A prospective, open-label, multicenter, observational study to evaluate the efficacy and safety of bortezomib-melphalan-prednisone as initial treatment for autologous stem cell transplantation-ineligible patients with multiple myeloma

Bortezomib-melphalan-prednisone (VMP) showed superior efficacy versus MP as first-line treatment for transplantation-ineligible multiple myeloma (MM). This study investigated the efficacy of VMP for Korean patients with MM. Overall, 177 MM patients received 9 cycles of VMP in this prospective, multicenter, observational study. The primary endpoint was 2-year progression-free survival (PFS). Thirty-nine (22%) patients were aged ≥ 75 years and 83 (47.4%) patients had International Staging System stage III. A median of 5 cycles were delivered. Overall response rate (ORR) was 72.9%, and complete response (CR) rate was 20.3%. With a median follow-up of 11.9 months, median PFS was 17 months. The 2-year PFS and overall survival (OS) rates were 29.2% and 80.0%, respectively. Median OS was not reached. PFS was significantly different depending on performance status (Eastern Cooperative Oncology Group < 2 vs. ≥ 2; p = 0.0002), β2-microglobulin level (< 5.5 vs. ≥ 5.5 mg/L; p = 0.0481), and cumulative dose of bortezomib (< 35.1 vs. ≥ 35.1 mg/m2; p < 0001). The common adverse events (AEs) were in line with the well-known toxicity profiles associated with VMP. In conclusion, VMP is a feasible and effective front-line treatment for transplant-ineligible older patients with MM in Korea. Continuing therapy with prompt adjustment of treatment according to AEs may be important to improve outcomes of elderly patients.


INTRODUCTION
Multiple myeloma (MM) is a progressive plasma cell neoplasm characterized by reduced resistance against infection, skeletal injuries (bone pain and fracture), renal failure, and anemia. The prognosis is mostly recurrent, with a median survival of approximately 3 to 4 years. Melphalan-prednisone (MP) has been the standard therapy for patients with newly diagnosed MM for over 40 years, and is associated with a median survival of 29 to 37 months [1,2]. Studies have shown that treatment with MP resulted in partial response (PR) or greater responses in approximately half of the treated patients; however, complete response (CR) was relatively rare and median survival was approximately 3 years [3][4][5][6]. During the past decade, high-dose therapy with hematopoietic stem cell transplantation has become the preferred treatment for patients under the age of 65 years, but older patients and patients with clinically significant comorbidities usually do not tolerate this treatment.
With increasing incidence of MM among patients aged ≥ 70 years, it is becoming increasingly important to investigate treatment options in patients who are not eligible for autologous stem cell transplantation [7]. Several recent studies have proved the efficacy and safety of bortezomib in patients with recurrent or refractory MM [8] and the Assessment of Proteasome inhibition for Extending Remissions (APEX) study has demonstrated the efficacy and safety of bortezomib as secondary therapy [9]. Based on the results of the Velcade as Initial Standard Therapy in Multiple Myeloma (VISTA) study, which showed a significant difference between bortezomib plus melphalan and prednisone (VMP) therapy compared to MP therapy in terms of CR, time to progression (TTP), and overall survival (OS), VMP is now recognized as a standard therapy for MM patients aged ≥ 65 years [10]. A retrospective analysis of the VISTA study suggested that higher cumulative doses of bortezomib, reflecting prolonged treatment duration and/ or greater dose intensity, could lead to improved OS [11].
The incidence of MM in Korea has increased steadily, and it is the second most common hematologic malignancy in Korea since 2012 [12]. Currently, VMP is the most commonly used regimen for treating patients who are ineligible for transplantation. However, data on the efficacy and safety of VMP therapy in Asian patients with MM are limited.
Thus, we performed a prospective, multicenter, observational study to investigate the clinical effectiveness and safety of VMP treatment for Korean patients with MM.

Patient characteristics
In total, 179 patients were enrolled into this observational study at 38 centers in Korea from May 22, 2011 to May 29, 2014, of whom 177, who received at least 1 dose of the study drug, were included in the analyses. The study population comprised 102 (57.6%) men and 75 (42.4%) women, with a median age of 71 years; 39 (22%) patients were aged ≥ 75 years. The most common subtype of MM at the time of diagnosis was immunoglobulin (Ig) G type of MM in 108 (61.0%) patients, followed by IgA type in 43 (24.3%) patients, and IgM type in 2 (1.1%) patients. Overall, 20 (11.3%) patients had light chain disease and 4 (2.3%) had the non-secretory type of MM. According to the International Staging System (ISS), 22 (12.6%) patients were in stage I, 70 (40.0%) were in stage II, and 83 (47.4%) were in stage III (Table 1). In total, 83 (47.4%) patients had a serum β 2 -microglobulin level of > 5.5 mg/L and 129 (73.7%) had glomerular filtration rate < 60 mL/min.
Cytogenetic test results were collected in 145 patients at the time of diagnosis of MM. The high-risk cytogenetics group included 24 (13.6%) patients, classified on the basis of karyotypic deletion 13 or hypodiploidy or the presence of deletion 17p, translocation (4;14), or translocation (14;16) on interphase florescence in situ hybridization.

Treatment data
At 100% dose intensity, the maximum planned cumulative dose of bortezomib was 67.6 mg/m 2 , including 41.6 mg/m 2 during cycles 1-4 and 26 mg/m 2 during cycles 5-9. The maximum planned cumulative dose of melphalan and prednisone was 324 mg/m 2 and 2160 mg/ m 2 , respectively. The median number of cycles delivered was 5 (range, [1][2][3][4][5][6][7][8][9], and the median cumulative dose of bortezomib was 35.1 mg/m 2 . The dose intensity of bortezomib, which is the median cumulative dose during the initial 4 cycles, was 25.6 mg/m 2 (median relative dose intensity (RDI), 83.08%), while the median cumulative dose intensity from cycle 5 onwards was 20.0 mg/m 2 (median RDI, 87.35%). The median cumulative dose of melphalan and prednisone was 144 mg/m 2 and 1200 mg/ m 2 , respectively. Of 177 patients, 58 completed 9 cycles of VMP therapy and 52 completed the 2-year follow-up. Among 119 patients who terminated the therapy before the end of the 9 cycles, the most common reason for termination of therapy was adverse events (AEs) in 26 patients, death in 20 patients, disease progression in 19 patients, and initiation of the next therapy in 17 patients. For 39 patients who were aged ≥ 75 years, the median number of treatment cycles was 3, and the median cumulative dose of bortezomib was 28.8 mg/m 2 .

DISCUSSION
Although the superiority of VMP over MP therapy in transplant-ineligible MM patients was demonstrated in the large randomized phase III VISTA study [10], prospective studies supporting the efficacy of VMP therapy in Asian countries are limited. This prospective multicenter study evaluated the efficacy and safety of VMP therapy for Korean patients with MM. Considering the potential gap between efficacy and effectiveness of new treatments in elderly myeloma patients, this population-based observational study is meaningful as it reflects outcomes in clinical practice.   The results were comparable to the overall efficacy results of recently published VMP trials [10,[13][14][15]. Table 6 summarizes the baseline characteristics and VMP treatment results from recently published studies [11,14,15]. The ORR in our study was similar to that from previous VMP studies. However, the PFS of patients in our study was shorter than that of patients in the VISTA study. This discrepancy may be because patients with advanced disease and poor performance were more common in our population. The US community-based phase IIIB UPFRONT study compared three frontline bortezomibbased regimens in transplant-ineligible patients with MM. The median PFS in the UPFRONT study was 17.3 months, similar to our results [14]. This shorter PFS may    also reflect the modification of treatment or differences between patients in the community setting. In our study, patients received a median of 5 cycles of VMP treatment compared to 8 cycles in the VISTA trial. The median time to CR was similar to that in the VISTA trial. The CR rate may be lower because the median number of treatment cycles was lower than in other studies. Considering that prolonged treatment might improve the quality of response, early discontinuation of treatment may have negatively affected the outcomes of this study.
In a phase I/II study of VMP in Japanese patients, VMP with 1.3 mg/m 2 of bortezomib showed an ORR of 69.8% and survival outcome was not reported. Similar to our study, the median number of treatment cycles was 4.5 [15]. The incidence of grade 4 neutropenia and thrombocytopenia was 30% and 22%, respectively. Peripheral neuropathy was the most common cause of discontinuation of study treatment. Owing to the limitation of an observational study design, the frequency and severity of AEs in our study and the UPFRONT study seem to be mostly underestimated. However, the incidences of herpes zoster infection and pneumonia were highest in our study. The treatment may have been terminated early due to AEs in both the Japanese and Korean studies.
Post-hoc landmark analysis of the VISTA study suggested that a higher cumulative dose of bortezomib and continued VMP treatment following attainment of CR might result in improved OS [11]. In our subgroup analysis, cumulative dose of bortezomib was also  an important factor for favorable outcome. Experts have recommended prompt dose adjustment of novel myeloma drugs according to the patient's condition because continuous treatment until disease progression or intolerability increases the depth of response and extended survival [16]. Early adjustment of treatment according to frailty status and AEs is essential to continue treatment and improve outcome of patients treated with VMP regimen. Subcutaneous injection of bortezomib showed improvements in tolerability of treatment [17]. A less intensive VMP regimen with weekly bortezomib schedule was investigated to prolong treatment duration, and similar outcomes were achieved [16,18]. Dose reductions based on geriatric assessment may help reduce treatment toxicity and avoid early discontinuation of treatment [19]. Intriguingly, none of the potential prognostic factors such as advanced age, renal impairment, and high-risk cytogenetic profiles were found to predict survival with VMP therapy. This is consistent with the results of previous studies with bortezomib, suggesting that it may overcome some of the poor prognostic impact of these factors [9][10][11]13]. Although VMP therapy is a well-established standard treatment for patients with MM who are ineligible for highdose therapy, it is not clear whether very elderly patients should be treated with VMP, considering the toxicities. In our study, there was no difference in PFS for patients who were aged ≥ 75 years. Based on this, it is suggested that VMP may be an effective treatment option even in very elderly patients. Few studies have been dedicated to patients over the age of 75 years, and currently no studies have been designed based on frailty. Prospective studies are warranted to improve outcomes of these populations. Recently, alkylator-free continuous lenalidomide-dexamethasone (Rd) given until disease progression showed superior PFS and OS to melphalan-prednisone-thalidomide (MPT) in transplantineligible patients with myeloma [20]. According to the updated results, continuous Rd also demonstrated benefits over MPT for patients older than 75 years [21]. Currently, both fixed duration of alklyator-combining therapy and continuous alklyator-free regimen are considered as standard treatment for transplant-ineligible MM patients. Further prospective studies may clarify strategies that are more effective for elderly patients. This is one of the largest multicenter studies to evaluate prospectively the efficacy of VMP therapy in transplant-ineligible MM patients in Asian countries. VMP therapy showed similar results as in previous studies in Korean MM patients. We confirmed that VMP is a feasible

Ethics statement
Investigation has been conducted in accordance with the ethical standards and according to the Declaration of Helsinki and according to national and international guidelines and has been approved by the authors' institutional review board.

Patients
The study population included patients with untreated, symptomatic, measurable MM who were not eligible for autologous stem cell transplantation. Symptomatic MM was defined as the presence of intramedullary monoclonal plasma cells ≥ 10% or histologically confirmed plasmacytoma, or presence of monoclonal protein in the serum or urine, or myelomarelated organ impairment. Measurable disease was defined as the presence of quantifiable M protein in serum or urine for secretory MM or confirmed abnormal free light chain ratio for non-secretory MM. The exclusion criteria were asymptomatic MM or monoclonal gammopathy of undetermined significance, previous treatment for MM, severe peripheral neuropathy (grade ≥ 2 according to National Cancer Institute Common Toxicity Criteria for Adverse Events [NCI-CTCAE] version 4.0), pregnancy or breastfeeding, mental illness, or other serious medical conditions.

Study design and treatments
The patients received VMP treatment guided by approved label which comprised nine 6-week cycles of melphalan (at a dose of 9 mg/m 2 ) and prednisone (at a dose of 60 mg/m 2 ) on days 1 to 4 in combination with bortezomib (at a dose of 1.3 mg/m 2 ) on days 1,4,8,11,22,25,29, and 32 during cycles 1 to 4, and on days 1, 8, 22, and 29 during cycles 5 to 9.
With one cycle consisting of 6 weeks (42 days) from the day when VMP was started, the planned treatment duration was up to 9 cycles, and the follow-up period was 2 years from the day when VMP was started. Considering the observational nature of the study, doses, administration interval, and total treatment cycles could be modified based on the investigator's discretion. After completion of treatment or withdrawal of study drug (due to SAEs or disease progression), patients were followed up for 2 years from the start of VMP treatment. Follow-up was discontinued and considered completed when the next therapy was initiated because of disease progression or death during the 9 cycles of VMP therapy or the followup period.

Study endpoints and assessments
The primary endpoint was the 2-year PFS rate. The secondary endpoints were ORR, CR rate, time to response, and OS. Response and progression were assessed by investigators according to the International Myeloma Working Group uniform criteria [22].
Efficacy and safety were evaluated for all subjects who had received at least one dose of bortezomib. All AEs were reported from the start date of bortezomib administration to 30 days after the last administration date. The severity of the AEs was evaluated according to the NCI-CTCAE version 4.0 (http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/ctc.htm).
PFS was defined as the length of time from the day of bortezomib first administration to disease progression, relapse from CR, or death, whichever occurred first, in 2 years. OS was defined as the time between bortezomib first administration and death. Death, regardless of the cause, was considered as an event. Duration of response was defined as the time from the date of first evidence of achievement of at least a minor response until date of disease progression, relapse, or death from any cause.

Statistical analysis
Demographic and baseline data as well as effectiveness data were summarized using descriptive statistics. Descriptive statistics were presented as continuous variables, which included the mean, standard deviation, median, and range (minimum and maximum), and as categorical variables, which included frequencies and their respective percentages. Time-to-event outcome, including OS, PFS, and duration of response, was analyzed using Kaplan-Meier method.
Differences between groups were compared using the chi-square test or Fisher's exact test for categorical variables and t-test for continuous variables. Survival curves between subgroups were compared using the logrank test for univariate analysis, and multivariate analysis was performed using Cox's proportional hazard model for survival. Factors with p values < 0.1 in univariate analyses were examined using multivariate regression models. For the multivariate analyses, a stepwise approach was used. All statistical tests were 2-sided, with significance defined as p < 0.05. Analyses were performed using SAS version 9.2.