• Users Online: 157
  • Print this page
  • Email this page


 
 
Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 17  |  Issue : 4  |  Page : 327-331

Frequency and prognostic significance of hypercalcemia in patients with multiple myeloma


1 Department of Hematology, Hiwa Cancer Hospital, Sulaymaniyah, Iraq
2 Department of Medicine, University of Duhok, Duhok, Iraq
3 Department of Pathology, College of Medicine, University of Sulaymaniyah, Sulaymaniyah, Iraq
4 Department of Medicine, College of Medicine, Hawler Medical University, Erbil, Kurdistan Region, Iraq
5 Department of Pathology, College of Medicine, University of Duhok, Duhok, Iraq
6 Department of Pathology, College of Medicine, Hawler Medical University, Erbil, Kurdistan Region, Iraq
7 Department of Hematology, Nanakali Hospital, Erbil, Kurdistan Region, Iraq

Date of Submission07-Aug-2020
Date of Acceptance27-Aug-2020
Date of Web Publication14-Dec-2020

Correspondence Address:
Kanar J Karim
Department of Hematology, Hiwa Cancer Hospital, Sulaymaniyah, Kurdistan Region
Iraq
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/MJBL.MJBL_54_20

Get Permissions

  Abstract 


Background: Multiple myeloma (MM) is defined as a clonal B-cell malignancy of the bone marrow. Hypercalcemia is associated with cancers in general and in MM specifically becomes more obvious with frequent adverse outcomes. Objectives: The objective is to determine the frequency of hypercalcemia in MM patients and survival rate after 3 years of diagnosis with the assessment of relationship between MM prognosis and hypercalcemia. Materials and Methods: Retrospective data were reviewed from the Hematology and Cancer Centers of Kurdistan Region of Iraq (KRI, Erbil, Sulaymaniyah, and Duhok) from January 2012 to December 2017 on a sample of 130 patients with MM. The diagnosis of MM and hypercalcemia was done according to the International Myeloma Working Group definition of MM and serum calcium of ≥11 mg/dl. Results: The prevalence of hypercalcemia among MM patients after calcium correction was 17.7%. Serum creatinine level is significantly higher among MM patients with hypercalcemia. There was a significant association between high death rates and MM patients with hypercalcemia. The mean survival of MM patients was 4.5 years and 72% of the MM patients had 3-year survival, which decreased to <41% for 6-year survival. The survival of MM patients with hypercalcemia was significantly shorter than survival of patients without hypercalcemia. Conclusions: The frequency of hypercalcemia among MM patients in KRI is within the international acceptable range and is regarded as a poor prognostic factor that is associated with higher mortality and shorter survival.

Keywords: Hypercalcemia, multiple myeloma, survival


How to cite this article:
Karim KJ, Hassan AM, Getta HA, Khoshnaw NS, Jalal SD, Mohammed AM, Hasan KM, Abdullah DA, A. Badi AI, Yassin AK, Safar BM, Abdulla BK, Shamoon RP, Amin TA, Mohamed ZA, Mohammed AI, Hussein DJ, Mohammed NS, Rajab RN, Hiwaizi F. Frequency and prognostic significance of hypercalcemia in patients with multiple myeloma. Med J Babylon 2020;17:327-31

How to cite this URL:
Karim KJ, Hassan AM, Getta HA, Khoshnaw NS, Jalal SD, Mohammed AM, Hasan KM, Abdullah DA, A. Badi AI, Yassin AK, Safar BM, Abdulla BK, Shamoon RP, Amin TA, Mohamed ZA, Mohammed AI, Hussein DJ, Mohammed NS, Rajab RN, Hiwaizi F. Frequency and prognostic significance of hypercalcemia in patients with multiple myeloma. Med J Babylon [serial online] 2020 [cited 2021 Jun 12];17:327-31. Available from: https://www.medjbabylon.org/text.asp?2020/17/4/327/303257




  Introduction Top


Multiple myeloma (MM) is defined as a clonal B-cell malignancy of the bone marrow accompanied by different clinical features, such as renal failure, skeletal disorders, anemia, and infection.[1] MM represented 1% of all recorded cancers globally, and it is the second most common hematologic malignancy after lymphoma with an age-specific incidence rate of 32.6%.[2],[3] The epidemiological features in Kurdistan Region of Iraq (KRI) showed equal male to female affected by MM with predominant backache, bone pain, and anemia.[4]

The clinical presentation of MM is commonly caused by the effect of plasma cells on the bone or kidney. However, in some cases, the clinical presentation is nonspecific.[5] Recent updated diagnostic criteria for MM as described by the International Myeloma Working Group (IMWG) included three specific biomarkers essential for diagnosis of MM in the absence of specific clinical features; clonal bone marrow plasma cells (≥60%), serum-free light chain ratio (≥100), and more than one focal lesion on magnetic resonance imaging. In addition, computerized tomography (CT) and positron emission tomography-CT are important in early diagnosis of MM bone diseases.[6] MM treatment is dependable on patient physical status and health. In patients less than 65 years of age who are eligible for transplantation, MM treatment includes immunomodulatory drug (IMID) and proteasome inhibitor (PI) in combination with glucocorticoids, followed by autologous stem-cell transplantation and maintenance therapy with low-dose IMID or PI.[7]

Bone destruction present in 80% of MM patients leads to severe bone pain, pathologic fractures, spinal cord compression, and hypercalcemia. The hypercalcemia is recorded in about one-third of MM patients.[8] The main etiology of hypercalcemia in MM is the widespread tumor-induced bone destruction, which is related to elevated osteoclastic bone resorption caused by potent cytokines expressed or secreted locally by the myeloma cells or over-expressed by other cells in the local microenvironment that in turn leads to efflux of calcium into the extracellular fluid.[9] The relationship between hypercalcemia and MM patients with poor prognosis is still unclear but may attribute to increased amount of bone-resorbing activity, severe renal insufficiency, and higher plasma cell leukemia.[10],[11]

Hypercalcemia among patients with MM is accompanied with lower prognosis rates globally.[12],[13] For that, our study aimed to measure the frequency of hypercalcemia in MM patients and survival rate after 3 years of diagnosis with the assessment of relationship between MM prognosis and hypercalcemia.


  Materials and Methods Top


Study design and patients

This study is a retrospective study with data reviewed and collected in Hematology and Cancer Centers of KRI (Erbil, Sulaymaniyah, and Duhok, Iraq) from January 1, 2012, to December 31, 2017, on a sample of 130 patients with MM.

Inclusion criteria for selected sample were confirmed by the diagnosis of MM according to the IMWG diagnostic criteria, symptomatic patients with availability of full data of complete frequent visits to Hematology and Cancer Centers of KRI. The exclusion criteria were asymptomatic patients (smoldering myeloma, localized plasmacytoma) with amyloidosis and monoclonal gammopathy of undetermined significant.

The saved data were collected by the researcher from KRI including Erbil, Sulaymaniyah, and Duhok cancer centers and hospitals. The questionnaire included age (<60 and ≥60 years), gender (male or female), the Eastern Cooperative Oncology Group (ECOG) score (0–1 or ≥2), anemia defined by hemoglobin <10 gm/dl (yes or no), serum albumin (<3.5 or >3.5 g/dl) serum creatinine (<2 or ≥2 mg/dl), lactate dehydrogenase (LDH) (normal or higher than upper limit of normal), hypercalcemia (serum calcium >11 mg/dl), Durie-Salmon staging (I–III), International Staging System (ISS) staging (I–III), and current patient status (alive or dead). The investigations implemented for patients were done in Laboratories of Cancer Centers in KRI. The survived patients were followed up retrospectively in general for a duration of 6 years. The diagnosis of hypercalcemia was done by the researcher in accordance with the IMWG definition of serum calcium of >11 mg/dl.

Ethical consideration

Ethical considerations were taken in consideration according to the Helsinki Declaration by taking approval of study from Ethical Committee of Kurdistan Board and Cancer Centers authorities in addition to taking in consideration confidentiality of patients' data.

Statistical analysis

Statistical analysis was carried out using Statistical Package of the Social Sciences software version 22 (SPSS, IBM Company, Chicago, IL 60606, USA). Chi-square test and Fisher's exact test were applied for analyzing the data as suitable. Kaplan–Meier curve was used to assess the survival of MM patients. Level of significance (P value) was regarded statistically significant if it was 0.05 or less.


  Results Top


This study included 130 MM patients with a mean age of 59.3 years and range of 35–89 years. Male patients were more than females with male-to-female ratio of 1.2:1. The ECOG of MM patients were ECOG 0–1 (37.7%) and ECOG ≥2 (62.3%). Furthermore, anemia was present among 47.7% of MM patients. The serum albumin was low among 40.8% of MM patients, while serum creatinine and LDH were high in 20% and 68.5% of MM patients, respectively. The prevalence of hypercalcemia among MM patients after calcium correction was 17.7% [Table 1].
Table 1: Demographic, clinical and laboratory characteristics of multiple myeloma patients

Click here to view


Durie-Salmon staging of MM patients showed commonly Stage II (53.8%). ISS staging of MM patients revealed predominantly Stage II (47.7%). Of the MM patients, 79.2% of them were alive and 20.8% were dead [Table 2].
Table 2: Staging and outcome of multiple myeloma patients

Click here to view


No significant differences were observed between MM patients with or without hypercalcemia regarding age of the patients (P = 0.43), gender (P = 0.81), and ECOG (P = 0.14). Furthermore, no significant differences were observed between MM patients with or without hypercalcemia regarding anemia (P = 0.98), serum albumin (P = 0.77), and LDH (P = 0.29). Serum creatinine level is significantly high among MM patients with hypercalcemia (P = 0.01) [Table 3].
Table 3: Distribution of patients' demographic, clinical and laboratory characteristics

Click here to view


A significant association was observed between advanced Durie-Salmon stages of MM patients and hypercalcemia (P = 0.01). No significant differences were observed between MM patients with or without hypercalcemia regarding ISS staging (P = 0.213). There was a significant association between high death rates and MM patients with hypercalcemia (P = 0.01) [Table 4].
Table 4: Distribution of patients' general characteristics according to hypercalcemia

Click here to view


As shown in [Figure 1], the mean survival of MM patients was 4.5 years (95% confidence interval [CI] 3.9–5.1 years). The 3-year survival among cases was 72%, while the 6-year survival was 41%.

The 3-year survival among hypercalcemic cases was 61% while among nonhypercalcemic cases was 75%. The 6-year survival of nonhypercalcemic patients was 42% [Figure 2].
Figure 1: Kaplan.Meier curve for survival of multiple myeloma patients, X = Cumulative survival in %, Y = Duration of follow.up in years

Click here to view
Figure 2: Kaplan–Meier curve for survival of multiple myeloma patients according to hypercalcemia prevalence

Click here to view



  Discussion Top


The hypercalcemia is represented as the most interesting complication of MM with unclear pathogenesis till now.[8] The current study showed a frequency of 17.7% for hypercalcemia among MM patients. This finding is lower than results of Kastritis et al.'s[13] study in Greece which found that 21% of patients with MM had hypercalcemia by reviewing data of newly diagnosed MM cases reported by Greek Myeloma Study Group. However, our study's frequency is higher than the results of Kyle et al.'s[14] study in the USA which revealed that 13% of patients with MM had hypercalcemia. In general, the hypercalcemia related to malignancy was found to be prevalent in about 20% of all cancer patients during their clinical course, and the most common malignancies related to hypercalcemia is MM with highest prevalence of hypercalcemia reaching to range of 15%–20%.[15] In the UK, the first systematic analysis population-based study carried out by Jick et al.[16] reported that the hypercalcemia prevalence increased in general among cancer patients, but higher increase was obvious among patients with lung cancer, MM, and Stage IV of cancers.

In the present study, the serum creatinine level was significantly higher among MM patients with hypercalcemia (P = 0.01). Similarly, Eleutherakis-Papaiakovou et al.'s[17] study in Greek found that hypercalcemia in MM patients is considered as high prevalent with renal insufficiency.

The current study showed a significant association between advanced Durie-Salmon stages of MM patients and hypercalcemia (P = 0.01). This finding agrees with the reports of many literature regarding as hypercalcemia one of elements of Durie-Salmon staging of MM.[18],[19] In our study, MM patients with hypercalcemia had a significantly higher mortality rate (39.1%) than MM patients with no hypercalcemia (16.8%). Consistently, a retrospective review study carried out in Spain by Lakhwani et al.[20] found that hypercalcemia increased aggressiveness and death rates of MM. Many authors found that hypercalcemia accompanying malignancy is related to severe clinical signs and symptoms and is often an oncologic emergency.[21],[22]

The mean survival of MM patients in our study was 4.5 years and the 3-year survival was 72% that declined to 41% for 6-year survival. These survival rates of MM patients are better than the survival of MM patients in Baghdad as reported by Alwan's study in Iraq which reported a mean survival of 2.9 years.[23] However, these findings are lower than the results of Hameed et al.'s[24] study in Pakistan which found that 85% of MM patients had 3-year survival rate with 4-year overall survival. These differences might be attributed to advances in supportive care with increasing in number of new novel agents each year, with possible differences in genetic and ethnic background of each patient population.

Our study showed a shorter survival of MM patients with hypercalcemia than the survival of patients without hypercalcemia. This finding coincides with results of Zagouri et al.'s[12] study in Greece which found that hypercalcemia remains as a poor prognostic characteristic of MM despite the introduction of novel therapies. In addition, Yusuf et al.'s[25] study in the USA reported that increased age, male gender, previous comorbidities, anemia, and hypercalcemia are common risk factors for early death of newly diagnosed MM patients.


  Conclusions Top


The frequency of hypercalcemia among MM patients in KRI is within international acceptable range. The hypercalcemia accompanying MM is regarded as a poor prognostic factor that is associated with higher mortality and shorter survival. Implementing strict guidelines in the treatment of hypercalcemia for patients with MM is essential for improving prognosis.

Acknowledgment

Special thanks and appreciation for all colleagues and medical workers in Hematology and Cancer Centers in KRI for their support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Shi H, Chen Z, Xie J, Chen N. The prevalence and management of multiple myeloma-induced kidney disease in China. Kidney Dis (Basel) 2016;1:235-40.  Back to cited text no. 1
    
2.
Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011;364:1046-60.  Back to cited text no. 2
    
3.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30.  Back to cited text no. 3
    
4.
Yassin AK. Clinical and laboratory profiles of 109 patients diagnosed as multiple myeloma in Erbil city. J Fac Med Baghdad 2013;55:121-4.  Back to cited text no. 4
    
5.
Fazel F, Bassa F. An approach to the diagnosis and management of multiple myeloma. SAMJ S Afr Med J 2019;109:723-7.  Back to cited text no. 5
    
6.
Rajkumar SV. Updated diagnostic criteria and staging system for multiple myeloma. Am Soc Clin Oncol Educ Book 2016;35:e418-23.  Back to cited text no. 6
    
7.
Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med 2017;376:1311-20.  Back to cited text no. 7
    
8.
Oyajobi BO. Multiple myeloma/hypercalcemia. Arthritis Res Ther 2007;9 Suppl 1:S4.  Back to cited text no. 8
    
9.
Oyajobi BO, Mundy GR. Pathophysiology of myeloma bone disease. In: Gahrton G, Durie BG, Samson DS, editors. Multiple Myeloma and Related Disorders. 2nd ed. London, UK: Arnold; 2004. p. 74-88.  Back to cited text no. 9
    
10.
García-Sanz R, Orfão A, González M, Tabernero MD, Bladé J, Moro MJ, et al. Primary plasma cell leukemia: Clinical, immunophenotypic, DNA ploidy, and cytogenetic characteristics. Blood 1999;93:1032-7.  Back to cited text no. 10
    
11.
Tuttle KR, Kunau RT, Loveridge N, Mundy GR. Altered renal calcium handling in hypercalcemia of malignancy. J Am Soc Nephrol 1991;2:191-9.  Back to cited text no. 11
    
12.
Zagouri F, Kastritis E, Zomas A, Terpos E, Katodritou E, Symeonidis A, et al. Hypercalcemia remains an adverse prognostic factor for newly diagnosed multiple myeloma patients in the era of novel antimyeloma therapies. Eur J Haematol 2017;99:409-14.  Back to cited text no. 12
    
13.
Kastritis E, Katodritou E, Pouli A, Hatzimichael E, Delimpasi S, Michalis E, et al. Frequency and prognostic significance of hypercalcemia in patients with multiple myeloma: An Analysis of the database of the Greek Myeloma Study Group. Blood 2011;118:5083.  Back to cited text no. 13
    
14.
Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003;78:21-33.  Back to cited text no. 14
    
15.
Vakiti A, Mewawalla P. Malignancy-Related Hypercalcemia. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482423/.  Back to cited text no. 15
    
16.
Jick S, Li L, Gastanaga VM, Liede A. Prevalence of hypercalcemia of malignancy among cancer patients in the UK: Analysis of the Clinical Practice Research Datalink database. Cancer Epidemiol 2015;39:901-7.  Back to cited text no. 16
    
17.
Eleutherakis-Papaiakovou V, Bamias A, Gika D, Simeonidis A, Pouli A, Anagnostopoulos A, et al. Renal failure in multiple myeloma: Incidence, correlations, and prognostic significance. Leuk Lymphoma 2007;48:337-41.  Back to cited text no. 17
    
18.
Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009;23:3-9.  Back to cited text no. 18
    
19.
Hari PN, Zhang MJ, Roy V, Pérez WS, Bashey A, To LB, et al. Is the International Staging System superior to the Durie-Salmon staging system? A comparison in multiple myeloma patients undergoing autologous transplant. Leukemia 2009;23:1528-34.  Back to cited text no. 19
    
20.
Lakhwani SL, Hernández MT, Lorenzo-Barreto P, Cabrera-Brito D, Fernández-González M, Machado-Machado P, et al. Early death in multiple myeloma. Analysis of patients in real-world practice. Blood 2018;132 (Supp 1):5595.  Back to cited text no. 20
    
21.
Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med 2005;352:373-9.  Back to cited text no. 21
    
22.
Zagzag J, Hu MI, Fisher SB, Perrier ND. Hypercalcemia and cancer: Differential diagnosis and treatment. CA Cancer J Clin 2018;68:377-86.  Back to cited text no. 22
    
23.
Alwan AF. Survival of patients with multiple myeloma diagnosed at the national center of hematology in Baghdad. Iraqi J Cancer Med Genet 2014;7:133-9.  Back to cited text no. 23
    
24.
Hameed A, Ali J, Munawar K, Arshad F, Badar F, Siddiqui N. Characteristics and outcomes of patients with multiple myeloma: Data from a developing country. Med J Islam Repub Iran 2018;32:1.  Back to cited text no. 24
    
25.
Yusuf AA, Natwick T, Werther W, Felici D, Mahue M, Bridges KR, et al. A retrospective analysis to examine factors associated with mortality in Medicare beneficiaries newly diagnosed with multiple myeloma. Curr Med Res Opin 2016;32:1989-96.  Back to cited text no. 25
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

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



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusions
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed623    
    Printed26    
    Emailed0    
    PDF Downloaded65    
    Comments [Add]    

Recommend this journal