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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 3  |  Issue : 2  |  Page : 27-30

Outcomes of Multiple Myeloma in The Era of Novel Agents: A Retrospective Study from Tertiary Cancer Centre


1 Department of Medical Oncology, Indira Gandhi Institute of Medical Sciences, Patna, India
2 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India
3 Department of Cytogenetics, Tata Memorial Hospital, Mumbai, India

Date of Web Publication11-Dec-2020

Correspondence Address:
Pandey Avinash
Assistant Professor, Medical oncology, IGIMS, Patna
India
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Source of Support: None, Conflict of Interest: None


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  Abstract 


Background: Multiple myeloma is a plasma cell neoplasm characterised by skeletal destruction, renal failure, anaemia and hypercalcemia. Use of novel agents have led to significant increase in response rates and hence, limited the benefits of transplant.
Aims and Objectives: To evaluate outcomes and toxicities with use of novel agents. To evaluate Progression Free Survival, Overall Survival and factors affecting outcome.
Material and Methods: Case records of all patients diagnosed as Multiple Myeloma registered between 1st January 2012 to 31st December 2013 have been retrospectively analysed. Demographic data was collected along with response rates, date of progression and death. Toxicity with use of novel agents was recorded. Progression free survival and Overall Survival was analyzed with the Kaplan-Meier method. Log-rank tests was utilized to assess the differences in outcomes between various subgroups.
Results: Total 101 patients were analysed out of which 90 were multiple myeloma and 11 had light chain disease. Median age of presentation was 56 years with male:female ratio of 3:1. Median time to best response was 4 months. Median follow up was 36 months with median time to second treatment 18 months. Response rates with VGPR (very good partial response) and PR (partial response) was seen in 60% of patients. Median progression free survival was 18 months while median overall survival was not reached. Out of 15 deaths, 7 patients had progressive disease, 6 had stable disease and 2 had partial response at the time of last assessment.
Conclusion: Use of novel agents in the management of multiple myeloma improved response rates and outcomes. Majority of patients including those with higher stage or high risk cytogenetic enjoyed better response rates and longer duration of remission. Despite such advances, prognosis of stage III patients needs further improvement with newer strategies for better outcome.

Keywords: Cytogenetics, Myeloma, Novel agents


How to cite this article:
Avinash P, Manju S, Pratibha A, Navin K, Bhausaheb B, Hari M. Outcomes of Multiple Myeloma in The Era of Novel Agents: A Retrospective Study from Tertiary Cancer Centre. J Indira Gandhi Inst Med Sci 2017;3:27-30

How to cite this URL:
Avinash P, Manju S, Pratibha A, Navin K, Bhausaheb B, Hari M. Outcomes of Multiple Myeloma in The Era of Novel Agents: A Retrospective Study from Tertiary Cancer Centre. J Indira Gandhi Inst Med Sci [serial online] 2017 [cited 2021 Dec 7];3:27-30. Available from: http://www.jigims.co.in/text.asp?2017/3/2/27/303142




  Introduction Top


Multiple myeloma is a clonal plasma cell neoplasm with anemia, hypercalcemia, renal failure and lytic bone lesion being the most common presentation. India, the median age of patients presenting with myeloma is 55 years-a decade less than that in USA.[1] As compared to US, the incidence of skeletal abnormalities and renal dysfunction are higher among Indian population.[2] Autologous stem- cell transplantation (ASCT) improves CR(complete response) rates and prolongs overall survival in multiple myeloma by approximately 12 months.[3],[4] Use of novel agents including Proteosome inhibitors and Immunomodulatory drugs (IMiDS) have led to significant increase in response rates and survival, though patients with high risk cytogenetics continue to have inferior outcomes.[5],[6],[7] There is paucity of data from India, specially in the era of novel agents and cytogenetic risk stratification. Hence, we evaluated outcomes of patients with multiple myeloma treated with novel agents without ASCT.


  Material and Methods Top


Case records of all patients diagnosed as Multiple Myeloma registered between 1st January 2012 to 31st December 2013 have been retrospectively analysed. Only patients who fulfilled the following criteria were selected for analysis; (1) Registered in our hospital as new untreated case. (2) Received at least 3 cycles of first line novel agents and (3)First response assessment available.101 out of 130 patients were hence taken for final analysis.[Table 1]
Table 1: Distribution of patient profiles of Multiple myeloma

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Details including history, age, sex, physical examination, date of diagnosis, diagnostic imaging, hemoglobin, serum creatinine, serum calcium, Serum immunoelectrophoresis, International staging system (ISS) stage, bone marrow aspiration/Biopsy, cytogenetic profile, use of first line and subsequent therapy, response rates, disease progression and survival status were recorded.[Table 2]. Demographic data) Responses were noted according to International Myeloma Working Group (IMWG) criteria. Outcomes in form of Response rates, Time to second treatment, Progression free survival and Overall survival was calculated with respect to novel agents, International Staging system and cytogenetic risk. Toxicity with the use of novel agents were recorded.
Table 2: Demographic and Laboratory data of patients selected for final analysis

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Progression free interval was defined as interval between date of diagnosis to date of progression or death from any cause. Overall survival was defined as interval between dates of diagnosis to date of death from any cause. Time to second treatment was defined as interval between day of starting of first regime and day of starting of second regime at time of relapse/progression.

Progression free survival and Overall Survival were analyzed with the Kaplan-Meier method. Log-rank test was utilized to assess the differences in outcomes between various subgroups. Patients who were lost to follow up were telephonically called and treatment details and current status obtained and updated.


  Results Top


Out of 101 patients, 90 (89%) were Multiple myeloma while 11 (11%) were light chain myeloma. Median age of diagnosis was 56 years, with male: female ratio of 3:1. Out of primary presenting complain data available (N=80), backache was the most common presentation seen in 46 (57.5%), followed by chest pain in 6 (7.5%). Para paresis/paraplegia was seen in 3 patients (3.75%).49(49%) of patients had bone fracture( including vertebrae) as presenting feature. As per International Staging System (ISS); Stage I, Stage II and Stage III were 21,15 and 65 patients respectively. Common monoclonal type immunoglobulin was IgG in 68 patients (76.8%), followed by IgA 14 patients (17.2%),{N=82}

Cytogenetic profile was available in 83 patients (82%). 10 (12%) patients were of high risk cytogenetics {17p del, t(14;16), t(14;20), p53 del,}, while 20 (24%) and 53 (64%) were of intermediate {del 13,hypodiploidy,t (4;14), monosomy13} and standard risk{ t(11;14), Hyperdiploid }respectively.VCD (Bortezomib+ cyclophosphamide+ dexamethasone) and VTD(bortezomib+ thalidomide+ dexamethasone) were the most common first line regimen used (38% and 24% respectively), which was followed by CTD (cyclophosphamide +thalidomide+ dexamethasone) (14%).

Median follow up was 36 months. Median number of cycles received before first response evaluation was 3 cycles. Median time to best response was 4 months, while total median duration of first line therapy was 8 months. With the use of novel agents, very good partial response (VGPR) was 37 (37%), followed by 24% and 32% of partial response (PR) and stable disease (SD) respectively.[Table 3]
Table 3: Response rates achieved with first line novel therapy

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Median progression free survival was 18 months while median overall survival had not reached. 2 year progression free survival was 38.4%, while 2 year overall survival was 80%.[Figure 1]
Figure 1: Progression free survival with first line novel agents for Multiple myeloma.

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Median time for second treatment was 18 months. Out of 15 deaths, 7 patients had progressive disease, 6 had stable disease and 2 had partial response at the time of last assessment. Grade 3/4 peripheral neuropathy was documented in 6 patients, out of which 4 with Bortezomib and 2 with thalidomide based regime. Myelosuppression grade ¾ was seen in 3 patients, with change required from CTD to TD (thalidomide dexamethasone) in 1 patient. Pneumonia was the most common infection seen in 5% of patients, while 2% patients developed documented deep venous thrombosis( DVT)


  Discussion Top


Multiple myeloma is one of the most common haematological malignancies with clonal plasma cell proliferation characterised by renal dysfunction, lytic bone lesions, anaemia and hypercalcemia. The management and outcomes of patients with multiple myeloma from Indian subcontinent in the era of novel agents have not been reported before. Incorporating combination of novel agents including bortezomib, lenalidomide and thalidomide to the chemotherapeutic backbone has improved response rates and outcomes of myeloma. We report retrospective analysis of case records of multiple myeloma patients treated at our centre.

In our analysis, median age of presentation was 56 years which is about 5 years younger as compared to the European studies with male to female ratio of 3:1.8 In contrast to western data where in majority of patients present in ISS stage I and II, our study had 64% patients presenting in stage III,9 thus reflecting a late presentation and higher disease burden. However, only 12% of our patients had high risk cytogenetics compared to more than 20% reported in other series.[10]

Bortezomib and dexamethasone backbone were the backbone of regimes which incorporated either cyclophosphamide or thalidomide as third agent in approximately 60 % of patients. Overall response rates (VGPR+PR) was 61% with 37% VGPR and 24% PR, which is slightly inferior to that reported by the Italian group.[9] Best response rates was seen with VTD (55% VGPR+PR) and VCD (60 % VGPR +PR) which was similar to that reported by the PETHEMA and Italian groups, though our numbers are smaller.[9],[10] In our study VCD was the most common regime(37%) followed by VTD (24%). Our impressive response rates with VCD and VTD mimics results published by Chim et al in Chinese population.[11],[12] Lenalidomide dexa (LD) -26% followed by CTD 13% were the common regimes used as salvage regimes, with VGPR in 23% and 35% respectively, though the data on relapse was available in 32 patients only. Time to second treatment in our data was 17 months which is similar to that reported by IFM group.[13]

With median follow up of 36 months and recent follow up status updated in 85% of patients our median progression free survival was 18 months which is inferior to IFM group(24 months) and PETHEMA group (33 months).[9],[10] Stratified with respect to stage at presentation, median PFS was not reached in stage I while in stage II and III it was 19 and 15 months respectively which was inferior to Chinese data where stage III had median PFS upto 23 months.[11],[12] The progression free survival correlates well with response rates. Response rates had strong prognostic significance on outcomes with median progression free survival of patients who achieved VGPR was not reached, while that for PR and SD was 12 and 08 months respectively (p=0.03,cox regression).

Compared to PETHEMA group, where high risk cytogenetic was present in 21% of study population, our data had only 7% high risk patients. However our median survival for high and standard risk was inferior to that reported by PETHEMA group (15 months and 20 months in our data versus 18 months and 35 months in PETHEMA group study).[10] In patients with high risk cytogenetics, bortezomib and dexamethsone backbone was used in 70% patients with VGPR achieved in 50% of all high risk patients. Our study shows that among the several known prognostic factors higher stage , high risk cytogenetic and poor response are strong prognostic factors for inferior outcome.

Use of novel agents in management of multiple myeloma improved response rates and outcomes. Majority of patients including those with higher stage or high risk cytogenetic enjoyed better response rates and longer duration of remission. Thus in developing countries with economical and logistic constraints, use of novel agents can be a good alternative to induction chemotherapy followed by autologous stem cell transplant which is considered to be the gold standard.[14],[15] Though bortezomib containing regimes were superior, use of non bortezomib based regimes also produced impressive response rates in more than one third of patients. Despite such advances prognosis of stage III patients needs improvement and requirement for newer strategies for better outcome.[16],[17]



 
  References Top

1.
National Cancer Registry Programme. Two year report of the Population based Cancer registries 1999-2000. New Delhi:Indian Council of Medical Research; 2005.  Back to cited text no. 1
    
2.
Advani SH, Soman CS, Talwalkar GV, Iyer YS, Bhatia HM. Multiple myeloma: Review of 231 cases. Indian J Cancer 1978;15:55-61.  Back to cited text no. 2
    
3.
Attal M, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996; 335:91-97  Back to cited text no. 3
    
4.
Child JA, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003; 348:1875-1883  Back to cited text no. 4
    
5.
Zonder JA, et al. Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232). Blood. 2010; 116:5838-5841.  Back to cited text no. 5
    
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Richardson PG, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010; 116:679-686.  Back to cited text no. 6
    
7.
Fonseca R, Blood E, Rue M, Harrington D, Oken MM, Kyle RA, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 2003;101:4569-4575.  Back to cited text no. 7
    
8.
Buda G, Orciuolo E, Carulli G, Galimberti S, Ghio F, Cervetti G. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus doxorubicin anddexamethasone as induction therapy in previously untreated multiple myeloma patients. Acta Haematol. 2013;129(1):35-9  Back to cited text no. 8
    
9.
Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone asinduction therapy before, and consolidation therapy after, double autologous stem-cell transplantation innewly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85  Back to cited text no. 9
    
10.
Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy inmultiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 23;120(8):1589-96  Back to cited text no. 10
    
11.
Chor Sang Chim, Albert Kwok Wai Lie, Eric Yuk Tat Chan, Herman Sung Yu Liu, Ching Wa Lau, Sze Fai Yip. Treatment outcome and prognostic factor analysis in transplant-eligible Chinese myeloma patients receiving bortezomib-based induction regimens including the staged approach, PAD or VTD. J Hematol Oncol. 2012; 5:28.  Back to cited text no. 11
    
12.
Hye Jung Chang, Jae Hoon Lee, Young Rok Do, Sung-Hwa Bae, Jung-Lim Lee. A Combination of Melphalan, Prednisone, and 50 mg Thalidomide Treatment in Non-Transplant-Candidate Patients with NewlyDiagnosed Multiple Myeloma. Korean J Intern Med. 2011 December; 26(4): 403-409.  Back to cited text no. 12
    
13.
Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 2009;27:3664-3670  Back to cited text no. 13
    
14.
Qazilbash MH, Saliba RM, Hosing C, et al. Autologous stem cell transplantation is safe and feasible in elderly patients with multiple myeloma. Bone Marrow Transplant 2007;39:279-283  Back to cited text no. 14
    
15.
Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma: intergroupe Francais du Myelome. N Engl J Med 1996;335:91-97  Back to cited text no. 15
    
16.
Mitsiades CS, Davies FE, Laubach JP,et al: Future directions of nextgeneration novel therapies, combination approaches, and the development of personalized medicine in myeloma. J Clin Oncol2011;29:1916-1923.  Back to cited text no. 16
    
17.
Avet-Loiseau H, Leleu X, Roussel M,et al: Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol2010;28:4630-4634.  Back to cited text no. 17
    


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