Beth’s Blog

Autologous Stem Cell Transplantation in Patients of 70 Years and Older With Multiple Myeloma: Results From a Matched Pair Analysis

Thanks to Carol for finding this new study.

Autologous Stem Cell Transplantation in Patients of 70 Years and Older With Multiple Myeloma: Results From a Matched Pair Analysis
Am J Hematol. 2008 Aug 1;83(8):614-617, SK Kumar, D Dingli, MQ Lacy, A Dispenzieri, SR Hayman, FK Buadi, SV Rajkumar, SV Rajkumar, MA Gertz

Multiple myeloma (MM) accounts for 1% of all malignancies and approximately 10% of all hematologic malignancies. In the United States, an estimated 19,900 new cases of MM were diagnosed in 2007, and 10,790 patients were expected to die of this disease. Patients with MM have a median age of onset in the seventh decade of life and 3- to 4-year median survival when treated with conventional chemotherapy. Newer combination chemotherapeutic agents have not improved the survival outcome achieved with melphalan and prednisone, which have been used for >30 years. High-dose chemotherapy (HDT) followed by autologous stem cell rescue has resulted in improved survival and quality of life compared with conventional strategies. For patients with MM who qualify for HDT, this approach has become the standard of care.

Many of the larger clinical trials in which HDT was examined only included patients <65 years of age. However, a significant proportion of MM patients are >65 years. Therefore, it remains unclear whether the benefits observed in younger patients would extend to an older population. This case-controlled study evaluated the outcome of HDT in patients with MM who were >70 years.

A total of 93 patients were included in the study. All had undergone HDT and stem cell transplantation for MM. The study group included 33 patients >70 years and a matched control group of 60 patients <65 years. The baseline characteristics of the 2 groups were comparable, with the only difference being the type of conditioning regimen used. The dose of the melphalan conditioning regimen was reduced in 30% of patients in the elderly group as opposed to only 5% of patients in the younger group.

A trend toward a longer hospital stay after transplant was noted for the elderly vs the younger group (8 vs 3 days). By day 15, engraftment occurred in 94% of the elderly group vs 78% of the control group (P = .08). The adverse reactions most often seen were nausea, vomiting, hypertension, and tachycardia; no significant differences between the groups were evident. The overall response rates were 97% and 98% for the elderly and control groups, respectively. A complete response was achieved by 42% of the elderly group vs 28% of the control group. The patients were observed for a median of 27.2 and 38.3 months in the elderly and younger groups, respectively. The post-transplant median overall survival duration was 53.3 months in the younger patient group; the elderly patient group did not reach its median overall survival during follow-up. In the subset of patients receiving reduced-dose melphalan, there was no difference in time to progression or overall survival compared with
patie
nts receiving standard-dose melphalan.

Previous trials have clearly shown a benefit of HDT in patients <65 years of age. However, investigators have not studied the benefit of HDT for patients 70 years of age and older. This study showed that patients older than 70 years have outcomes similar to those in younger patients (<65 years of age). The treatment-related mortality rate and the kinetics of engraftment were similar between the 2 study groups. Despite a greater proportion of the older group of patients receiving a reduced dose of melphalan, no significant differences were evident with respect to response rate or time to progression between the 2 groups. This retrospective study showed a benefit for patients >70 years who underwent HDT for MM. Age alone should not be the sole factor used when evaluating whether a patient is eligible to undergo HDT. Dose reduction should be considered for the older population of patients when appropriate.

SYNTHETIC MOLECULES COULD ADD SPICE TO FIGHT AGAINST CANCER

Thanks to Sandy for telling me about this.

COLUMBUS, Ohio – Seeking to improve on nature, scientists used a spice-based compound as a starting point and developed synthetic molecules that, in lab settings, are able to kill cancer cells and stop the cells from spreading.

The researchers are combining organic chemistry, computer-aided design and molecular biology techniques in developing and testing pharmaceutical compounds that can fight breast and prostate cancer cells. The synthetic molecules are derived from curcumin, a naturally occurring compound found in the spice turmeric.

Centuries of anecdotal evidence and recent scientific research suggest curcumin has multiple disease-fighting features, including anti-tumor properties. However, when eaten, curcumin is not absorbed well by the body. Instead, most ingested curcumin in food or supplement form remains in the gastrointestinal system and is eliminated before it is able to enter the bloodstream or tissues.

“Newer evidence describes how curcumin interacts with certain proteins to generate anti-cancer activity inside the body. We’re focusing on the pathways that are most involved in cancer and trying to optimize for those properties,” said James Fuchs, assistant professor of medicinal chemistry and pharmacognosy at Ohio State University and principal investigator on the project.

Fuchs presented the research today (8/17) at the American Chemical Society meeting in Philadelphia. He described a selection of the 40 compounds developed to date, emphasizing the synthetic molecules that appear to have the most potential to serve as the basis for anti-cancer drug development.

Fuchs and colleagues are continuing to refine compounds that are best structured to interact with a few overactive proteins that are associated with cell activity in breast and prostate cancers. Blocking these molecular targets can initiate cell death or stop cell migration in the cancers.

A major component of their strategy is called structure-based, computer-aided design, a relatively new technology in the drug discovery field. Before ever working with an actual compound, the scientists can make manipulations to computer-designed molecules and observe simulated interactions between molecules and proteins to predict which structural changes will make the most sense to pursue.

“Very small changes that may seem insignificant can have dramatic effects on these toxicity properties,” Fuchs said. “But most of the compounds we’ve made have been more potent than curcumin against the cancer cells.”

“Most of the interaction between our compound and the overactive protein comes from what are called hot spots on the protein’s surface,” said Chenglong Li, assistant professor of medicinal chemistry and pharmacognosy at Ohio State and an expert in computational chemistry. “For each spot, we can design small chemical fragments and link them together to make a molecule. This is what computer-aided design and modeling can do.”

Some of the most effective compounds have been tested for their effectiveness against human cancer cell lines – as well as whether they might be toxic to healthy cells. So far, the molecule favored by the researchers has a nearly 100-fold difference in toxicity to cancer cells vs. healthy cells, meaning it takes 100 times more of the compound to kill a healthy cell than it does to kill a cancer cell.

“Very small changes that may seem insignificant can have dramatic effects on these toxicity properties,” Fuchs said. “But most of the compounds we’ve made have been more potent than curcumin against the cancer cells.”

The computer-based predictions have suggested that the most effective compound developed to date can interact with proteins believed to be active in about 50 percent of all breast and prostate cancers.

“To be able to develop a drug that in the future could have potential to treat 50 percent of these cancers would be a major contribution,” said Jiayuh Lin, an investigator in Ohio State’s Comprehensive Cancer Center and an associate professor of pediatrics. Lin tests the experimental compounds in different types of breast and prostate cancer cell lines. He said some of the compounds also show potential to kill pancreatic cancer cells and inhibit cancer cell migration.

The computer-aided design also offers hints at the compounds’ suitability as the basis for a drug, such as whether the molecules will remain stable during metabolism and whether they will maintain a structure that the body can absorb into the bloodstream and tissues. The team is planning to continue refining the compounds before advancing to animal studies to test their effectiveness. The scientists hope to develop a chemotherapeutic agent available in pill form.

Additional members of the research group, dubbed the OSU Molecular Target Team, are Pui-Kai Li, chair and associate professor, and graduate students Jonathan Etter, Dalia Abdelhamid, Nicholas Regan, Deepak Bhasin, Bulbul Pandit and Katryna Cisek, all of Ohio State’s Division of Medicinal Chemistry and Pharmacognosy; and Ling Cen, Li Lin and Brian Hutzen of the Center for Childhood Cancer in the Research Institute at Nationwide Children’s Hospital in Columbus.

This work is supported by the Department of Defense Prostate Cancer Research Program, the James S. McDonnell Foundation, the National Foundation for Cancer Research, Ohio State’s Comprehensive Cancer Center and Ohio State’s College of Pharmacy.

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Contact: James Fuchs, (614) 247-7377; Fuchs.42@osu.edu or Chenglong Li, (614) 247-8786; cli@pharmacy.ohio-state.edu
http://researchnews.osu.edu/archive/curcumin.htm

Written by Emily Caldwell, (614) 292-8310; Caldwell.151@osu.edu

Treatment with anti-anemia drugs may not be safe for multiple myeloma patients

How will this affect the treatment of anemia? Will it mean more transfusions and less ESAs? I’ve only ever had a few shots of Procrit, and have never had red blood cells (just platelets). What I’m afraid will happen is that people will be afraid of ESAs. If you think about it, the statement at the end of the summary makes a lot of sense. Were the patients in the group who were given the ESAs just more sick, with a poorer prognosis?

Public release date: 4-Aug-2008

Contact: Sean Wagner
swagner@wiley.com
781-388-8550
Wiley-Blackwell
Treatment with anti-anemia drugs may not be safe for multiple myeloma patients

Thessaloniki, Greece - August 4, 2008 - A recent study published in American Journal of Hematology demonstrated that Erythropoiesis-stimulating agents (ESAs), a widely used drug to treat anemia, may have a negative impact on the survival of myeloma patients. In the study, 323 multiple myeloma patients were evaluated over a 20 year period in Greece from 1988 to 2007. The investigators reviewed their medical records and observed an association between ESA exposure and a reduction in progression-free and overall survival.

The study demonstrated that ESA administration may influence the course of the disease, in that people who received ESA may progress earlier than those who did not receive ESA. The median survival rate was 31 months for patients who were administered ESAs, compared to 67 months in those who were not exposed to ESAs. The median progression-free survival for patients in the ESA group was 14 months, and 30 months for those without ESA exposure.

For the past 15 years, erythropoiesis-stimulating agents have been used in the management of cancer-related anemia, but researcher Eirini Katodritou stresses the possible harmful effects ESAs may have on cancer patients. “Physicians should use ESAs with caution, based on the International Guidelines for ESA administration in cancer and on certain prognostic indicators to guide their use. Physicians need to identify the appropriate group of cancer patients who will benefit from ESA administration, while avoiding possible detrimental effects,” said Katodritou.

The question of whether ESAs are harmful in patients with myeloma is a pressing clinical issue with at least eight prospective controlled clinical trials in the last five years reporting poorer outcomes with ESA use in patients with cancer, according to Dr. David P. Steensma of the Mayo Clinic. However, only two of those studies included some patients with myeloma. Dr. Steensma pointed out that the patients in the retrospective Greek study were imbalanced for many of the known prognostic markers in myeloma, indicating that sicker patients were given ESAs preferentially and that this group would have been predicted to do more poorly anyway. Although this imbalance might explain the results, Dr. Steensma discussed the importance of additional prospective studies of ESA safety in myeloma and other forms of cancer.

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How Molecules Out Of Balance Lead To Human Multiple Myeloma And Other Cancers

ScienceDaily (2008-07-28) — An international team of scientists has identified processes that are heavily implicated in human multiple myeloma and other B cell cancers, moving us closer to developing quick tests and readouts that could help in the tailored treatment of patients.

“We already know that the over-expression or mutation of molecules known as NIK and TRAF3 in B cells is associated with human multiple myeloma,” said Professor Mackay. “Our collaborative research uncovered two distinct processes involving these molecules that help explain why.”

http://www.sciencedaily.com/releases/2008/07/080729133616.htm

MMSupport.net unveils “Ask the Expert”, featuring Multiple Myeloma physician and scientist, James R. Berenson, M.D.

MMSupport.net unveils “Ask the Expert”, featuring Multiple Myeloma physician and scientist, James R. Berenson, M.D.
 
Ask the Expert is a free online web-forum where Myeloma and Bone Cancer specialist, Dr. James R. Berenson offers medical answers to questions surrounding quality of life and longevity issues for patients living with this rare form of cancer.
 
Los Angeles, CA – MMSupport.net and the Institute for Myeloma and Bone Cancer Research are proud to announce the creation of “Ask the Expert”, a free online web-forum featuring Multiple Myeloma expert, Dr. James R. Berenson.
 
MMSupport.net is the creation of myeloma-advocate, Beth Morgan.  The website serves to foster community in the form of an online forum where patients and caregivers could learn more about Multiple Myeloma, a plasma cell cancer that resides in the bone marrow.  Thousands of people visit MMSupport.net every day.  Many visitors are Myeloma and Bone Cancer patients, caregivers and other medical professionals who actively participate in online discussions about treatment options and personal experiences.  “Ask the Expert” is the latest addition to the MMSupport.net website and is available at no charge by registering on the site.  Visit www.mmsupport.net for more information.
 
James R. Berenson, MD has 25 years experience in treating Multiple Myeloma and Bone Cancer patients.  Dr. Berenson is CEO and Medical Director for The Institute for Myeloma and Bone Cancer Research and CEO and President of Oncotherapeutics, an oncology-specific clinical trials management service.  Dr. Berenson is an active clinician who treats patients daily in his Los Angeles offices and acts as a specialist consult to patient’s primary oncologist or primary care physician throughout the world. For more information, visit www.berensononcology.com
 
The Institute for Myeloma and Bone Cancer Research, based in Los Angeles, California, is an independent cancer research institute with a primary focus on hematologic cancers.  Established in 2004, the IMBCR is a 501 c (3) non-profit organization.  Over the last four years, the IMBCR has created novel breakthrough therapies that have substantially increased the longevity and quality of life of myeloma patients. The latest initiative at the institute is “The Cure Myeloma Project”, a multi-year research project that targets myeloma cells while keeping the non-cancerous cells intact.  For more information or to make a donation, visit www.imbcr.org
 
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Media contact:
Beth Morgan, MMsupport.net beth.morgan@connectnc.com or,
Cheryl A. Cross, MPH, Institute for Myeloma and Bone Cancer Research ccross@imbcr.org 866-900-1035

Dr. Durie talks about the possible causes of myeloma

Dr. Durie talks about the possible causes for myeloma.  Here’s an earlier link to another NBC video I posted.  These open in new windows. Click on the picture to see the video.

New findings in myeloma research

Dr. Durie Appears on the NBC Nightly News (but neither of them is him)

Fighting multiple myeloma - Click on this link or the picture to see the video.

Dr. Durie Scheduled to Appear On The NBC Nightly News Tonight

This is the NBC Nightly news with Brian Williams.  Scheduling is always subject to what happens today that could prove more neweworthy but we’ve
been told that his segment will air tonight.  Dr. Durie is the chairman of the International Myeloma Foundatoin and a leader in the myeloma scientific and clinical community for over 30 years.

Norepinephrine could hasten the progression of certain blood cancers

From an Ohio State University Press Release
http://researchnews.osu.edu/archive/yangvegf.htm

COLUMBUS, Ohio – Researchers here have shown that in cell cultures, the stress hormone norepinephrine appears to promote the biochemical signals that stimulate certain tumor cells to grow and spread.

The finding, if verified, may suggest a way of slowing the progression and spread of some cancers enough so that conventional chemotherapeutic treatments would have a better chance to work. Eric Yang Ronald Glaser

The study also showed that stress hormones may play a completely different role in cancer development than researchers had once thought.

The results appear in the current issue of the journal Brain, Behavior and Immunity.

“We would not be surprised if we see similar effects of norepinephrine on tumor progression in several different forms of cancer,” explained Eric Yang, first author of the paper and a research scientist with the Institute for Behavioral Medicine Research (IBMR) at Ohio State University.

Yang and colleague Ron Glaser, a professor of molecular virology, immunology and medical genetics, last year showed that the stress hormone norepinephrine was able to increase the production of proteins in cultures of nasopharyngeal carcinoma tumor cells that can foster the aggressive spread of the disease, a process known as metastasis. Glaser is director of the IBMR and a member of the Comprehensive Cancer Center at Ohio State.

In this latest study, the researchers looked at a different type of cancer – multiple myeloma. One of several types of cancers of the blood, multiple myeloma strikes nearly 20,000 Americans each year, killing at least half that many annually. Patients diagnosed with this disease normally survive only three to four years with conventional treatments.

Yang and Glaser focused on three multiple myeloma tumor cell lines, each representing a different stage in the life of the disease, for their experiments. While all three tumor cell lines reacted to the presence of norepinephrine, only one, a cell line known as FLAM-76, responded strongly to the hormone. “The fact that this one cell line, of the three multiple myeloma cell lines studied, closely represents the early stages of the tumor, and that this is where we see the biggest effect, is what makes this work more clinically relevant.”

The norepinephrine binds to receptors on the surface of the cells, sending a signal to the nucleus to produce a compound known as VEGF — vascular endothelial growth factor – that is key to the formation of new blood vessels, which the tumor must have to grow.

The FLAM-76 cell line was prepared from multiple myeloma tumor cells taken from a patient whose disease had not yet progressed too far from its original site in the bone marrow where blood cells are formed.

“It turns out that FLAM-76 tumor cells more closely represent the earlier stages of the disease when blood vessel formation, a process called angiogenesis, is needed for disease progression,” Yang said.

“The fact that this one cell line, of the three multiple myeloma cell lines studied, closely represents the early stages of the tumor, and that this is where we see the biggest effect, is what makes this work more clinically relevant,” Glaser said.

The researchers believe that blocking these receptors would slow the process of the growth of more blood vessel to the tumor, delaying disease progression and perhaps allowing treatments to be more effective. Widely used “beta-blocker” drugs now prescribed for high blood pressure work by blocking these same particular cell surface receptors, Yang said.

“This approach wouldn’t kill the tumor cells but it would diminish the blood supply to the tumor cells and slow them down, and that could translate into a longer and better quality of life for the patient,” Glaser said.

The researchers and their colleagues are now working with other forms of cancer to test the effects of stress hormones like norepinephrine on their growth.

Glaser added that these kinds of results may change the way scientists are looking at a link between stress and the development and spread of cancer. In the past, he said, the focus was on how stress hormones weakened the immune system, allowing certain tumors to evade the body’s defenses.

“Now we have these stress hormones, not only affecting the immune response, but also acting directly on the tumor cells and inducing changes in the molecules made by those same tumor cells,” Glaser said.

“This has important implications for the spread of the tumor and metastasis.”

Elise Donovan, a researcher with the IBMR, and Don Benson, a researcher with Ohio State’s Comprehensive Cancer Center, also worked on the project. The research was funded in part by the National Cancer Institute.

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Contact: Eric Yang, (614) 292-0364; yang.3@osu.edu or Ron Glaser, (614) 292-5526; glaser.1@osu.edu.

Written by Earle Holland, (614) 292-8384; Holland.8@osu.edu.