Hematological cancers such as lymphoma and myeloma are both malignant diseases arising from lymphocytes, a subset of blood cells, and commonly involve lymph nodes and the bone marrow.

One of these cancers, multiple myeloma is a hematologic cancer, or cancer of the blood, that starts in plasma cells, a type of white blood cell that make antibodies and work with the immune system to help protect the body from germs and other harmful substances.

Incidence of multiple myeloma
Multiple myeloma is the second most prevalent hematologic cancer accounting for approximately 10% of hematological malignancies after non-Hodgkin’s lymphoma [1] It represents approximately 1% of all cancers and 2% of all cancer deaths.

There are approximately 45,000 people in the United States living with multiple myeloma, and the American Cancer Society estimates that each year about 11,200 men and 9,010 women are diagnosed with multiple myeloma in the United States. This condition occurs more often in as people get older, with 98% of patients aged 40 or older. The disease is also more likely to develop in men than in women. The incidence multiple myeloma also varies by race. The risk of multiple myeloma is highest among African Americans and lowest among Asian Americans. While the peak age of onset is between 65 and 70 years of age, recent statistics seem to suggest that incidence and earlier age of onset are increasing. The etiology is unknown but some research point to an increased risk in those who have a past history of radiation exposure.

Myeloma and bone marrow
Myeloma begins when a plasma cell becomes abnormal anddivide. The new, abnormal cells divide too, creating even more abnormal cells. These abnormal plasma cells are myeloma cells. The disease is called multiple myeloma when more than one abnormal plasma cell is present.

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Over time, myeloma cells collect in bone marrow and cause too much bone to break down without new bone to replace it, making bones fragile and more likely to break. Myeloma cells multiply and crowd out normal cells in the bone marrow. As a result, bone marrow is unable to produce enough red blood cells, a type of cell called platelets, or normal white blood cells. This leads to anemia, bruising and bleeding and leukopenia.

Lymphoma, another hematological malignancy,is acancers originating in the lymphatic system. There are two primary types of lymphoma, Hodgkin lymphoma (HL), a disease which spreads in an orderly manner from one group of lymph nodes to another, and non-Hodgkin lymphoma (NHL), which spreads through the lymphatic system in a non-orderly manner. [2]

Acquired mutations
Lymphomas, like all cancers, result from acquired mutations to the DNA of a single lymph- or blood-forming stem cell. The development of lymphoma begins with damage to the DNA of T-cells and B-cells (lymphocytes), immune cells that protect the body from infections. The damaged DNA then start cancer development in genes called oncogenes or tumor-suppressor genes, which play important roles in maintaining a balance between cell death and cell growth.

Two critical proteins: bcl-2 and bcl-6
As a result of malfunction of the proteins that control cell growth, division and cell death, excessive cell growth occurs in lymphoma, leading to numerous genetic abnormalities and malfunction of cell controls. Two critical proteins involved in lymphoma development are bcl-2 and bcl-6. The identification of these genetic irregularities has important implications for treating lymphoma, as it indicates potential targets for treatment.

In 2010, about 628,415 people are living with lymphoma or are in remission. This number includes about 153,535 people with Hodgkin lymphoma and 474,880 people with NHL. Furthermore, a combined total of approximately of 137,260 people in the United States were diagnosed with lymphoma or myeloma in 2010. [2]

Risk factors
Lymphomas are linked to a variety of risk factors such as diet, medical history, environmental exposure to chemicals, and infections. Conventional medical treatment for lymphoma has been based on combinations of chemotherapy, radiotherapy, and stem cell therapy. However, new treatments for lymphoma now add to these traditional therapies the use of substances that can specifically target the delivery of radiotherapy to lymphoma cells (radioimmunotherapy) or activate the immune system to kill lymphoma cells (chemoimmunotherapeutics)

Progress: new treatment options
Although considerable progress has been made in the treatment of these diseases, they remain a significant challenge for patients and their hematologists. New research introducing unique treatment approaches and targets for lymphoma and myeloma will be presented at the 53rd Annual Meeting of the American Society of Hematology (ASH), being held in San Diego, December 10 ? 13, 2011.

?New insights into the biology of the hematologic malignancies, especially lymphoma and multiple myeloma, are facilitating the design of novel treatment strategies,? said Jane N. Winter, MD, Professor of Medicine in the Division of Hematology-Oncology at Northwestern University Feinberg School of Medicinein Chicago. ?With new therapies that reflect our improved understanding of the molecular basis of these diseases, we are seeing valuable improvements in outcomes for patients.?

Cereblon Expression
A new study uncovers the genetic mechanisms that regulate whether commonly used immune-modulating drugs for multiple myeloma, known as IMiDs, will work in certain patients who may be less responsive to therapy.

Birth defects
Thalidomide,an immunomodulatory agent, became well-known in the early 1960s for its link to severe birth defects when administered to pregnant mothers to treat morning sickness. However, in 1999, investigators discovered that the drug worked well in about one-third of patients with multiple myeloma. Since this discovery, thalidomide and other drugs like it (such as lenalidomide and pomalidomide, together known as IMiDs) have proven to be highly effective in the treatment of blood cancers like multiple myeloma.

Distinguishing positive properties
The exact mechanisms and targets through which these therapies work to enhance immune response or kill cancer cells has been largely unknown; therefore, it has been challenging to understand which patients to treat and to distinguish the positive properties of these drugs from the side effects. After recent research identified a specific protein known as cereblon as a primary mediator of the birth defects caused by thalidomide, a hypothesis emerged that cereblon may also be responsible for the anti-tumor properties of IMiDs.

To test whether the presence of cereblon in myeloma cells might be partly responsible for resistance or response to multiple myeloma treatment, and thus may potentially serve as a target for therapeutic intervention, researchers examined multiple myeloma cell lines resistant to IMiDs and found that expression of the cereblon gene was either low or entirely absent, suggesting a possible link between resistance to IMiDs and presence of the protein.

Resistance to lenalidomide
The team then lowered the level of cereblon expression in five human-derived multiple myeloma cell lines, which caused the cell lines to become almost completely resistant to lenalidomide (compared with control cell lines) yet remain sensitive to other myeloma therapies such as melphalan, dexamethasone, and bortezomib. The investigators then examined the DNA of 10 multiple myeloma patients who were resistant to IMiD therapy and f
ound low levels of cereblon expression in eight of those 10 patients, further emphasizing that cereblon expression appears necessary for IMiDs to work properly. Interestingly, some resistant patients had normal cereblon levels, suggesting that while cereblon may be an absolute requirement for response, there are likely other mechanisms present that play a role in drug resistance.

?These findings help us understand which patients may be more or less likely to respond to therapy and will allow us to focus on other ways we can target cereblon as a possible biomarker to improve treatment and patient outcomes in multiple myeloma,? said senior author Keith Stewart, MD, Professor of Medicine in the Division of Hematology-Oncology at Mayo Clinic in Scottsdale, Arizona. ?This work also suggests that we can begin to isolate the cause of birth defects from the anti-cancer properties in order to develop safer drugs in the future.?

Yuan Xiao Zhu, PhD, will present this study in an oral presentation on Sunday, December 11, at 4:30 p.m. PST

For more information:
Program: Oral and Poster Abstracts
Type: Oral
Session: 651. Myeloma – Biology and Pathophysiology, excluding Therapy: Mechanisms of Drug Action and Resistance
When: Sunday, December 11, 2011: 4:30 PM
Where: Room 6DE (San Diego Convention Center)

[1] Collins CD Problems monitoring response in multiple myelomaCancer Imaging. 2005; 5(Spec No A): S119?S126. Published online 2005 November 23
[2] The Leukemia & Lymphoma Society (LLS) Facts 2010-2011

Also read:
Better Overall Survival with Standard Chemotherapy in Patients with Limited-Stage Hodgkin Lymphoma.

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