Long‐term survival with cyclophosphamide, bortezomib and dexamethasone induction therapy in patients with newly diagnosed multiple myeloma

The past two decades have seen remarkable improvement in the outcomes for patients with multiple myeloma (MM) (Kumar et al, 2008). High dose melphalan and stem cell transplantation (SCT) has improved responses and lengthened survival (Harousseau et al, 2009). Advances in science have ushered in new classes of drugs including immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs). Combinations of these novel agents with the alkylating drugs (melphalan, cyclophosphamide) have improved and deepened responses over single agent therapy. A phase 2 clinical trial for newly diagnosed MM patients was conducted at Mayo Clinic Arizona (MCA) and Princess Margaret Hospital, Toronto (PMH), utilizing an induction regimen of cyclophosphamide, bortezomib and dexamethasone (CyBorD). This triplet combination produced rapid and deep responses in previous studies (Reeder et al, 2009, 2010). We report long-term follow-up data for all 63 patients treated on CyBorD at MCA and PMH. Eligible patients were ≥18 years of age with newly diagnosed multiple myeloma, had measurable disease, and had an Eastern Cooperative Oncology Group performance score ≤2, creatinine <309·4 μmol/l, absolute neutrophil count ≥1 × 109/l, and platelet count ≥ 1 × 109/l. All patients were symptomatic and needed therapy. All patients signed an informed consent. Sixty-three patients with newly diagnosed and symptomatic myeloma were enrolled between 2006 and 2008 on a phase 2 trial of weekly oral cyclophosphamide 300 mg/m2, IV bortezomib 1·3 mg/m2 days 1, 4, 8, 11 (Cohort 1) or 1·5 mg/m2 days 1, 8, 15, 22 (Cohort 2) and dexamethasone in high dose (Cohort 1) or high dose for 2 cycles, then low dose for 2 cycles (Cohort 2) in a 28 day cycle. Patients received prophylactic acyclovir and a quinolone antibiotic. Response after 4 cycles was the primary goal. Secondary goals were progression-free survival (PFS), overall survival (OS), toxicity of this combination and ability to harvest stem cells. Patients were stratified to high risk or standard risk by Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) criteria (Dispenzieri et al, 2007). It was assumed that most patients would proceed to SCT after stem cell collection and no maintenance after SCT was planned as part of the trial. Survival was calculated using the Kaplan Meier method. OS was defined as time from registration to death from any cause. PFS was defined as time from registration to progression or death. The trial was approved by the institutional review board/research ethics board of both treating centres and was monitored by the Mayo Clinic Cancer Center Data and Safety Monitoring Board. Data was frozen as of 26 February, 2014. The overall response (ORR) for all patients (n = 63) was 89% with 62% achieving a very good partial response (VGPR) or better. For patients completing all 4 cycles of therapy the ORR was 93% and with 67% in a VGPR or better. Forty-nine of 63 patients underwent autologous SCT after induction and 2 had a subsequent SCT after additional therapy (51/63, 81%). Maintenance therapy with either lenalidomide or thalidomide was administered in 18 patients (29%) due to concern for a high risk of early relapse in cytogenetic high-risk patients, and was at the discretion of the treating physician. The median PFS was 40·0 months. The 5-year PFS and OS rates were 42% (95% confidence interval [CI]: 31–57) and 70% (95%CI: 59–82) for the entire group (Fig 1). Twenty-four of the 63 patients were considered high risk (38%) and had responses equal to standard risk patients (88% vs. 90%, P = 1·0) However, the median PFS was shorter in high risk patients at 27·6 months vs. 55·7 months in the standard risk patients. High-risk patients had a 5-year PFS of 33% (95%CI: 19–59) vs. 48% (95%CI: 33–69) in the standard risk group. Likewise a lower OS rate (54% (95%CI: 37–78) vs. 81% (95%CI: 69–95)) (P = 0·04) was seen compared to standard risk patients (Fig 2). Combinations of 2, 3 or even 4 drugs have become common practice for induction therapy in newly diagnosed MM patients and can produce ORRs of ≥90%. Short term (1–2 years) survival with these doublet and triplet treatments is excellent, but long-term follow-up for many of the newer induction regimens has yet to be reported. Commonly used regimens employ bortezomib and dexamethasone alone (VD), or with either lenalidomide (VRD), thalidomide (VTD) or cyclophosphamide (CyBorD, VCD). The two platforms of carfilzomib with RD and RVD have generated ORR of 98% and 100%, respectively, with VGPR of 75% in both as part of prospective studies, pointing to the potent synergy of the PIs and IMiDs (Richardson et al, 2010; Jakubowiak et al, 2012). Whilst RVD is different to VRD in that both the schedule of dexamethasone is different as is the dose, which is less in the latter, VRD versus CyBorD showed similar outcomes (Kumar et al, 2012). Another common induction combination is lenalidomide and dexamethasone (RD). A comparison of RD, CyBorD and CRD showed similar survival at 3 years, but there are no prospective randomized trials comparing these regimens (Khan et al, 2012). In a recent analysis of patients treated with RD, the 5-year survival was 71%, similar to our patients teated with CyBorD (Srivastava et al, 2013). High-risk patients appear to have better PFS with CyBorD than RD (2·3 vs. 1·7 years) though no regimen has totally eliminated the deleterious impact of adverse cytogenetics on OS. Several recent studies show improved PFS for post-SCT treatment and one even suggests benefit in OS. At the time of our trial, post-transplant therapy was not routine practice although concern of early relapse in high-risk patients led to the additional therapy in 18 of the 63 patients (29%). CyBorD maximizes responses and allows for stem cell collection and transplantation, which can further consolidate response and improve outcome. This combination preserves the opportunity for future IMiD therapy. CyBorD employed in a once weekly schedule is not associated with thrombosis or severe neuropathy. The result is excellent survival for MM patients, with a 5-year OS of 70%. Eighty-one percent of standard risk patients are alive at 5 years. CyBorD builds on the preclinical synergy of PIs and alkylation and is an important option that is both highly active as initial therapy in MM and IMiD sparing. This trial was funded by support from Millennium. CBR wrote the paper. DER, VK, JRM, CC, ST, RF, PLB, JFL, RT and AKS revised the paper. KL and HV analysed the data. All authors approved the final paper. Dr. Reeder receives research funding from Novartis, Celgene and Millennium. Dr Fonseca has received a patent for the prognostication of MM based on genetic categorization of the disease. He has received consulting fees from Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium and AMGEN. He also has sponsored research from Cylene and Onyx. Dr. Stewart receives honoraria and research funding from Millennium and Onyx and honoraria from Celgene. The remaining authors have no conflicts of interest.

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