RNA-seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature.

Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.

Autologous stem cell transplantation for follicular lymphoma is of most benefit early in the disease course and can result in durable remissions, irrespective of prior rituximab exposure.

The role of autologous stem cell transplantation (ASCT) and the optimal timing of such transplants in patients with follicular lymphoma (FL) remains contentious. We present a single-centre experience documenting the outcomes of 70 FL patients who underwent BEAM (carmustine, cytarabine, etopside, melphalan)-conditioned ASCT between 1988 and 2009. With a median follow-up of 6·8 years (0·1-19·2), the 7-year overall survival (OS) and progression-free survival (PFS) from the date of ASCT was 76% and 60%, respectively. A significant difference in OS was found when comparing the patients transplanted in first or second remission versus those transplanted in later remissions (P = 0·02) and this significance was maintained when OS was calculated from the date of diagnosis (P = 0·03). There was a plateau on the PFS curves for patients transplanted in either first or second remissions after 9·3 and 6·4 years respectively, suggesting that these groups may never relapse. No differences were seen in OS or PFS in those treated with rituximab prior to transplant versus those who were not. Our data shows that BEAM ASCT can be a highly effective treatment in patients with FL early in the disease course, and that a proportion of patients experience prolonged disease-free survival and may be cured.

Actions of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro.

BACKGROUND AND OBJECTIVES: The staurosporine derivative PKC412 (CGP41251) is a more selective inhibitor of the conventional isoforms of protein kinase C (PKC) than is the parent compound. In addition to its growth inhibitory properties, PKC412 reverses the efflux function of the multidrug resistance (MDR)-1 gene product, P-glycoprotein (P-gp). DESIGN AND METHODS: The in vitro actions of PKC412 were investigated in peripheral blood lymphocytes (PBL) from 4 normal volunteers, B-cell isolates from 3 normal tonsils and 31 patients with B-cell chronic lymphocytic leukemia (B-CLL). Following incubation with PKC412 for 2 days, the viability of B-CLL cells was decreased relative to that of controls (63+/-23% at 1 micromole/L; 52+/-30% at 10 micromole/L; n=20). Normal PBL were significantly more resistant to the drug (91+/-5% viable cells at 1 micromole/L; 73+/-18% at 10 micromole/L; n=4). Thirteen of the B-CLL patients were treated with oral PKC412 in a phase II trial. RESULTS: PKC activity in malignant cells from these patients showed a reduction post-treatment of 25-96% of their respective pre-treatment levels. Morphologic analysis, as well as in situ assay for DNA strand breaks (TUNEL assay) showed that B-CLL cells were killed by an apoptotic mechanism. In B-CLL cells the mean IC50, for PKC412, as measured by the reduction of 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), was 2.1 micromol/L in 16 samples in which the IC50 were below the maximum concentration of PKC412 used for the assay. In tonsillar B-cells, the mean IC50 was 11 micromol/L whereas PBL cells were resistant. Four of eight and 1/3 B-CLL samples that were resistant to chlorambucil and fludarabine, respectively, were sensitive to PKC412. In 15/31 B-CLL samples a dose-dependent reversal of P-gp-mediated drug efflux by PKC412 was observed. A statistically significant correlation (p<0.001) was observed between P-gp protein expression as measured by FACScan analysis and the reversal of efflux activity by either PKC412 or verapamil. PKC412 increased the sensitivity of B-CLL cells to 2'-chlorodeoxyadenosine and chlorambucil. INTERPRETATION AND CONCLUSIONS: This study establishes the in vitro cytotoxic and multidrug resistance (MDR) modulatory properties of PKC412 towards malignant cells from B-CLL patients. The direct antitumor activity combined with the potential for P-gp modulation make PKC412 an attractive drug for the treatment of malignancies expressing the MDR phenotype, or in combination with conventional drugs.