Background: Female sex hormones are known to have immunomodulatory effects. Therefore, reproductive factors and exogenous hormone use could influence the risk of multiple myeloma in women. However, the role of hormonal factors in multiple myeloma etiology remains unclear because previous investigations were underpowered to detect modest associations.

Methods: We conducted a pooled analysis of seven case–control studies included in the International Multiple Myeloma Consortium, with individual data on reproductive factors and exogenous hormone use from 1,072 female cases and 3,541 female controls. Study-specific odds ratios and corresponding 95% confidence intervals (CI) were estimated using logistic regression and pooled analyses were conducted using random effects meta-analyses.

Results: Multiple myeloma was not associated with reproductive factors, including ever parous [OR = 0.92; 95% confidence interval (CI), 0.68–1.25], or with hormonal contraception use (OR = 1.04; 95% CI, 0.80–1.36). Postmenopausal hormone therapy users had nonsignificantly reduced risks of multiple myeloma compared with never users, but this association differed across centers (OR = 0.65; 95% CI, 0.37–1.15, I2 = 76.0%, Pheterogeneity = 0.01).

Conclusions: These data do not support a role for reproductive factors or exogenous hormones in myelomagenesis.

Impact: Incidence rates of multiple myeloma are higher in men than in women, and sex hormones could influence this pattern. Associations with reproductive factors and exogenous hormone use were inconclusive despite our large sample size, suggesting that female sex hormones may not play a significant role in multiple myeloma etiology. Cancer Epidemiol Biomarkers Prev; 25(1); 217–21. ©2015 AACR.

Multiple myeloma is a malignancy characterized by the accumulation of clonal plasma cells in the bone marrow, abnormal secretion of monoclonal protein, and end organ damage (1). Incidence rates are higher in men than in women (2). Because female sex hormones have immunomodulatory effects, reproductive factors, and exogenous hormone use may affect risk for multiple myeloma. However, the role of hormonal factors in multiple myeloma etiology remains unclear. A few studies addressed possible associations between multiple myeloma risk and reproductive factors, such as parity (3–6) or use of postmenopausal hormone therapy (HT; refs. 6–8), but yielded inconsistent results as most studies were underpowered. We conducted a pooled analysis of case–control studies included in the International Multiple Myeloma Consortium (IMMC) to clarify the role of hormonal factors in the etiology of multiple myeloma.

We pooled individual-level questionnaire data from the seven IMMC case–control studies that collected information on reproductive factors among women (1,072 cases and 3,541 controls). These studies were: Los Angeles County Multiple Myeloma Case-Control Study (LAMMCC), Roswell Park Cancer Institute (RPCI), Utah, Epilymph, Fred Hutchinson Cancer Research Center (FHCRC) 1980s, National Cancer Institute (NCI)-Yale, and Molecular and Genetic Epidemiology Study (iMAGE). Enrollment period, age eligibility, study design, sample sizes, and participation rates within each study are summarized in Supplementary Table S1. Parity was defined as number of live births in NCI-Yale, iMAGE, and RCPI, and as number of children in all other studies.

Within each study, we computed ORs with corresponding 95% confidence intervals (CI) using unconditional logistic regression, adjusting for age group (four categories), race (except for Epilymph, which did not collect these data), and study center (for multicentric studies: Epilymph and FHCRC 1980s). Random-effects models were used to calculate pooled estimates using the DerSimonian and Laird method. Heterogeneity between studies was assessed using the I2 statistic and Pheterogeneity using the Mantel–Haenszel method. Analyses on parity and gravidity were restricted to women ages 45 or older, as they are likely to have completed their reproductive history. Analyses on hormonal therapy were restricted to postmenopausal women, defined as women who reported cessation of their menstrual periods. Wald tests were utilized to assess heterogeneity between strata.

In this pooled analysis, we did not observe any statistically significant association between multiple myeloma and age at menarche or at menopause, ever pregnant, number of pregnancies, ever parous, number of children, age at first birth, or cause of menopause (Table 1). The association between multiple myeloma and ever use of hormonal contraceptives was not significant [OR = 1.04; 95% confidence interval (CI), 0.80–1.36; Table 1]. Similarly, we saw no significant associations or consistent patterns for age and year at first use, duration, or time since last hormonal contraceptive use.

Table 1.

Associations between reproductive factors and exogenous hormone use and multiple myeloma risk

CoCaPooled OR (95% CI)*I2Pheterogeneity
Reproductive factors 
 Age at menarchea 
  Total 1,335 482   No. centers = 4 
  ≤11 256 86 Ref   
  12–13 717 271 1.20 (0.89–1.63) 0.0% 0.58 
  ≥14 362 125 1.03 (0.73–1.45) 0.0% 0.57 
 Ever pregnantc 
  Total 2,321 691   No. centers = 6 
  No 228 69 Ref   
  Yes 2,093 622 0.90 (0.57–1.44) 48.2% 0.09 
 No of pregnanciesb 
  Total 1,494 593   No. centers = 5 
  None 142 64 Ref   
  1 145 52 0.80 (0.39–1.64) 55.2% 0.06 
  2 329 134 0.83 (0.57–1.20) 0.0% 0.78 
  3 296 118 0.90 (0.50–1.60) 51.8% 0.08 
  ≥4 582 225 0.91 (0.54–1.54) 50.3% 0.09 
 Ever parousd 
  Total 3,075 1,007   No. centers = 7 
  Never 408 150 Ref   
  Ever 2,667 857 0.92 (0.68–1.25) 41.8% 0.11 
 No of childrend 
  Total 3,075 1,007   No. centers = 7 
  None 408 150 Ref   
  1 410 138 0.95 (0.66–1.38) 30.9% 0.19 
  2 802 274 0.96 (0.75–1.24) 0.0% 0.46 
  3 635 190 0.91 (0.60–1.37) 53.1% 0.05 
  ≥4 820 255 0.91 (0.64–1.30) 41.3% 0.12 
 Age at first birthe 
  Total 1,941 449   No. centers = 4 
  Nulliparous 255 64 Ref   
  <20 237 66 0.97 (0.50–1.89) 54.4% 0.09 
  20–<25 749 167 0.99 (0.58–1.70) 56.1% 0.08 
  25+ 700 152 0.96 (0.59–1.57) 44.8% 0.14 
 Age at menopauseb 
  Total 1,265 524   No. centers = 5 
  ≤45 414 184 Ref   
  45–49 313 118 1.00 (0.74–1.35) 0.0% 0.46 
  ≥50 538 222 1.12 (0.86–1.45) 0.0% 0.58 
 Cause of menopausef 
  Total 800 397   No. centers = 4 
  Natural 433 197 Ref   
  Surgical/therapeutic 367 200 1.11 (0.80–1.54) 36.7% 0.19 
Exogenous hormone use 
 Ever hormonal contraceptiong 
  Total 2,450 590   No. centers = 5 
  Never used 1,805 426 Ref   
  Ever used 645 164 1.04 (0.80–1.36) 0.0% 0.66 
 Age at first hormonal contraceptiong 
  Total 2,434 587   No. centers = 5 
  Never used 1,805 426 Ref   
  ≤25 421 101 1.07 (0.76–1.49) 0.0% 0.80 
  >25 208 60 1.08 (0.76–1.54) 0.0% 0.42 
 Year at first hormonal contraceptiong 
  Total 2,434 587   No. centers = 5 
  Never used 1,805 426 Ref   
  <1975 353 119 1.19 (0.87–1.62) 0.0% 0.87 
  ≥1975 276 42 1.18 (0.65–2.14) 19.6% 0.29 
 Time since last hormonal contraceptiong 
  Total 2,421 588   No. centers = 5 
  Never used 1,891 428 Ref   
  ≤20 275 70 1.22 (0.84–1.76) 0.0% 0.50 
  >20 255 90 1.09 (0.75–1.58) 15.2% 0.32 
 Years of hormonal contraceptiong 
  Total 2,415 582   No. centers = 5 
  Never used 1,805 426 Ref   
  <5 217 69 1.30 (0.92–1.83) 0.0% 0.89 
  ≥5 393 87 0.96 (0.57–1.63) 55.6% 0.06 
 Ever postmenopausal hormonal therapya 
  Total 1,076 432   No. centers = 4 
  Never used 703 307 Ref   
  Ever used 373 125 0.65 (0.37–1.15) 76.0% 0.01 
 Age first used postmenopausal hormonal therapya 
  Total 1,057 425   No. centers = 4 
  Never used 703 307 Ref   
  <50 197 72 0.60 (0.31–1.17) 71.5% 0.01 
  ≥50 157 46 0.61 (0.41–0.90) 4.5% 0.37 
 Year first used postmenopausal hormonal therapya 
  Total 1,057 425   No. centers = 4 
  Never used 703 307 Ref   
  <1980 143 54 0.58 (0.33–1.04) 38.9% 0.18 
  ≥1980 211 64 0.81 (0.37–1.77) 75.3% 0.01 
 Time since last postmenopausal hormonal therapy consumptiona 
  Total 1,055 424   No. centers = 4 
  Never used 703 307 Ref   
  Current 150 41 0.84 (0.30–2.38) 77.1% <0.01 
  ≤10 116 46 0.90 (0.37–2.16) 76.5% 0.01 
  >10 86 30 0.52 (0.21–1.26) 57.9% 0.07 
 Years of hormonal therapy usea 
  Total 1,056 423   No. centers = 4 
  Never used 703 307 Ref   
  <5 136 54 0.64 (0.30–1.37) 71.4% 0.01 
  ≥5 217 62 0.56 (0.33–0.97) 57.6% 0.07 
CoCaPooled OR (95% CI)*I2Pheterogeneity
Reproductive factors 
 Age at menarchea 
  Total 1,335 482   No. centers = 4 
  ≤11 256 86 Ref   
  12–13 717 271 1.20 (0.89–1.63) 0.0% 0.58 
  ≥14 362 125 1.03 (0.73–1.45) 0.0% 0.57 
 Ever pregnantc 
  Total 2,321 691   No. centers = 6 
  No 228 69 Ref   
  Yes 2,093 622 0.90 (0.57–1.44) 48.2% 0.09 
 No of pregnanciesb 
  Total 1,494 593   No. centers = 5 
  None 142 64 Ref   
  1 145 52 0.80 (0.39–1.64) 55.2% 0.06 
  2 329 134 0.83 (0.57–1.20) 0.0% 0.78 
  3 296 118 0.90 (0.50–1.60) 51.8% 0.08 
  ≥4 582 225 0.91 (0.54–1.54) 50.3% 0.09 
 Ever parousd 
  Total 3,075 1,007   No. centers = 7 
  Never 408 150 Ref   
  Ever 2,667 857 0.92 (0.68–1.25) 41.8% 0.11 
 No of childrend 
  Total 3,075 1,007   No. centers = 7 
  None 408 150 Ref   
  1 410 138 0.95 (0.66–1.38) 30.9% 0.19 
  2 802 274 0.96 (0.75–1.24) 0.0% 0.46 
  3 635 190 0.91 (0.60–1.37) 53.1% 0.05 
  ≥4 820 255 0.91 (0.64–1.30) 41.3% 0.12 
 Age at first birthe 
  Total 1,941 449   No. centers = 4 
  Nulliparous 255 64 Ref   
  <20 237 66 0.97 (0.50–1.89) 54.4% 0.09 
  20–<25 749 167 0.99 (0.58–1.70) 56.1% 0.08 
  25+ 700 152 0.96 (0.59–1.57) 44.8% 0.14 
 Age at menopauseb 
  Total 1,265 524   No. centers = 5 
  ≤45 414 184 Ref   
  45–49 313 118 1.00 (0.74–1.35) 0.0% 0.46 
  ≥50 538 222 1.12 (0.86–1.45) 0.0% 0.58 
 Cause of menopausef 
  Total 800 397   No. centers = 4 
  Natural 433 197 Ref   
  Surgical/therapeutic 367 200 1.11 (0.80–1.54) 36.7% 0.19 
Exogenous hormone use 
 Ever hormonal contraceptiong 
  Total 2,450 590   No. centers = 5 
  Never used 1,805 426 Ref   
  Ever used 645 164 1.04 (0.80–1.36) 0.0% 0.66 
 Age at first hormonal contraceptiong 
  Total 2,434 587   No. centers = 5 
  Never used 1,805 426 Ref   
  ≤25 421 101 1.07 (0.76–1.49) 0.0% 0.80 
  >25 208 60 1.08 (0.76–1.54) 0.0% 0.42 
 Year at first hormonal contraceptiong 
  Total 2,434 587   No. centers = 5 
  Never used 1,805 426 Ref   
  <1975 353 119 1.19 (0.87–1.62) 0.0% 0.87 
  ≥1975 276 42 1.18 (0.65–2.14) 19.6% 0.29 
 Time since last hormonal contraceptiong 
  Total 2,421 588   No. centers = 5 
  Never used 1,891 428 Ref   
  ≤20 275 70 1.22 (0.84–1.76) 0.0% 0.50 
  >20 255 90 1.09 (0.75–1.58) 15.2% 0.32 
 Years of hormonal contraceptiong 
  Total 2,415 582   No. centers = 5 
  Never used 1,805 426 Ref   
  <5 217 69 1.30 (0.92–1.83) 0.0% 0.89 
  ≥5 393 87 0.96 (0.57–1.63) 55.6% 0.06 
 Ever postmenopausal hormonal therapya 
  Total 1,076 432   No. centers = 4 
  Never used 703 307 Ref   
  Ever used 373 125 0.65 (0.37–1.15) 76.0% 0.01 
 Age first used postmenopausal hormonal therapya 
  Total 1,057 425   No. centers = 4 
  Never used 703 307 Ref   
  <50 197 72 0.60 (0.31–1.17) 71.5% 0.01 
  ≥50 157 46 0.61 (0.41–0.90) 4.5% 0.37 
 Year first used postmenopausal hormonal therapya 
  Total 1,057 425   No. centers = 4 
  Never used 703 307 Ref   
  <1980 143 54 0.58 (0.33–1.04) 38.9% 0.18 
  ≥1980 211 64 0.81 (0.37–1.77) 75.3% 0.01 
 Time since last postmenopausal hormonal therapy consumptiona 
  Total 1,055 424   No. centers = 4 
  Never used 703 307 Ref   
  Current 150 41 0.84 (0.30–2.38) 77.1% <0.01 
  ≤10 116 46 0.90 (0.37–2.16) 76.5% 0.01 
  >10 86 30 0.52 (0.21–1.26) 57.9% 0.07 
 Years of hormonal therapy usea 
  Total 1,056 423   No. centers = 4 
  Never used 703 307 Ref   
  <5 136 54 0.64 (0.30–1.37) 71.4% 0.01 
  ≥5 217 62 0.56 (0.33–0.97) 57.6% 0.07 

Abbreviations: Co, controls; Ca, cases.

*Adjusted for center, age (four categories), and race (white, black, and others).

aStudies with data on periods starting, ever postmenopausal hormonal therapy use, number of years postmenopausal hormonal therapy was used, years since last postmenopausal hormonal therapy consumption, and age at first post-menopausal HT use were LAMMCC, RPCI, NCI-Yale, and iMAGE. Analyses on postmenopausal hormonal therapy variables were performed among postmenopausal women.

bAnalyses on periods stopping were performed among postmenopausal women. Analyses on number of pregnancies were performed among women aged 45 or older at reference date. Studies with data on periods stopping and number of pregnancies were LAMMCC, RPCI, NCI-Yale, iMAGE, and Utah.

cAmong women ages 45 or older at reference date. Studies with data on ever being pregnant were LAMMCC, RPCI, NCI-Yale, iMAGE, Utah, and Epilymph.

dAmong women ages 45 or older at reference date. All studies collected data on parity and number of children.

eAmong women ages 45 or older at reference date. Studies with data on age at first child were RPCI, Epilymph, NCI-Yale, and iMAGE.

fAmong postmenopausal women. Studies with data on cause of menopause were LAMMCC, RPCI, Utah, and iMAGE.

gStudies with data on hormonal contraception use, number of years hormonal contraception was used, years since last hormonal contraception consumption, and age at first hormonal contraception use were LAMMCC, RPCI, Epilymph, NCI-Yale, and iMAGE.

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Hormonal therapy use showed nonsignificant decreased risks of multiple myeloma (OR = 0.65; 95% CI, 0.37–1.15), but also showed significant heterogeneity between centers (I2 = 76.0%; P = 0.01, Fig. 1). Further adjustment for BMI, education, tobacco, and alcohol yielded a similar risk estimate (OR = 0.70; 95% CI, 0.39–1.25). Inverse associations were observed among women taking hormonal therapy at ages 50 or older, or for more than 5 years, compared with never use (OR = 0.61; 95% CI, 0.41–0.90; and OR = 0.56; 95% CI, 0.33–0.97, respectively), although heterogeneity between centers hampered interpretation (Supplementary Fig. S1). Stratified analyses by cause of menopause, education, and BMI did not reveal statistically significant heterogeneity (data not shown).

Figure 1.
Figure 1. Study-specific risks of multiple myeloma for ever versus never parous, hormonal contraceptives, and postmenopausal hormone therapy.
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Study-specific risks of multiple myeloma for ever versus never parous, hormonal contraceptives, and postmenopausal hormone therapy.

Figure 1.
Figure 1. Study-specific risks of multiple myeloma for ever versus never parous, hormonal contraceptives, and postmenopausal hormone therapy.
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Study-specific risks of multiple myeloma for ever versus never parous, hormonal contraceptives, and postmenopausal hormone therapy.

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This large pooled analysis of 1,072 female cases and 3,541 controls yielded null associations between multiple myeloma and reproductive factors. To our knowledge, 3 case–control studies (3–5, 8) and 3 cohorts (4, 6, 7) have previously evaluated associations between reproductive factors, or exogenous hormone use and risk of multiple myeloma. Inconsistent results were observed for parity and multiple myeloma, with both significant inverse associations (5), increased risks (4), and null results (3, 6). Previously reported associations for hormonal contraceptives and multiple myeloma have been null (5, 6). Significant inverse associations for hormonal therapy use were observed in an Italian case–control study (8), but these associations were not corroborated in two cohort studies (6, 7). However, conclusions in these studies have been limited by small sample sizes of women using hormonal therapy.

Our study was based on a large dataset with individual-level information on reproductive factors and exogenous hormone use, yet we did not observe consistent patterns with these factors and multiple myeloma risk. We had the ability to control for a variety of potential confounders, including education, BMI, and alcohol use. Ignoring these variables may have biased previous studies of hormonal therapy and cancer, due to the potential for selection bias and a healthy user effect. We did not observe clear evidence of confounding by those variables in the present analysis, although residual confounding cannot be discarded in explaining some of our results, in particular for hormonal therapy. Also, use of controls that may not be representative of the population from which the cases arose was an inherent limitation of some of the participating studies' design. In summary, our data do not support a significant role for reproductive factors or exogenous hormones in myelomagenesis.

No potential conflicts of interest were disclosed.

Conception and design: L. Costas, B.M. Birmann, D. Baris, P. Boffetta, A. Staines, E.E. Brown, S. de Sanjosé

Development of methodology: L. Costas, K.B. Moysich, P. Brennan, P. Boffetta

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): K.B. Moysich, A.J. De Roos, J.N. Hofmann, D. Baris, S.S. Wang, N.J. Camp, G. Tricot, D. Atanackovic, P. Brennan, P. Cocco, A. Nieters, N. Becker, M. Maynadié, L. Foretová, A. Staines, E.E. Brown

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): L. Costas, B.H. Lambert, B.M. Birmann, K.B. Moysich, A.J. De Roos, D. Baris, S.S. Wang, P. Boffetta, E.E. Brown, S. de Sanjosé

Writing, review, and/or revision of the manuscript: L. Costas, B.H. Lambert, B.M. Birmann, K.B. Moysich, A.J. De Roos, J.N. Hofmann, S.S. Wang, N.J. Camp, D. Atanackovic, A. Nieters, M. Maynadié, L. Foretová, P. Boffetta, A. Staines, E.E. Brown, S. de Sanjosé

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): L. Costas, J.N. Hofmann, A. Staines

Study supervision: L. Costas, K.B. Moysich, P. Cocco, P. Boffetta, E.E. Brown, S. de Sanjosé

The work conducted by L. Costas was supported by grants from the Spanish Ministry of Economy and Competitiveness - Carlos III Institute of Health (Río Hortega CM13/00232 and M-AES MV15/00025) and the University of Barcelona (Research Abroad Grant 2012). This work was partially supported by the public grants from Spanish Ministry of Economy and Competitiveness - Carlos III Institute of Health (PI11/01810, PI14/01219), and Catalan Government (2014SGR756). Epilymph was supported by European Commission 5th Framework Programme (QLK4-CT-2000-00422); 6th Framework Programme (FOOD-CT-2006-023103); Carlos III Institute of Health (FIS PI081555, RCESP C03/09, RTICESP C03/10, RTICRD06/0020/0095, CIBERESP and European Regional Development Fund-ERDF); Marató TV3 Foundation (051210); International Agency for Research on Cancer (IARC-5111); MH CZ - DRO (MMCI, 00209805), RECAMO CZ.1.05/2.1.00/03.0101; Fondation de France (1999 008471; EpiLymph-France); Italian Association for Cancer Research (AIRC, Investigator Grant 11855); Italian Ministry of Education, University and Research, PRIN programme (2007WEJLZB, 20092ZELR2); and the German Federal Office for Radiation Protection (StSch4261 and StSch4420; Epilymph Germany). Funding for the Utah study was, in part, from the Leukemia and Lymphoma Society 6067-09 (to N.J. Camp) and the NCI CA152336 (to N.J. Camp). Data collection for the Utah resource was made possible by the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). Partial support for all datasets within the UPDB was provided by the University of Utah Huntsman Cancer Institute (HCI) and the HCI Cancer Center Support grant, P30 CA42014 from the NCI. The UCR is funded by contract HHSN261201000026C from the NCI SEER program with additional support from the Utah State Department of Health and the University of Utah. The work conducted by B.M. Birmann was supported, in part, by grants from the NCI (K07 CA115687, R01 CA127435, R01 CA149445) and the American Cancer Society (RSG-11-020-01-CNE). The work conducted by E.E. Brown was supported, in part, by grants from the NCI (U54CA118948, R21CA155951, R25CA76023, R01CA186646, and the University of Alabama at Birmingham Comprehensive Cancer Center Support Grant P30CA13148) and the American Cancer Society (IRG60-001-47). The work conducted by S.S. Wang was supported, in part, by federal funds from the NCI, NIH, under R01CA036388, R01CA077398, and K05CA136967 and by the City of Hope Comprehensive Cancer Center Support Grant P30CA033572. The NCI-Yale Myeloma Study was supported in part by the Intramural Research Program of the NIH.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Supplementary data

Supplemental Table 1.

Characteristics of the studies included in the analysis of reproductive factors, exogenous hormone use, and risk of multiple myeloma.

- docx file
Supplemental Figure 1.

Study-specific risks of multiple myeloma for postmenopausal hormone therapy (HT), age at first HT use and years of HT use.

- pptx file