Category: Research

Predicting Early or Late Mortality in Multiple Myeloma?

Would you want to know if your myeloma was likely to result in early vs late mortality?  I would like to know. What’s your feeling about this?

Multiple myeloma flame shaped plasma cell
Multiple myeloma flame shaped plasma cell (UVA photo)

Gene Variants Can Predict Early or Late Mortality in Multiple Myeloma
Elsevier Global Medical News. 2008 Nov 11, MG Sullivan

Genetic variants in the DNA of patients with multiple myeloma appear to strongly influence survival, a groundbreaking new genomic study has concluded.

In this first pass at identifying genetic markers for survival, treatment response, and complications in the disease, a group of 3,400 variants predicted early or late mortality 76% of the time, Dr. Brian Van Ness said in an interview about the initial report (BMC Medicine 2008 Sept. 8 [doi: 10.1186/1741-7015-6-26]).

“Clearly, inherited genetics influenced survival,” said Dr. Van Ness
of the University of Minnesota, Minneapolis. “What we have not yet done is identify which specific variants are responsible for these differences. Our hypothesis is that it won’t be a single variant driving response or survival, but a complex interaction of many.”

After narrowing down the initial 3,404 candidate single nucleotide polymorphisms (SNPs), Dr. Van Ness and his colleagues are now focusing on 1,000 SNPs found to be most strongly associated with the outcome
measures. More studies are on the way using this genetic panel, he said.

Indeed, just 2 weeks after the first study appeared, a coinvestigator, Dr. Gareth Morgan of London’s Royal Marsden Hospital, published findings on the association between certain SNPs and the incidence of
treatment-associated venous thromboembolism (VTE). The analysis showed that some of the variants associated with thalidomide-related VTE occurred in pathways important in drug transport and metabolism.

“The effects of the SNPs associated with thalidomide-related VTE may be functional at the level of the tumor cell, the tumor-related microenvironment, and the endothelium,” Dr. Morgan and his colleagues wrote (Blood 2008 Sept. 19 [Epub ahead of print]).

“Another study, currently submitted, has identified an association between some of the variants and the development of severe myeloma bone disease,” Dr. Van Ness said.

The initial investigation used a genetic screen developed from two DNA data sets: cells from the Coriell Institute for Medical Research, and samples obtained from multiple myeloma patients enrolled in two
randomized drug trials, as well as some unaffected spouses. The samples came from white, black, Hispanic, and Asian patients from North America and Europe. The candidate SNPs, occurring on 983 genes, were chosen based on the most recent genetic research and included on a myeloma-specific gene-testing chip.

The investigators chose extremes of survival as the first test of the panel, because this comparison was most likely to show the effects of any genetic variant. “We took the worst outcomes – people who died in
the first year of their disease – and the best outcomes – those who survived at least 3 years without progression,” Dr. Van Ness said. After repeatedly running the screen on both data sets, the team concluded that, as a whole, it discriminated the survival groups correctly 76% of the time.

Further drilling down identified several SNPs of particular interest, including some associated with drug metabolism, transport, and export; a variant that induces myeloma apoptosis; one associated with cellular
migration and angiogenesis; and several linked to proliferative responses.

Although not designed to detect racial differences, the initial screen did identify some interesting variations: 401 of the SNP variants occurred only in black patients. In whites, there was no difference in these SNPs between cases and controls.

“We know that African Americans have a two- to threefold increase in the incidence of myeloma, but we don’t yet know why,” Dr. Van Ness said. “We’ll be trying to identify those genetic variants that might uniquely increase the risk for one race to develop myeloma over another.”

Neither this initial analysis nor subsequent ones will examine the possible interplay of environment with genetics. But, Dr. Van Ness said, such studies may be forthcoming. The International Myeloma Foundation of North Hollywood, Calif., is conducting a patient survey to begin assessing what role – if any – environmental exposure plays in disease development. The 36-page survey asks patients to detail their environmental, dietary, and geographical exposures. The National Cancer Institute will collaborate with the group in evaluating the data.

The International Myeloma Foundation is also the curator of the DNA samples used in the analysis through its Bank on a Cure program. “Bank on a Cure was developed by an international group of physicians and scientists to deal with a disease that’s difficult to deal with,” Dr. Van Ness said. “It’s not a high-incidence cancer, so it’s not easy to research.”

The Bank on a Cure group developed cooperative agreements with national and international clinical trial groups, and the studies were funded by the International Myeloma Foundation. While exploration of genetic variants relevant to multiple myeloma is in its infancy, Dr. Van Ness predicted the effect could be profound.

“It’s already fairly well established that the genetics of the tumor cells themselves impact response and survival,” he said. “But beyond this is the impact of every individual patient’s genetics – how they absorb, distribute, metabolize, and export drugs, even what race they are. If we understand why someone doesn’t respond to a drug, we could better target their therapy. If we could predict which patient might develop a life-threatening blood clot during treatment, we could take steps to prevent it.”
Copyright © 2008 International Medical News Group

Source: http://www.oncologystat.com/news-and-viewpoints/news/Gene_Variants_Can_Predict_Early_or_Late_Mortality_in_Multiple_Myeloma_US.html

Fred Baron, Myeloma and Tysabri

Have you read about the furor over Fred Baron’s quest to get Tysabri to attempt to treat his myeloma?

According to his son’s blog, they believe it could help prolong his life. Andrew Baron says that Biogen, the maker of Tysabri (a drug used to treat MS), will not allow him to have the drug.  It is, however, being tested on MM patients in a phase I trial.

I still have to do some reading on this drug. The side effects are potentially serious, but, when you have only weeks left to live, I don’t suppose that matters.

Andrew’s blog:  http://dembot.com/post/54498664/open-letter-to-james-c-mullen-ceo-of-biogen
http://www.pharmalot.com/2008/10/biogen-tysabri-a-dying-democratic-fundraiser/

Good discussions over at HealthBlogs.org

http://lowsaltgirl.healthblogs.org/ – What are your ideas about cutting down on salt? I was personally never worried about it, because I never used to add salt to anything.  Processed foods are packed with sodium though, and there’s the problem.

Cindy has been keeping us up to date with her condition at http://cakassel55.healthblogs.org/.  I think it’s good to read about other peoples’ experiences because they help us to recognize things when they happen to us.

Margaret is trying to stay on top of a mountain of research, and posts it to her blog: http://margaret.healthblogs.org/. I’m about to give some of her experiments a try.  I’m still stable a year after the SCT, and want to keep it that way as long as possible.

I’ll post about some more blogs at a later time.

I stayed home from work today because I felt ill from the early morning on. I’m having some tea now, and am starting to feel better.  I should be back to normal tomorrow.

http://healthblogs.org

Untapped Potential Of Antidepressants For Cancer

ScienceDaily (Sep. 13, 2008) — A comprehensive review of current scientific literature, published in the peer-reviewed journal ecancer, has suggested that antidepressants can help the human body fight cancer by boosting its own immune response, amongst other mechanisms.

Not only this but they can help with side effects from chemotherapy such as aiding sleep, stimulating appetite, combating pain and avoiding depression.

Antidepressants work by affecting levels of chemicals known as prostaglandins. These are ephemeral, infinitesimal signallers self-regulating every cell in the body, including those serving mood and immunity. When first discovered they were perceived as a master switch, but are now believed to regulate every component of cellular microanatomy and physiology, including those of the organelles, cytoskeleton, proteins, enzymes, nucleic acids and mitochondria.

Prostaglandins are responsible, paradoxically, for both cell function and dysfunction. Excessive prostaglandin synthesis depresses immune function and may induce cancer.

An ideal anticancer agent would inhibit prostaglandins in such a manner as to shut down the pathogenesis of cancer. The article indicates that antidepressants have such properties.

Report author, Dr Julian Lieb of Vermont, USA, concludes that antidepressants have the potential to arrest, prevent, reverse and palliate cancer. He also points out that short of that they have many other uses in cancer care.

Antidepressants can reduce the severity and frequency of hot flushes in patients treated with chemotherapy, and venlafaxine (Effexor) remit acute neurosensory symptoms secondary to oxaliplatin chemotherapy. The monoamine oxidase inhibitors deprenyl and clorgyline protect nonmalignant cells from ionizing radiation and chemotherapy toxicity, and such antidepressants as nefadazone are capable of reversing chemotherapy-induced vomiting.

The report notes that as the response to antidepressants is highly specific, many patients require multiple trials before responding. It found that some subjects are non-responsive to all antidepressants, and some may relapse due to getting used to the drug. However, adjusting prostaglandins can induce both pro and anti-cancer actions. The constant presence of this paradox means that antidepressants may be capable of initiating or accelerating cancer and thus maintaining close clinical observation and limiting the duration of drug trials is essential.

The review also points out that epidemiological studies have failed to confirm the suspicion that antidepressants may induce breast cancer. However, breast cancer has been reported in three men taking selective serotonin reuptake inhibitors.

Dr Lieb added: “Wherever prostaglandin-synthesizing enzymes convert arachidonic acid to prostaglandins there are possible sites of action of antidepressants. By maintaining these enzymes within physiological limits, antidepressants shut down the mechanisms of carcinogenesis. Considerable evidence now shows that antidepressants are cytotoxic, cytostatic, convert multidrug resistant cells to sensitive, and protect nonmalignant cells from ionizing radiation and chemotherapy.

Antidepressants have potent pain relieving properties alone, or through enhancing narcotics, and they enhance sleep, appetite and occasionally energy. Their immuno-stimulating and antimicrobial properties may help with infection secondary to chemotherapy or radiation. Alleviation of anxiety, depression, fear of death, recrimination and remorse by antidepressants can be very beneficial, though care must be taken to monitor for negative effects such as intensification of depression or pain. Overall, the positive effects of antidepressants in cancer therapeutics far outweigh the negatives.”

ecancermedicalscience (2008, September 13). Untapped Potential Of Antidepressants For Cancer. ScienceDaily. Retrieved September 14, 2008, from http://www.sciencedaily.com­ /releases/2008/09/080911142620.htm#

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
patients 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