Support for pesticides playing a role in onset of multiple myeloma

September 10, 2014 Ola Landgren, M.D., Ph.D.

Chief, Myeloma Service Memorial Sloan-Kettering Cancer Center, New York www.MSKCC.org

What is multiple myeloma?

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: abnormal plasma cells in the bone marrow

Multiple myeloma: lytic bone lesions Hillengass and Landgren. Leuk Lymphoma 2013

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) Risk of developing multiple myeloma (0.5-1% per year) Year of follow-up Kyle, Am J Med 1978; Turesson et al. Blood 2014

Myeloma consistently preceded by precursor state “MGUS”

>77,000 cancer free men and women; stored annual blood tests

Up to 10 years of follow-up Landgren et al. Blood 2009

Multiple myeloma (n=71)

Risk factors for multiple myeloma; what are the causes?

Risk factors for multiple myeloma; what are the causes?

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

Rusiecki et al, Env Health Perspect 2009

Agricultural Health Study

• 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

Rusiecki et al, Env Health Perspect 2009

Agricultural Health Study: myeloma

• 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

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Results based on 15 exposed cases

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

Rusiecki et al, Env Health Perspect 2009

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

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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

NHANES Study

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

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

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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

Summary and conclusions

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

Selected ongoing studies (collaborators)

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Agricultural Health Study: part II (NCI)

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Agent Orange exposed veterans (CDC/VA)

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

Thank you for your attention!

Ola Landgren, M.D, Ph.D.

Chief, Myeloma Service Memorial Sloan-Kettering Cancer Center 1275 York Avenue, New York, NY 10065, USA Email: [email protected]

Phone: 212-639-5126