Support for pesticides playing a role in onset of multiple myeloma

September 10, 2014Ola Landgren, M.D., Ph.D.Chief, Myeloma ServiceMemorial Sloan-Kettering Cancer Center, New Yorkwww.MSKCC.org

What is multiple myeloma?

• Second most common blood cancer in the U.S.; over 83,000 affected in 2014

• Bone marrow cancer (plasma cells)

• No established curative treatment; average survival 5-7 years

Multiple myeloma

Multiple myeloma: abnormal plasma cells in the bone marrow

Hillengass and Landgren. Leuk Lymphoma 2013

Multiple myeloma: lytic bone lesions

Multiple myeloma: genetic heterogeneity within each patient

Lohr et al. Cancer Cell 2014

Multiple myeloma and its precursor “MGUS”

“Monoclonal gammopathy of undetermined significance” (MGUS)

Kyle, Am J Med 1978; Turesson et al. Blood 2014

Risk of developing multiple myeloma (0.5-1% per year)

Cum

ulati

ve ri

sk (%

) of m

yelo

ma

Year of follow-up

Myeloma consistently preceded by precursor state “MGUS”

Landgren et al. Blood 2009

Multiple myeloma

(n=71)>77,000 cancer free men

and women; stored annual blood tests

Up to 10 years of follow-up

Risk factors for multiple myeloma; what are the causes?

•Older age•Male gender• Family history of myeloma•African American descent•Obesity• Farming/pesticides

Risk factors for multiple myeloma; what are the causes?

Rusiecki et al, Env Health Perspect 2009

Agricultural Health Study

Rusiecki et al, Env Health Perspect 2009

• Cancer incidence among pesticide applicators exposed to permethrin

• Permethrin: synthetic pyrethroid insecticide widely used in agriculture and many U.S. homes and gardens

• Prospective cohort 49,093 licensed pesticide applicators in Iowa and North Carolina

• Self-administered questionnaires; average follow-up 9 years

Agricultural Health Study: myeloma

Rusiecki et al, Env Health Perspect 2009

• No excess risk for non-Hodgkin lymphoma, leukemia, melanoma, cancers of the colon, rectum, lung, or prostate

• 6-fold excess risk of multiple myeloma, compared with applicators reporting never used permethrin

• Results based on 15 exposed cases

• Findings similar across variety of alternative exposure metrics, exposure categories, and reference groups; warrants further evaluation

Agricultural Health Study: MGUS

Landgren et al, Blood 2009

Agricultural Health Study: MGUS

• 678 pesticide applicators (30-94 years) participated to assess risk of MGUS

• Serum samples analyzed by electrophoresis; discrete or localized band subjected to immunofixation

• Age-adjusted prevalence compared with MGUS prevalence in 9469 controls from Minnesota

Landgren et al, Blood 2009

Agricultural Health Study: MGUS

• 38 had MGUS (prevalence 6.8%); age-adjusted prevalence 2-fold higher in pesticide applicators

• Excess risk of MGUS associated with chlorinated insecticide dieldrin, the fumigant mixture carbon-tetrachloride/carbon disulfide, and the fungicide chlorothalonil

• These findings support hypothesis that specific pesticides causatively linked to myelomagenesis

Landgren et al, Blood 2009

National Health and Nutritional Examination Survey (NHANES)

Landgren et al, Leukemia 2014

NHANES Study

• Stored serum samples from 12,482 individuals >50 years (NHANES III and NHANES 1999–2004)

• Serum samples analyzed by electrophoresis; discrete or localized band subjected to immunofixation

• Define prevalence and risk factors of MGUS in large cohort representative of US population

Landgren et al, Leukemia 2014

• Prior study from Olmsted County, Minnesota, found 3.2% MGUS prevalence

• NHANES overall MGUS prevalence was 2.4% (2.3% in whites)

• Interestingly, MGUS prevalence was 3.1% in North/Midwest and 2.1% in South/West, respectively (P=0.052)

Landgren et al, Leukemia 2014

NHANES Study

• According to SEER; death rates from multiple myeloma much higher in Minnesota than other regions of the country

• The observed strong geographic disparity in prevalence of MGUS between the North/Midwest versus the South/West regions of U.S. has etiologic implications

Landgren et al, Leukemia 2014

NHANES Study

Summary and conclusions

• Studies show pesticide exposure associated with MGUS and multiple myeloma

•Geographic disparity of MGUS/multiple myeloma: high prevalence in North/Midwest

•Ongoing studies to confirm findings and better understand underlying mechanisms

Summary and conclusions

• Agricultural Health Study: part II (NCI)

• Agent Orange exposed veterans (CDC/VA)

•World Trade Center rescue workers (FDNY/Albert Einstein College of Medicine)

Selected ongoing studies (collaborators)

Thank you for your attention!

Ola Landgren, M.D, Ph.D.Chief, Myeloma Service

Memorial Sloan-Kettering Cancer Center1275 York Avenue, New York, NY 10065, USA

Email: landgrec@mskcc.org Phone: 212-639-5126