 10 patients and for the remaining patients at 20 mg on days of Velcade and the day after. Updated results from 40/40 evaluable patients show 93% partial response rate (≥ PR) with 43% CR/nCR and 63% > VGPR (Jakubowiak et al., IMW 2007, Abstract PO-721). Bone marrow aspirates were obtained before therapy from patients who had given an optional consent for research samples. MM cells were negatively selected using RossetteSep myeloma antibody cocktail. Gene expression profiling was performed with 20 samples using Affymetrix Human Genome U133 Plus 2.0 microarray, of which 19 samples were evaluable. These samples were classified based on the modified uniform response criteria with an addition of nCR and minor response (MR) (

Durie et al,
Leukemia
2006
;
20
:
1467
) as either ≥ VGPR, (includes VGPR and CR/nCR), or <VGPR (includes PR and MR). There were 9 samples classified as ≥VGPR and 10 samples that were <VGPR. GEP analysis revealed 166 genes that were differentially expressed in patients with ≥ VGPR compared with patients with <VGPR (p < 0.001). Further analysis indicated that many of these genes may play a role in cell cycle control, signal transduction, apoptosis, and gene transcription. We plan a comparison of GEP signatures of patients with ≥ VGPR to VDD with those identified in the APEX studies for Velcade alone. The study described here provides evidence that GEPs of samples derived from patients before treatment is a useful tool in clinical trials to prospectively evaluate MM patients for individualized therapy with the goal of minimizing toxicity and maximizing efficacy.

Author notes

Disclosure:Employment: GM is an employee of Millennium Pharmaceuticals. Research Funding: Ortho Biotech provided funding for the clinical trial. Honoraria Information: AJ recieved honoraria as part of the Speakers Bureau for Ortho Biotech and Millennium Pharmaceuticals. Membership Information: AJ is on the Speakers Bureau for Ortho Biotech and Millenium Pharmaceuticals.