|Year : 2017 | Volume
| Issue : 3 | Page : 129-134
Bortezomib in multiple myeloma: treatment response and survival outcome
Eslam S.M Bassiony, Ashraf F Barakat, Amr A.E Ghannam, Essam A Abozena
Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt
|Date of Submission||22-Feb-2017|
|Date of Acceptance||01-Jul-2017|
|Date of Web Publication||29-Nov-2017|
Eslam S.M Bassiony
Clinical Oncology, Faculty of Medicine, Tanta University, Tanta, 31511
Background Bortezomib, a first-in-class proteasome inhibitor, was approved by the Food and Drug Administration in 2003. Bortezomib has come a long way since its development as one of the most effective drugs currently available for treating multiple myeloma. With improved efficacy of combination regimens, we have seen increasing use of its therapeutic spectrum ranging from frontline induction to maintenance therapy. Bortezomib has been integrated into the treatment of myeloma at every disease stage.
Aim The aim of this study was to evaluate the disease response and survival outcome in patients with multiple myeloma who were treated with bortezomib as first-line or second-line treatment who had recurrent or refractory disease after systemic chemotherapy.
Patients and methods This retrospective study included 23 patients with multiple myeloma who were treated at Clinical Oncology and Nuclear Medicine Department, Tanta University Hospital, Faculty of Medicine, Tanta University, and were diagnosed between January 2012 and January 2016.
Nine patients received bortezomib as a first-line treatment, whereas 14 patients received it as a second-line treatment.
Results Bortezomib shows better response rate and survival outcome especially in patients who received it as the first line of treatment. About 52.5% of patients show partial response or better response.
Conclusion Bortezomib with dexamethasone gives a response rate and survival outcome better than conventional treatment, dexamethasone alone, or bortezomib single agent. However, bortezomib combination with other chemotherapeutic agents gives more response rate than bortezomib with dexamethasone.
Keywords: bortezomib, myeloma, response, survival
|How to cite this article:|
Bassiony ES, Barakat AF, Ghannam AA, Abozena EA. Bortezomib in multiple myeloma: treatment response and survival outcome. Tanta Med J 2017;45:129-34
|How to cite this URL:|
Bassiony ES, Barakat AF, Ghannam AA, Abozena EA. Bortezomib in multiple myeloma: treatment response and survival outcome. Tanta Med J [serial online] 2017 [cited 2019 Feb 21];45:129-34. Available from: http://www.tdj.eg.net/text.asp?2017/45/3/129/219439
| Background|| |
Over the past decade, significant advances have been made in the field of multiple myeloma (MM). Introduction of the so-called novel agents and improved supportive care measures have resulted in significant improvement of outcome. Autologous stem cell transplantation is currently considered the standard of care for MM in young patients with adequate organ function. However, relapse remains an issue for the majority of patients. Recently, with the advent of newer new agents, a marked change in treatment strategies in both the transplant and nontransplant settings has taken place. These agents are now incorporated at different disease stages and with various sequences and combinations. The current ongoing studies are aimed toward further refining the different treatment strategies with the aim of further improving efficacy and tolerability. Thus, because of the increasing availability of such novel drugs and treatment goals, the standard of care in myeloma is rapidly evolving, and it is likely that the choice of the optimal approach is one that must be gauged on a patient-by-patient basis as general evidence-based recommendations are being constantly updated. This is why we need to understand the limitations of each approach, and carefully weigh the chances and risks of each decision: in general, the availability of treatments, their expected benefit and side effects, and individual treatment histories and disease characteristics need to be taken into consideration. Bortezomib, a first-in-class proteasome inhibitor, was approved by the Food and Drug Administration in 2003; since that time, further studies of bortezomib alone and as part of combinations regimens have shown the versatility of this agent. We will review and assess the role of bortezomib in the treatment of newly diagnosed and relapsed and/or refractory MM ,,,.
| Aim|| |
The aim of this study was to evaluate the disease response and survival outcome in patients with MM who were treated with bortezomib as first-line or second-line treatment with recurrent or refractory disease after systemic chemotherapy.
| Patients and methods|| |
This is a retrospective study that included 23 patients with confirmed MM treated at Clinical Oncology and Nuclear Medicine Department, Tanta University Hospital, Faculty of Medicine, Tanta University, between January 2012 and January 2016.
Newly diagnosed patients with MM, patients for whom chemotherapy had relapsed and/or those with refractory MM, those with Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2, and those with adequate liver functions were included in this study.
Patients with ECOG performance status more than 2, patients with a pre-existing grade 4 peripheral neuropathy, and those with other intolerable comorbidities were excluded from the study.
| Methods|| |
All patients were subjected to the following for accurate diagnosis and proper staging: complete history in detail, clinical examination, and performance status assessment. Laboratory investigations included complete blood count (hemoglobin level, total leukocytic, and platelet count), blood chemistry (renal function tests, liver function tests, uric acid level, serum calcium level and B2 microglobulin, erythrocyte sedimentation rate, and serum alkaline phosphatase), protein studies (serum protein electrophoresis, serum protein immunofixation, and urine protein electrophoresis, 24-h collection), bone marrow aspirate, and/or biopsy. Radiological investigations included skeletal survey (radiograph of skull, spine, ribs, pelvis, both femurs, and both humeri), commuted tomography scan, and/or MRI for symptomatic bony sites with negative skeletal survey. MRI was recommended if any patient developed back pain or extremities weakness to exclude spinal cord compression.
All patients included in this study received bortezomib at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11, as well as at 3 weeks, subcutaneously in the thigh or abdomen. Dexamethasone was orally received on the same days of bortezomib and on the next day (days 1–2, 4–5, 8–9, 11–12) at a dose of 20 mg daily. Before each cycle of bortezomib, complete blood count and serum creatinine were mandatory, and serum calcium was requested; however, unavailable results did not delay the treatment protocol. Bortezomib was discontinued when no further response was detected for at least three cycles (usually established by plateau of M paraprotein level). Whenever progressive disease developed during treatment, bortezomib was stopped and changed to the other line of treatment. In addition, bortezomib was stopped when there was progressive disease or intolerable toxicity recorded. Patients received zoledronic acid in the fourth week of the cycle; also, renal supportive treatment was received by the patients in each cycle.
Treatment response assessment was performed after every three cycles of treatment. Treatment response was evaluated according to European Group for Blood and Marrow Transplantation.
Patients were evaluated every 3 weeks by physical examination and laboratory investigations. Occurrence and nature of any adverse events were recorded. Toxicity grading was based on ECOG toxicity criteria.
Data were analyzed using IBM SPSS statistics software package version 20 (IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). Quantitative data were expressed using range, mean, and SD, whereas qualitative data were expressed in frequency and percent. Qualitative data were analyzed using Monte Carlo test. Survival analysis was done using Kaplan–Meier method. P value was assumed to be significant at 0.05.
| Results|| |
The median age of our study patients was ±60 years (range, 48–70 years). Male to female ratio was 1.55 : 1. Only about 8.7 percentage of patients presented with ECOG performance status (PS) 0, while most patients presented with ECOG PS 2 in 47.8% and 1 in 43.5% of patients. Regarding disease stage, stage III was the most common, which was seen in 52.2% of patients, followed by stage II in 34.8%, whereas stage I was the least common, and it was seen in only 13% of patients. Most of our patients presented with myeloma subtype immunoglobulin G (69.6%) followed by immunoglobulin A (26.1%), whereas light-chain type was presented in only one patient (4.3%). The median percentage of plasma cells in bone marrow was ±25% (range, 19–34%), whereas the median level of B2 microglobulin was ±3.4 mg/l (range, 3–3.8 mg/l). The median hemoglobin level was ±9 g/dl (range, 7.9–10.5 g/dl). Median platelet count was ±160 000 cells/mm3 (range, 123 000–192 000 cells/mm3), serum creatinine median level was ±2.4 mg/dl, serum albumin median level was ±3.6 g/dl, and serum calcium median level was ±10.8 mg/dl ([Table 1]). Regarding treatment response to bortezomib, about 52.5% of patients show response in the form of complete response (CR) 8.7%, very good partial response (VGPR) 30.4%, and partial response (PR) 30.4%, whereas 43.5% of patients show stable disease. One patient progressed during treatment with a percentage of 4.3%, who received bortezomib as second-line treatment ([Table 2]). The 2-year overall survival (OS) for all patients recorded in our study was 56.5%, with 95% confidence interval of 21.46–25.84, whereas 18-month OS was 86.5%. The median progression-free survival (PFS) was ±18 months for all patients and 95% confidence interval (15.99–19.54) and 1-year PFS was about 90% of all patients ([Figure 1]). Multiple different prognostic factors were affecting the OS and PFS such as early stage, young age, lower plasma percentage, lower B2 microglobulin, higher hemoglobin levels, and good renal functions, which were associated with better OS and PFS. According to the side effects of bortezomib therapy, gastrointestinal tract (GIT) manifestations such as diarrhea, nausea, and vomiting were the most common side effects in 17 (73%) patients, with a 95% confidence interval of 1.66–1.95, followed by neuropathy reported in 10 (43%) patients, with a 95% confidence interval of 1.3–2.7, whereas hematological adverse events were the least in form of anemia, thrombocytopenia, and neutropenia, with 95% confidence interval of 1.6–1.95 ([Table 3]).
|Figure 1 The 18-month progression-free survival for bortezomib treatment line.|
Click here to view
| Discussion|| |
The past decade had a revolution in the treatment of MM as a result of introduction of several new effective drugs, which in conjunction with increased use of autologous stem cell transplantation and improved supportive care strategies have resulted in significantly improved survival outcomes for these patients. The introduction of novel agents such as thalidomide, bortezomib, and lenalidomide, as part of frontline treatment in both transplant and nontransplant candidates, represent one of the major advances in management of patients with MM . These drugs have markedly improved the rate of complete remission, time to progression, and PFS, and OS has significantly increased. The proteasome inhibitors make an important class of anti-myeloma drugs that disrupt the proteolytic machinery of the tumor cells, preferentially enhancing their susceptibility to apoptosis. Bortezomib, in particular, has shown significant clinical efficacy in myeloma treatment. It is the most commonly used proteasome inhibitor and has been tested to be effective in prolonging the OS in several trials. The success with its lower dosage in elderly and its proven efficacious subcutaneous use makes bortezomib a useful agent for maximizing patient compliance and minimizing therapy-related toxicity and costs . In this study, we aimed to evaluate the treatment response and survival outcome of bortezomib in myeloma patients. This retrospective study included 23 patients with MM. Nine (39.1%) patients received bortezomib as first-line treatment, whereas 14 (60.8%) patients received it as a second-line treatment. Regarding response rate in patients who received bortezomib with dexamethasone as a first-line treatment in this study, the overall response rate was about 88%, which is comparable to the overall response rate recorded by Jagannath et al. , who reported the overall response (ORR) of a combined regimen of bortezomib and dexamethasone to be 90%. In our study, CR and PR were reported in 52% of patients, which is lower than those reported by Jagannath et al. , who reported CR and PR of about 60%. This difference may be because of the fact that patients in our series were in a more advanced stage. In APEX trial, Richardson et al. , compared bortezomib with dexamethasone alone for relapsed MM patients. They achieved overall response rate in 89% of patients, whereas CR and PR were reported in 38% in the bortezomib arm, which is lower than reported in our patients who received bortezomib as a second-line treatment; we reported overall response rate in 93%, whereas CR and PR were achieved in 50% . Our better results could be explained by the addition of dexamethasone in our study, whereas the results of Richardson et al.  were based on bortezomib as a single agent. In the collaborative review of sterilization (CREST) study, a phase 2 study that compared two different doses of bortezomib as second-line therapy – 1.0 and 1.3 mg/m2 – with the same dose of dexamethasone, they found that CR and PR were reported in 37 and 52% of 1.0 and 1.3 mg/m2 regimens, respectively . In our study, patients received bortezomib at a dose of 1.3 mg/m2; we reported CR and PR in 50%, which is comparable to that reported by the CREST study in the same dose arm.
Many researchers combined bortezomib with chemotherapy to augment the response and survival outcome in MM patients. Mateos et al.  highlighted the benefits of using bortezomib in combination with melphalan–prednisone (VMP) in elderly untreated patients with MM. They reported an overall response rate of 92% with CR and PR in 80% of patients . Reeder et al.  evaluated the efficacy of bortezomib, cyclophosphamide, and dexamethasone regimen; they found an overall response rate of 96%, with CR and PR in 71% of patients.
Papot et al.  worked on bortezomib in combination with doxorubicin and dexamethasone and reported an overall response rate of 95% and CR and PR in 58%. All the previous studies that used bortezomib three-drug regimens achieved better CR and PR than that reported by using bortezomib as a single agent or combined with dexamethasone. Obviously, this difference is related to more intensive chemotherapy in bortezomib-based three-drug regimens.
On searching better treatment regimens for MM, Nilanjan et al.  combined two novel drugs bortezomib and thalidomide. They reported better CR and PR compared with the CR and PR reported with the previous studies that worked on single novel drug combined with chemotherapy .
Regarding survival outcome, 2-year OS and 18-month PFS were 56.5 and 47.8%, respectively, for all patients.
Regarding bortezomib line of treatment as first or second line, 2-year OS was 72 and 40%, respectively, whereas 18-month PFS was achieved in 55 and 42%, respectively.
Richardson et al.  and Dae et al.  evaluated bortezomib in newly diagnosed MM patients, Richardson et al.  recorded 2-year OS in 80% of patients, and Dae et al.  reported 2-year OS in about 70%. Both study results are comparable to those reported in our study (72%) ,.
As regards 18-month PFS, we reported results (55%) comparable to those reported (52%) in the study by Richardson et al. .
In the CREST study, they recorded 2-year OS of 54% in relapsed and/or refractory MM patients who received bortezomib as a second-line treatment, which is higher than that reported in our series (40%); this difference may be related to more tumor burden in our relapsed patients .
Combination of bortezomib with chemotherapy also improves survival outcome similar to improvement of response rate.
San et al.  reported data from VISTA trial evaluating VMP versus oral melphalan and prednisone. PFS in the VMP arm was 24 months, which is better than that reported in our study (18 months); this difference is explained by augmentation effects when bortezomib is combined with chemotherapy, whereas median PFS in oral melphalan and prednisone arm of vista trial was 16 months , which is lower than that reported in our study, because we use novel drug-based treatment.
On studying different factors that may affect OS and PFS, we found that younger age, lower plasma cell percentage, lower level of B2 microglobulin, higher hemoglobin level, good renal function, and early stage showed better outcome. These results were consistent with those reported in many studies. Shaji et al.  evaluated the risk of progression and survival in relapsing MM after therapy with bortezomib, and reported that higher albumin level, low B2 microglobulin, and early stage have a better survival outcome. Dae et al.  evaluated the prognostic markers in newly diagnosed MM patients and reported better OS and PFS with younger age, higher performance status, lower B2 microglobulin, lower bone marrow plasma cell percentage, and use of novel agents . The impact of all prognostic factors was clinically proved and statistically significant. However, in our study, the impact factors were clinically proved but statistically not significant, which may be explained by the smaller sample size of our study patients (23 patients) compared with these studies.
As regards treatment morbidity, most common effects reported in our study were GIT adverse events, diarrhea, and nausea in 52% and vomiting in 43% of patients, which is comparable to the results of Richardson et al.  in APEX trial, who recorded diarrhea and nausea in 57%. However, they reported lower vomiting percentage (35%) compared with our series .
Peripheral neuropathy is a common side effect of bortezomib; we attempted to decrease this side effect by giving prophylactic oral vitamin B12 supplementation. However, we reported peripheral neuropathy in 39% of patients, which is comparable to that reported by Richardson et al. , who reported neuropathy in 38% of patients.
Moreau et al.  compared subcutaneous versus intravenous routes of bortezomib administration, and they recorded neuropathy in 50% of patients in the subcutaneous group and 70% in the intravenous group. We reported a lower percentage of neuropathy than that reported by Moreau and colleagues, which may be explained by prophylactic use of vitamin B12, subcutaneous route of administration, and exclusion of patients with pre-existing peripheral neuropathy from this study. Hematological morbidity was the least reported adverse event of bortezomib in our study; bone marrow biopsy was used to differentiate progressive disease from treatment morbidity. Hematological adverse events were anemia in 26%, thrombocytopenia in 26%, and neutropenia in 22%, which are comparable to the results reported by Rosiñol et al. , who reported hematological adverse events in 24% of patients who received the bortezomib and dexamethasone regimen .
In conclusion, bortezomib with dexamethasone gave response rate and survival outcome better than conventional treatment, dexamethasone alone, or bortezomib single agent. However, bortezomib combination with other chemotherapeutic agents gives more response rate than bortezomib with dexamethasone.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Caers J, Vande broek I, De Raeve H, Michaux L, Trullemans F, Schots R et al.
Multiple myeloma: an update on diagnosis and treatment. Eur J Haematol 2008; 81:329–343.
Sandra K, Elizabeth B. Novel agents for the treatment of multiple myeloma: proteasome inhibitors and immunomodulatory agents. J Adv Pract Oncol 2013; 4:307–321.
Anuj M, Girindra R, Paulette M, Ruta B, Mei-Jie Z, Xiaobo Z et al.
New cancers after autotransplants for multiple myeloma. Biol Blood Marrow Transplant 2015; 21:738–745.
Barlogie B, Smith L, Alexanian R. Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med 1984; 310:1353–1356.
Rossi J-F, Manges RF, Sutherland HJ. Preliminary results of CNTO 328, an anti- interleukin-6 monoclonal antibody, in combination with bortezomib in the treatment of relapsed or refractory multiple myeloma. Blood 2008; 112:867–868.
Moreau P, San Miguel J, Ludwig H, Mohty M, Dimopoulos M, Dreyling M et al.
ESMO Guidelines Working Group. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24:133–137.
Jagannath S, Durie BG, Wolf J, Camacho E, Irwin D, Lutzky J et al.
Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 2005; 129:776–783.
Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T et al.
Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 2007; 110:3557–3560.
Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG et al.
A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 2004; 127:165–172.
Mateos MV, Hernandez JM, Hernandez MT, Gutiérrez NC, Palomera L, Fuertes M et al.
Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood 2006; 108:2165–2172.
Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J et al.
AK cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia 2009; 23:1337–1341.
Popat R, Oakervee HE, Hallam S, Curry N, Odeh L, Foot N et al.
Bortezomib, doxorubicin and dexamethasone (PAD) front-line treatment of multiple myeloma: updated results after long-term follow-up. Br J Haematol 2008; 144:512–516.
Nilanjan G, Xiaobu Y, Anna F, Carol A, Ivan B. Bortezomib and thalidomide, a steroid free regimen in newly diagnosed patients with multiple myeloma. Br J Haematol 2011; 152:593–599.
Richardson PG, Xie W, Mitsiades C, Chanan-Khan A, Lonial S, Hassoun H et al.
Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy. J Clin Oncol 2009; 27:3518–3525.
Dae S, Yu E, Ka-Won K, Se Ryeon L, Yong P, Sung HJ et al.
Myeloma prognostic index at diagnosis might be a prognostic marker in patients newly diagnosed with multiple myeloma. Korean J Intern Med 2016; 4:3–5.
San M, Schlag R, Khuageva N, Dimopoulos MA, Shpilberg O, Kropff M et al.
Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol 2013; 31:448–455.
Shaji K, Jae H, Juan J, Gareth M, Paul GR, John C et al.
Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a Multicenter International Myeloma Working Group Study. Leukemia 2012; 26:149–157.
Rosiñol L, Oriol A, Mateos MV, Sureda A, García-Sánchez P, Gutiérrez N et al.
Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma: efficacy and clinical implications of tumor response kinetics. J Clin Oncol 2007; 25:4452–4458.
Merz M, Salwender H, Haenel M, Mai EK, Bertsch U, Kunz C et al.
Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. Haematologica 2015; 100:964–969.
[Table 1], [Table 2], [Table 3]