Efficacy of VDT PACE-like Regimens in Treatment of Relapsed/Refractory Multiple Myeloma—a Single Center Experience

Introduction: Intensive cytotoxic chemotherapy for multiple myeloma (MM) using VDT PACE regimen (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide) and its modifications (together called VDT PACE-like regimens-VPLRs) have been studied only as part of Total Therapy protocols. Institutional experience with VPLRs is limited. We aimed to analyze the outcomes of patients with MM who received VPLRs at our center.

Methods: We reviewed the records of patients who received VPLRs at Mayo Clinic, Rochester from 10/2006 to 03/2017 in an intent-to-treat analysis. We collected data on patient characteristics, prior therapy, drugs used, response to VPLR, timing of progression and next therapy, use of stem cell transplant (SCT) after VPLR, hospital stay and readmission during first cycle (C1), and survival at last follow-up. Revised international staging system (RISS) stage at starting VPLR was calculated if required data were available. Survival outcomes were calculated from initiation of VPLR using Kaplan Meier method. We analyzed for factors affecting survival from initiation of VPLRs using Cox proportional hazards model.

Results: We identified 143 patients who received VPLRs, of whom 141 (98.6%) had relapsed/refractory MM (RRMM) and 2 (1.4%) had newly diagnosed MM. We included only patients with RRMM in further analysis. Patient characteristics at initiation of VPLR are shown in Table 1 . Ninety five (67.4%) patients received VDT PACE, 20 (14.2%) received VD PACE and 26 (18.4) received other VPLRs. Patients received a median of 1 cycle (range, 1-9) of VPLR. Forty five (31.9%) patients received ≥2 cycles of therapy. Of the 135 evaluable patients, after C1, we observed ≥minimal response (MR) in 88 (65.2%), ≥partial response (PR) in 69 (51.1%) and ≥very good PR (VGPR) in 10 (7.4%) patients. After entire course of VPLR, we observed ≥MR in 93(68.9%), ≥PR in 74 (54.8%) and ≥VGPR in 14 (10.4%) patients. Estimated median progression-free survival was 3.1 months (95%CI, 1.9-3.9) and time to next treatment was 1.9 months (95%CI, 1.7-2.2). Median overall survival (OS) was 8.1 months (95%CI, 6.2-9.9) from initiation of VPLR. Among 116 patients who received further therapy after VPLR, 71 (61.2%) received systemic chemotherapy as next line, while 38 (32.7%) and 7 (6%) received autologous SCT and allogeneic SCT respectively. Median OS for those who received SCT vs those who received chemotherapy after VPLR was 15.1 months (95%CI, 10.3-20.8) vs 7.3 months (95%CI, 5.6-9.5) (p<0.01). Twenty nine (20.6%) patients died within 100 days of initiating VPLR.

Patients were hospitalized for a median of 6 days (range, 4-42) during actual administration of drugs in C1. Seventy seven (55.4%) patients had re-admission after administration of chemotherapy in C1 with a median of 1 (range, 1-3) re-admission. Median cumulative duration of hospital stay was 9 days (range, 4-42) during C1. Neutropenic fever and nephrotoxicity were seen during C1 in 51 (36.9%) and 20 (14.8%) patients respectively, among those with available data. Median time to recovery of neutrophil count and platelet count from initiating VPLR were 18 (range, 12-44) and 21 (range, 11-45) days respectively. OS was short in patients who had ≥2 re-admissions [3.1 (95%CI, 1.8-8.3) vs 8.4 (95%CI, 7.3-10.9) months; p=0.02] and those who developed neutropenic fever [5.9 (95%CI, 3.4-9.6) vs 8.4 (95%CI, 7.4- 12.8) months; p=0.02] during C1.

We used age ≥65 years vs <65, serum creatinine >2 mg/dL vs ≤2 mg/dL, RISS III vs I/II stage, presence vs absence of extramedullary disease, high risk vs standard risk cytogenetics and being refractory to a proteasome inhibitor and an immunomodulatory drug, as independent variables in univariate analysis. Age ≥60 years (p<0.01) and RISS III stage (p=0.01) were associated with reduced OS. In multivariate Cox proportional model, age ≥65 [hazard ratio- 2.3 (95% CI, 1.4-3.7); p<0.01] and RISS III stage [hazard ratio- 2.4 (95% CI, 1.3-4.0); p<0.01] predicted shortened OS.

Conclusions: VPLRs provide an effective combination in RRMM. OS was better among patients who underwent an SCT after VPLR. Age ≥60 years and RISS III stage predicted reduced OS from initiation of VPLR. Complications including neutropenic fever and two or more re-admissions during first cycle of VPLR were associated with reduced OS.

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