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ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 4  |  Page : 537-540
 

Bortezomib in newly diagnosed patients with multiple myeloma: A retrospective analysis from a tertiary care center in India


Department of Medical Oncology, Nizam's Institute of Medical Sciences, Hyderabad, Andhra Pradesh, India

Date of Web Publication10-Mar-2016

Correspondence Address:
V G Linga
Department of Medical Oncology, Nizam's Institute of Medical Sciences, Hyderabad, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.178388

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 » Abstract 

INTRODUCTION: Bortezomib is a novel proteasome inhibitor in myeloma. There is a paucity of data from India regarding the efficacy and tolerance to bortezomib. MATERIALS AND METHODS: All patients with newly diagnosed multiple myeloma from January 2008 to December 2011 treated with bortezomib as the first-line therapy were studied in a retrospective analysis. The primary end point was the overall rate of response. Secondary end points were the progression free survival (PFS), reversibility of renal compromise and safety of bortezomib. RESULTS: Our study included 41 patients with newly diagnosed myeloma. The overall response to bortezomib was 88.5% (complete response [CR] 31.4%, very good partial response 34.2%, partial response [PR] 22.8%). A renal response (CR renal, PR renal or Minimal Response renal combined) was documented 96.2% patients with initial renal impairment. The median time to the first renal response was 21 days. 17 patients (41.4%) had severe toxicity (Grade 3 and 4). Bortezomib induced peripheral neuropathy (BIPN) was the most common toxicity seen (53.6%) and the most common cause for discontinuation of therapy. At a median follow-up of 9 months, median PFS was not reached. DISCUSSION: The results obtained in our study are comparable with those of established studies on bortezomib. Our patient population has similar responses and renal reversibility patterns. However, they are at an increased susceptibility to BIPN, leading to discontinuation of therapy. CONCLUSION: Bortezomib as first-line therapy has a good efficacy and safety.


Keywords: Bortezomib, myeloma, peripheral neuropathy, proteasome inhibitor, renal reversibility


How to cite this article:
Pragnya C, Linga V G, Thota N K, Gundeti S, Digumarti R. Bortezomib in newly diagnosed patients with multiple myeloma: A retrospective analysis from a tertiary care center in India. Indian J Cancer 2015;52:537-40

How to cite this URL:
Pragnya C, Linga V G, Thota N K, Gundeti S, Digumarti R. Bortezomib in newly diagnosed patients with multiple myeloma: A retrospective analysis from a tertiary care center in India. Indian J Cancer [serial online] 2015 [cited 2019 Dec 10];52:537-40. Available from: http://www.indianjcancer.com/text.asp?2015/52/4/537/178388





 » Introduction Top


Bortezomib is a novel proteasome inhibitor that has improved the outcomes of patients with myeloma. In treatment naïve patients, bortezomib has demonstrated superior overall response (OR) rates (80-100%), including a complete response/near-complete response (CR/nCR) rates of 20-30%.

Renal impairment is a major complication in myeloma. It adversely effects outcomes and is associated with poorer survival. It necessitates dose reduction of some anti-myeloma drugs precluding their use. Bortezomib pharmacokinetics is not affected by renal impairment and can be given in full doses. It has been shown to cause renal reversibility.

Bortezomib is generally well-tolerated. Bortezomib induced peripheral neuropathy (BIPN) is one of the major dose-limiting toxicity of this drug, seen in about 35% of treated patients.

There is a paucity of data from India regarding the efficacy and tolerance to bortezomib. In this regard, we evaluated the activity of bortezomib as the first-line therapy at our center in a retrospective analysis.


 » Aim of the Study Top


The aim of this study is to determine the efficacy and tolerance of bortezomib as first-line therapy in newly diagnosed multiple myeloma (MM) patients.


 » Materials and Methods Top


All patients with a diagnosis of MM with measurable disease from January 2008 to December 2011 were identified from a review of the hospital cancer registry database.

Patients who received bortezomib (1.3 mg/m 2 of body-surface area as an intravenous bolus twice weekly for 2 weeks, on days 1, 4, 8 and 11 in a 21-day cycle or weekly in a 28-day cycle) as first-line therapy were enrolled into the study.

Responses were evaluated at the end of even numbered cycles. Responses were assessed according to the criteria of the International Myeloma Working Group.[1] Hematological and renal parameters were assessed prior to each dose of bortezomib. Reversibility of renal impairment was assessed using the criteria proposed by Dimopoulos et al.[2] Adverse events were assessed at each visit and graded according to the National Cancer Institute common terminology criteria for adverse events version 4.0.

The primary end point was the overall rate of response to bortezomib (including CR and partial response [PR]). The secondary end points were the progression free survival (PFS), reversibility of renal compromise and safety of bortezomib. PFS was calculated from the time of starting bortezomib until progression, death from any cause or loss to follow-up. The associations of pre-treatment factors with response were analyzed by using univariate analysis (Fisher's exact two-tailed test). A P ≤ 0.05 considered as statistically significant. All statistical analysis was performed electronically using GraphPad QuickCalcs © sotftware.


 » Results Top


From January 2008 to December 2011, 41 patients with newly diagnosed myeloma received bortezomib as first-line therapy.

Mean age of the patients was 52 years with a range of 32-70 years. Only 7/41 (17%) of patients were ≥65 years of age. The male: female ratio was 1:0.7. Patients who had an eastern co-operative oncology group performance status (PS) ≥3 were 11/26.8% (no./percentage of patients). Baseline characteristics of patients are summarized in the [Table 1].
Table 1: Baseline characteristics of all patients

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Baseline glomerular filtration rate (GFR) <60 ml/min/1.73 m 2 was present in 27/41 patients (65.8%). A renal biopsy was available in four of these patients and showed light chain cast nephropathy in two patients and acute interstitial nephritis in two patients. Severity of renal impairment among patients is shown in [Table 2].
Table 2: Classification of renal insufficiency among all patients according to the KDIGO criteria for chronic kidney disease

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More than half of the patients (n = 27) received twice weekly bortezomib regimen. All other patients received weekly bortezomib therapy. All patients received dexamethasone (40 mg with bortezomib). In addition, four patients received thalidomide (100 mg PO daily for 21 days every 28 days) and three patients received lenalidomide (25 mg per oral (PO) daily for 21 days every 28 days) along with bortezomib induction therapy.

The median duration of treatment with bortezomib was 3.63 months (range 0.5-12 months). More than half the patients (51.2%) completed at least four cycles of bortezomib. Eight patients (19.5%) received ≥6 cycles of therapy.

Out of the 41 patients, 16 discontinued therapy [Figure 1]. Of these, 12 patients (31.7%) discontinued therapy because of adverse effects while four patients discontinued therapy due to financial constraints and one patient was lost to follow-up.
Figure 1: CONSORT diagram of progression of patients under study

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Of the 41 patients, response to bortezomib was evaluable in 35 patients. Six patients were not evaluable because they had not completed at least two cycles of chemotherapy that was required, prior to any response evaluation. Five of these six patients had the drug discontinued after the first cycle due to severe toxicity that included Grade 4 neuropathy (n = 2), Grade 4 thrombocytopenia (n = 1), Grade 4 pulmonary toxicity (n = 2).

The OR (CR, very good partial response [VGPR] and PR combined) to bortezomib was 88.5% [Table 3]. Among responders, the median time to achieve the best response was 4 months.
Table 3: Responses to bortezomib among evaluable patients (n=35)

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The median follow-up period in the study was 9 months from the time of diagnosis for all patients.

Among the 24 patients who were compliant with bortezomib (completed all required chemotherapy cycles until best response without dose reductions or discontinuations), only six patients progressed. The median PFS for these six patients was 7 months (range 3-20 months). Of the 11 patients who had achieved a CR to bortezomib induction therapy only three had progressed by the time of analysis.

Nine patients in the study had gone on to receive autologous stem cell transplant (ASCT). Six of these nine patients received all planned induction cycles with bortezomib. The median number of induction cycles was four. Response evaluation at the end of induction showed five patients in CR and four patients in VGPR. After ASCT, 3/4 patients with VGPR converted to a CR. Only one patient progressed after ASCT, 20 months after treatment.

A number of variables were assessed for prognostic significance. The response to bortezomib was not significantly influenced by gender, age, number of lytic lesions, hemoglobin level, serum calcium level, serum creatinine level and percentage of plasma cells in bone marrow.

A renal response (CR renal, PR renal or Minimal response (MR) renal combined) was documented in 23/27 (96.2%) patients with initial renal impairment [Table 4]. An increase in GFR ≥ 20 was seen in 66.6% of patients. The median time to the first renal response was 21 days.
Table 4: Reversibility of renal impairment (among patients with GFR <60 ml/min/1.73 m2) (n=27)

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A number of parameters were assessed for prognostic significance among renal responders versus non-responders. Renal responses were not altered based on age, gender, PS, schedule of bortezomib and greater degree of renal impairment [Table 5].
Table 5: Comparison between renal responders and poor renal responders

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The most common adverse events were peripheral neuropathy, diarrhea, fatigue, thrombocytopenia, thrombotic phenomena and acute respiratory distress syndrome [Table 6]. 17 patients (41.4%) had severe toxicity (Grade 3 and 4). Grade 4 events occurred in a total of 29.2% (12/41) of the patients. The median time to severe toxicity necessitating discontinuation of therapy in these patients was 3.69 months.
Table 6: Drug related adverse events

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BIPN was the most common toxicity seen in our patients and the most common cause for discontinuation of therapy. 22 patients (53.6%) developed BIPN. The median time to development of neuropathy was 2.5 months (range 0.5-5 months). The median cumulative dose of bortezomib at which neuropathy was seen was 13 mg/m2 (range 5.2-26 mg/m2). Painful peripheral sensory neuropathy was the most common form of BIPN. Pre-existing diabetes, alcoholism and renal impairment was not significantly associated with BIPN.


 » Discussion Top


Bortezomib acts by selectively inhibiting the 26S proteasome, preventing the degradation of key cell signaling proteins and leading to cell death. It also acts in the bone marrow micro-environment and inhibits the binding of myeloma cells to bone marrow stromal cells.

Bortezomib was the “ first-in-class” agent to enter clinical trials. It received accelerated approval in May 2003, for relapsed/refractory myeloma, based on data from Phase 2 studies.[3],[4] The dramatic results of the Phase 3 assessment of proteasome inhibition for extending remissions trial [5] led to the regular approval of the drug in 2005 for the treatment of patients with MM who had received at least one prior therapy. It was later approved in June 2008, as an initial treatment for patients with MM, based on the improved survival results of the velcade as initial standard therapy in MM (VISTA) trial.[6]

In our study, we retrospectively studied 41 patients with newly diagnosed MM who underwent induction therapy with bortezomib. The OR rate was 88.5%, including a CR rate of 31.4% and a VGPR of 34.2%. Response rate to therapy, although not correlative with survival, is an important surrogate of disease control in hematological malignancies. Complete or nCR represents symptom control, lesser necessity for supportive care and better quality-of-life.

The median time to disease progression in our study was not reached with only 6 out of 24 patients progressing, during the follow-up period. Only one patient who completed induction with bortezomib and was consolidated with ASCT progressed. ASCT seems to consolidate the responses achieved after induction with bortezomib.

In studies in relapsed/refractory patients, the OR to bortezomib was 38% (CR + PR).[5] Responses to bortezomib were bettered in an upfront setting. In the Phase 3 VISTA trial,[6] the OR in the patients on the bortezomib arm was 71% including a CR rate of 30% (23%, when regrouped under the International Uniform Response criteria). The median duration of the response was 19.9 months in the bortezomib group. Responses were not significantly affected by older age, renal impairment or high risk cytogenetics.

Outside of clinical trials, retrospective studies on the use of bortezomib in a frontline setting have yielded better responses. One study by Chanan-Khan et al.[7] reported an OR rate of 75% among the 20 patients with response data. Five patients had a CR (25%), one nCR (5%) and nine PR (45%).

In an analysis of the Singapore MM study group by Tan et al.,[8] the median overall survival was not reached in high risk patients on bortezomib. The most significant prognostic factor was quality of response. In a Swiss retrospective study of 29 patients, all patients had achieved a PR or better with initial bortezomib therapy and one-third achieved CR or nCR. With initial bortezomib treatment, the median time to response was 2.4 months, the median duration of first response was 7.3 months and the median time to progression was 10.7 months.[9]

An overwhelming 65.8% of our patients were renal impaired at diagnosis in our study. One third of these patients had severe compromise with a GFR <15 ml/min. However, bortezomib was useful in reversing renal injury in most of these patients.

Dimopoulos et al.[10] reported that 44% of 111 patients on the bortezomib arm of their trial with baseline GFR lower than 50 mL/min improved to higher than 60 mL/min on treatment. By multivariate analysis, younger age (<75 years; P < 0.006) and less severe impairment (GFR > 30 mL/min; P > 0.027) were associated with a higher reversal rates. Ludwig et al.[11] reported some renal response in 62% of patients (renal CR, 31%; renal PR, 7%; renal MR, 24%). Median GFR increased from 20.5 to 48.4 mL/min. GFR improvement correlated with tumor response; the greatest increase to 59.6 mL/min was seen in the group of patients with CR/nCR/VGPR. Piro and Molica [12] concluded that bortezomib is feasible and well-tolerated and its efficacy and safety are not substantially modified by renal failure patients.

Some renal response was documented in 96.2% of patients with initial renal impairment in our study. Of these, 70.3% had a CR. Majority of these responses were seen in the first cycle of therapy itself. Greater degrees of renal impairment were not significantly associated with a lesser likelihood of reversibility in our study. Rapid reversal of renal dysfunction makes bortezomib an attractive primary therapy for patients with renal disease.

In our study, 17/41 patients (41.4%) had Grade 3 or Grade 4 toxicities. Grade 4 events included sensory neuropathy in seven patients, thrombocytopenia in two patients, severe pulmonary toxicity in two patients and thromboembolism in one patient. The most common adverse events noted in the VISTA study,[6] were asthenia (61%), diarrhea (57%), nausea (57%), constipation (42%) and peripheral neuropathy (36%). 53% of bortezomib patients on the trial experienced serious adverse events of some sort. In our study, serious adverse events with bortezomib were less frequent than previously reported, with the exception of peripheral neuropathy.

BIPN was documented in 51.2% of our patients commonly after two cycles of bortezomib. BIPN was the most common cause of discontinuation of therapy. In a retrospective analysis of BIPN, in 78 patients with recurrent and/or refractory MM who were treated with bortezomib alone or in combination with thalidomide and/or chemotherapy, Badros et al.[13] noted that neuropathy affected 52% of patients, including Grade 3 and 4 neurotoxicity in 15% and 7%, respectively. Nine patients stopped bortezomib and dose reduction was applied in 11 patients because of BIPN.

The results obtained in our study are comparable with those of established studies on bortezomib. Our patient population has similar responses and renal reversibility patterns. However, they are at an increased susceptibility to BIPN, leading to discontinuation of therapy.


 » Conclusion Top


Bortezomib as first-line therapy in myeloma has a good OR rate. Bortezomib is instrumental in reversing renal impairment. The most common serious toxicity leading to discontinuation of bortezomib is peripheral neuropathy.

 
 » References Top

1.
Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia 2006;20:1467-73.  Back to cited text no. 1
    
2.
Dimopoulos MA, Roussou M, Gavriatopoulou M, Zagouri F, Migkou M, Matsouka C, et al. Reversibility of renal impairment in patients with multiple myeloma treated with bortezomib-based regimens: Identification of predictive factors. Clin Lymphoma Myeloma 2009;9:302-6.  Back to cited text no. 2
    
3.
Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003;348:2609-17.  Back to cited text no. 3
    
4.
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;127:165-72.  Back to cited text no. 4
    
5.
Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487-98.  Back to cited text no. 5
    
6.
Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: Updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol 2010;28:2259-66.  Back to cited text no. 6
    
7.
Chanan-Khan AA, Kaufman JL, Mehta J, Richardson PG, Miller KC, Lonial S, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: A multicenter retrospective study. Blood 2007;109:2604-6.  Back to cited text no. 7
    
8.
Tan D, Ong KH, Koh LP, Wong SS, Khin MT, Lee LH, et al. The impact of frontline risk-adapted strategy on the overall survival of patients with newly diagnosed multiple myeloma: An analysis of the Singapore multiple myeloma study group. Eur J Haematol 2012;89:136-44.  Back to cited text no. 8
    
9.
Taverna C, Voegeli J, Trojan A, Olie RA, von Rohr A. Bortezomib retreatment in patients with relapsed multiple myeloma in Switzerland. International myeloma workshop 2011. Haematologica 2011;96 Suppl 1:S86.  Back to cited text no. 9
    
10.
Dimopoulos MA, Richardson PG, Schlag R, Khuageva NK, Shpilberg O, Kastritis E, et al. VMP (Bortezomib, Melphalan, and Prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, and results in reversal of renal impairment: Cohort analysis of the phase III VISTA study. J Clin Oncol 2009;27:6086-93.  Back to cited text no. 10
    
11.
Ludwig H, Adam Z, Hajek R, Greil R, Tóthová E, Keil F, et al. Light chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple myeloma: Results of a phase II study. J Clin Oncol 2010;28:4635-41.  Back to cited text no. 11
    
12.
Piro E, Molica S. A systematic review on the use of bortezomib in multiple myeloma patients with renal impairment: What is the published evidence? Acta Haematol 2011;126:163-8.  Back to cited text no. 12
    
13.
Badros A, Goloubeva O, Dalal JS, Can I, Thompson J, Rapoport AP, et al. Neurotoxicity of bortezomib therapy in multiple myeloma: A single-center experience and review of the literature. Cancer 2007;110:1042-9.  Back to cited text no. 13
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]

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