Published Online: August 21, 2014
Velcade (bortezomib), developed by Millenium Pharmaceuticals Inc, is a proteasome inhibitor (Figure) currently approved for the treatment of multiple myeloma and relapsed mantle cell lymphoma.1 Several abstracts, presented on May 31, 2014, and June 1, 2014, at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago set forth data from trials that are under way to evaluate bortezomib for other indications.
Bortezomib and rituximab in the treatment of iNHL2
This study, conducted at multiple trial centers and led by clinicians at Northwestern University, Chicago, was designed to assess the tolerability of bortezomib and rituximab in patients with high tumor burden (HTB) non- Hodgkin’s lymphoma. Treatment in this multicenter phase 2 study consisted of 3 induction cycles of bortezomib and
rituximab, followed by an abbreviated consolidation. All outcomes were analyzed by intent to treat. All 42 patients enrolled in the trial were evaluable. The therapy was well tolerated, with few grade 3/4 toxicities and minimal neurotoxicity. Grade 3 adverse events (AE) included fever, infusion reaction, infection, cardiac, fatigue, diarrhea, hypokalemia, and bowel obstruction; the only grade 4 AEs were neutropenia and thrombocytopenia. Overall response rate (ORR) at the end of therapy was 70%, with a 40% complete remission (CR) rate (follicular lymphoma [FL]: ORR 76%, CR 44%). At a median follow-up of 50 months, 4-year progression-free survival (PFS) was 44%, with 4-year overall survival (OS) of 87% (FL: 44% and 97%, respectively). Interestingly, 4-year OS was superior for FL compared with non-FL histologies (97% vs 43%, respectively, P = .003). Altogether, bortezomib/rituximab is a targeted therapeutic regimen that was very well tolerated and resulted in long-term survival rates comparable to prior HTB FL rituximab/chemotherapy series.
Replacing vincristine with bortezomib in R-CHOP regimen in treating mantel cell lymphoma3
R-CHOP—rituximab, cyclophosphamide, doxorubicin (Hydroxydaunomycin), vincristine sulfate (Oncovin), prednisone—is standard therapy for newly diagnosed, bone-marrow transplant (BMT)-ineligible mantle cell lymphoma (MCL) patients. Bortezomib is approved in the United States for relapsed MCL. This study, registered as a collaborative trial between Millennium Pharmaceuticals and Johnson & Johnson Pharmaceuticals, evaluated whether replacing vincristine with bortezomib in R-CHOP
improves outcomes in newly diagnosed, BMT-ineligible MCL patients. Adults with treatment-naïve, measurable stage 2 through 4 MCL and ECOG PS 0 to 2 were
randomized to VR-CAP (velcade, rituximab, cyclophosphamide, doxorubicin, prednisone) or R-CHOP. The primary end point was PFS and secondary end points included time to progression, time to next treatment, OS, response by modified international lymphoma workshop response criteria (LWRC), and safety. Of the 487 patients, 244 were randomized to the R-CHOP arm and 244 to the VR-CAP arm, and were administered a median of 6 cycles. After 40 months median follow-up (298 PFS events), median
PFS was 14.4 months (R-CHOP) vs 24.7 months (VR-CAP). Rates of grade 3 or higher AEs were 85% (R-CHOP) versus 93% (VR-CAP), serious AEs were 30% versus 38%, discontinuations due to AEs 7% versus 9%, and on-treatment drugrelated deaths 3% versus 2%. This trial showed that VR-CAP significantly prolonged PFS and consistently improved secondary efficacy end points versus R-CHOP in newly diagnosed, BMT-ineligible MCL patients, with additional but manageable toxicity.
Phase 3 trial for myeloma comparing different iMiDs4
Treatment with immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) has dramatically increased response rates and survival for myeloma patients over the last decade, with triple drug combinations proving more effective than double or single agents. This trial, Myeloma XI—a collaborative study between the University of Leeds, Celgene Corportation, and Merck Sharp and Dohme Corporation—was a phase 3 randomized trial for newly diagnosed patients of all ages, which compared induction treatment with cyclophosphamide/lenalidomide/dexamethasone (CRD) to cyclophosphamide/thalidomide/dexamethasone (CTD), given to maximum response or intolerance. To evaluate the role of pretransplant consolidation with a proteasome inhibitor, patients achieving less than a very good partial response (VGPR) were randomized to additional cyclophosphamide/bortezomib/dexamethasone (CVD) versus no treatment. Fit patients went on to receive melphalan + autologous stem cell transplant. Of the 1939 patients analyzed, 1104 were on the intensive pathway arm (540 CRD vs 564 CTD) and 835 were on the nonintensive arm (411 CRDa vs 424 CTDa); 274 patients received additional bortezomib. The preplanned intent-to-treat analysis of combined CR+VGPR rates presented a significant difference between CRD and CTD treatment on multivariate analysis in favor of CRD, with odds ratio of 1.27 (95% CI 1.06-1.52, P = .009). Additional bortezomib therapy—for those with a suboptimal response—upgraded response in 51% of the patients, demonstrating that PI therapy can be effective in patients intrinsically resistant to IMiDs. Treatment with both IMiDs was well tolerated. The trial demonstrated an important difference in response between the IMiDs thalidomide, and lenalidomide; however, further follow-up is required to see whether this translates into prolonged PFS and OS. EBO
1. How Velcade (bortezomib) works. Velcade website. http://www.velcade.com/Understanding-velcade/About-velcade. Accessed June 1, 2014.
2. Evens AM, Smith MR, Lossos IS, et al. Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumor burden (HTB) indolent non-Hodgkin lymphoma
(iNHL): a multicenter phase II study. J Clin Oncol. 2014;32(5s suppl 1): Abstract 8545.
3. Cavalli F, Rooney B, Pei L, Van De Velde H, Robak T; on behalf of the LYM-3002 Investigators. Randomized phase 3 study of rituximab, cyclophosphamide, doxorubicin, and prednisone plus vincristine (R-CHOP) or bortezomib (VRCAP) in newly diagnosed mantle cell lymphoma (MCL) patients (pts) ineligible for bone marrow transplantation (BMT). J Clin Oncol. 2014;32(5s suppl 1): Abstract 8500.
4. Pawlyn C, Davies FE, Cairns DA, et al. Optimizing induction and pretransplant consolidation for myeloma: results of Myeloma XI, a phase III trial comparing different IMiDs. J Clin Oncol. 2014;32(5s suppl 1): Abstract 8537.