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Managing and Treating Cancer Pain from Cancer.Net 9/24/08

Posted by Eve on January 3, 2009

Managing and Treating Cancer Pain (Part I)

Many people don’t know that nearly all cancer pain can be treated successfully, either with or without the use of medication. In addition, many options are available to control or prevent pain related to cancer. In this two-part series, learn practical tips to better manage your pain. This article discusses basic facts about cancer-related pain, medications used to control it, and tips to document and communicate your pain issues with your health-care team.

Facts about cancer-related pain

Pain in people with cancer may occur due to (1) the effects of the cancer itself; (2) side effects of the cancer treatment; and (3) causes unrelated to the cancer, including other diseases, such as arthritis and diabetes. The following are some important facts for you to know about cancer pain and pain management:

Emotional distress can worsen pain, and pain can contribute to emotional distress.

Sleep deprivation can intensify pain, and uncontrolled pain can lead to sleep deprivation.

Lack of communication with health-care providers can result in pain not being managed as well as it could be.

The most complete and potentially successful approach often combines medical treatment with nonmedical treatment in an individualized plan.
Communication is important

After a thorough medical assessment of any pain, it is important to discuss your concerns and develop a plan with your health-care team. Some hospitals have professionals called pain specialists who are trained in helping people manage cancer pain. Nurses, pharmacists, and other health-care professionals can also help you learn about your options for controlling pain.

Although having cancer doesn’t mean you will always have pain, it is important to talk with your doctor about any pain you are experiencing. He or she can help determine the cause of your pain and help select the best treatment options with you.

Patients know their own pain best. So, it is important to discuss the pain you are feeling with your doctor in as specific terms as possible. In fact, a doctor’s role in managing pain is to listen to patients and offer an effective pain control solution.

Consider keeping a pain diary noting the date, time, and intensity level.

Keep a record of when the pain started, how long it lasted, and what activities aggravated the pain.

Make sure you communicate to a member of your health-care team where the pain started and if the pain was specific to one area or spread to other parts of the body.

It may be helpful to describe pain on a scale of 0 to 10, in addition to using words that describe the type of pain, such as “burning,” “stabbing,” or “throbbing.”

Note what type of pain control method you tried for relief and its level of effectiveness.
Every person’s need for pain relief is different

The intensity, type, and location of pain experienced differs from person to person. Therefore, the options used to treat and manage pain should also be individualized and should remain flexible. When choosing a pain management strategy, the doctor, patient, and patient’s family need to consider the stage, location, and type of cancer; the intensity of the pain, the patient’s tolerance for pain (called pain threshold), personal preferences, and previous responses to treatment. Finding an effective pain management solution is a collaboration between the cancer care team, the patient, and the family.

Controlling cancer pain

Controlling pain caused by cancer should be part of the overall cancer treatment plan. Preventing pain from occurring or worsening is one of the most effective ways to treat pain caused by cancer. When using medications to treat pain, patients should receive the medication at regular, scheduled intervals, with “rescue” doses for breakthrough pain (pain that surges suddenly through regular pain medications). Rarely is addiction to pain medication a problem. However, if it becomes a problem, there are still ways to manage the pain, even if pain medications called opioids (also called narcotics) are needed. When pain is not managed correctly, a person may experience fatigue, depression, anger, worry, and stress. With effective pain management, people can remain active, sleep better, improve their appetite, and enjoy activities and time spent with family and friends.

Doctors can treat pain in several ways.

Treating the source of the pain (such as the tumor or inflammation)

Changing the perception of pain (usually with pain medications)

Interfering with pain signals sent to the brain (through techniques such as spinal treatments or nerve blocks, whereby pain medication is injected into a nerve or surrounding a nerve to interfere with a pain signal)
Often, if pain control is not achieved, switching the dose or type of medication may be helpful, as there are many different drugs and ways to give them, depending on the source of the pain and the person’s overall health.

You may experience some side effects while taking pain medication. Opioids, which are used for moderate to severe pain, can cause constipation, nausea, sleepiness, confusion, or hallucinations. Several opioids are marketed under various brand names, but the generic names include fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Opioids used for breakthrough pain include fentanyl and fentanyl citrate. Also, short-acting versions of hydrocodone, hydromorphone, morphine, oxycodone, and oxymorphone may be used. Be sure to tell your doctor if you experience any side effects from your pain medication, as most side effects are easily treatable, sometimes by changing the timing, dose, or type of drug.

Managing and Treating Cancer Pain (Part II)

Many people have found that other methods besides drugs help control pain. This second article of a two-part series discusses other pain management techniques and ways to track their success.

Your doctor should be able to help you manage pain using more than one method. Share with your doctor any methods that have worked well for you. Ask if they have any suggestions for nonmedical treatment, and if there are any special considerations when selecting techniques in your situation. Make your pain management a priority in your care; you deserve to feel your best.

Self-care and support techniques as a supplement to medical care

The following techniques have helped many people with cancer achieve better pain management:

Counseling and support groups. Talking with a trained counselor or attending a cancer support group may provide a valuable forum for addressing worries about cancer and pain and help you develop coping strategies. Hearing about techniques that have worked for others in the same situation may help you identify what might work for you. Discussing concerns and getting support may also help relieve some of the physical and emotional tension that can make pain worse.

Imagery and visualization. Many imagery techniques are useful for pain and discomfort associated with treatment. The “magic glove” is a technique in which you imagine putting on a glove before getting a needle stick, and visualize that the glove protects your hand from the sensation of pain. The “light switch” method involves visualizing a light switch that you can control and that has the power to turn off pain signals. Or, you may benefit from simple visualization exercises in which you imagine a peaceful scene or a favorite memory, listen to music and imagine that music melting away your discomfort or lifting your pain away, or create a mental picture of a healing light that takes pain up and away.

Massage. A qualified massage therapist who has experience working with people with cancer can provide gentle therapeutic massage to alleviate tension, discomfort, and pain. Simple massage techniques including gentle, smooth, circular rubbing of feet, hands, or back can be done at home by a caregiver. You can also massage yourself by applying light, even pressure to your hands, arms, neck, and forehead.

Heat and cold. Many people with cancer find that applying hot or cold compresses, heating pads, or ice packs to aching, sore, or painful areas of the body can diminish discomfort. Discuss this approach with a health-care provider and follow any special instructions, particularly during or after radiation therapy or chemotherapy. Start with short applications of 5 to 10 minutes at moderate temperatures. Make sure not to apply heat or cold directly on bare or injured skin or to areas that have received recent radiation therapy. Wrap ice packs and compresses in a towel to protect skin and use heating pads over clothing, a sheet, or a towel. Gradually experiment with temperatures to find a method that provides relief comfortably. A warm bath is another way to get heat evenly applied to a large area at once.

Breathing exercises. Gentle breathing exercises can enhance relaxation, reduce tension, and decrease pain. They can be done while sitting up in a chair, arms relaxed gently at the sides, or while lying down in a reclining chair or bed. Try breathing in through the nostrils, counting one, two; then breathing out through the mouth, counting one, two. Continue for five minutes initially, gradually working up to 20 minutes. Or, while breathing gently in and out, repeat a calming word such as “peace” or “relax” with each inhalation.

Distraction. Activities such as taking a warm bath, reading a book, watching television or a movie, drawing, doing needlework, listening to music, or taking a short walk outdoors can provide an engaging way to distract the mind from pain. Choose an activity or media that will create the mood desired: relaxing, upbeat, soothing. While the mind is actively engaged in the chosen activity, many people find that their pain is diminished.

Table to track pain reduction

Health-care providers are often interested in tracking your success with pain management techniques. One idea is to create a table (see below) with the days of the week across the top and things you would like to track down the side, such as time of day, supportive techniques, activity level, or anything else you can think of. It’s not necessary to fill in every box every day. Simply write down what you can remember from your days and look for the trends of what is working for you. Pick a level you would like to reach; for example, a pain rating of 3 or less. At the end of the week, highlight all days in which you had that score or lower, and you will be able to see which situations and techniques are helping you on the road toward being pain-free.

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Coping With Fatigue 9/24/08

Posted by Eve on January 3, 2009

ASCO Expert Corner: Coping With Fatigue

Charles Loprinzi, MD Debra Barton, RN, PhD

Fatigue is a common symptom of people with cancer—about 70% to 90% of people experience fatigue during and after treatment. It can seriously affect a person’s daily activities, including the ability to work, be involved with family, or socialize. To learn more about fatigue and what people with cancer can do to better manage it, Cancer.Net talked with Charles Loprinzi, MD, and Debra Barton RN, PhD.

Q: What is fatigue and how does it differ from tiredness?

A: “Fatigue” and “tiredness” are often used to describe the same feeling. The more pressing question, we believe, concerns the difference between cancer fatigue and the more usual fatigue that people can get from lack of sleep and working too hard. Cancer fatigue is considered to be a kind of fatigue that does not get better with rest. It is also a deep fatigue that is not explained by the amount of activity one does. Cancer survivors describe it as a feeling of heavy arms and legs, an inability to think, and a lack of energy for many usual activities.

Q: What are the causes of fatigue in patients with cancer who are not receiving cancer treatment, and what are some ways to manage it?

A: There are multiple causes for cancer fatigue, independent of cancer treatment. Not all of them are well understood. Nonetheless, some are related to substances secreted by the cancer itself and/or the body in response to the cancer process. Some of these substances cause anorexia, a loss of appetite. This leads to decreased nutrition and can add to fatigue. Other cancer-secreted substances can also cause anemia (an abnormally low level of red blood cells that contain hemoglobin, which carries oxygen to all parts of the body) and electrolyte (such as sodium or calcium) imbalances. Abnormal amounts of both of these may cause fatigue. Pain associated with cancer can also interrupt sleep, which leads to fatigue.

In terms of ways to manage cancer fatigue, correction of abnormal blood counts and electrolytes may help resolve cancer fatigue. Thyroid function should also be corrected if it is abnormal. Resolution of pain, nutritional, and sleep troubles may also be helpful. Nonetheless, these measures often stop short of totally improving fatigue.

For a long time, recommendations centered on maintaining rest and trying to reserve strength for necessary activities. However, we know that too much time in bed or at rest can actually increase fatigue through a process called “deconditioning.” The best information available to date is that a regular exercise program, as opposed to a regular resting program alone, is the best thing to help alleviate cancer-related fatigue.

Although exercise has been studied and found the most helpful to date, it still does not totally manage this problem in most patients. There have been efforts to study medicinal substances for improving cancer fatigue. Erythropoietic agents (medications that help treat anemia caused by chemotherapy) to increase red blood cells have been studied, with maybe a little bit of success. However, there have been recent concerns with regards to the use of these agents in patients with cancer that have decreased their use. Antidepressants have also been studied in patients without established depression, but these do not appear to be helpful. Other medications, such as modafinil (Provigil), which is a stimulant approved for the treatment of excessive daytime sleepiness or narcolepsy, have looked moderately promising. A recent randomized placebo-controlled trial shows that it may be helpful in those with more severe fatigue. In addition, data from a placebo-controlled pilot trial (an initial study examining a new method or treatment), have suggested that the herbal agent, Wisconsin ginseng, looks promising for improving cancer fatigue.

Q: What are the main causes of fatigue in people undergoing cancer treatment, and what are some ways to manage it?

A: In addition to the cancer itself causing fatigue, cancer treatments can cause fatigue. This applies to radiation therapy and multiple drug therapies, including, most notably, chemotherapy and interferon treatment. The toxic effect of these treatments on normal body cells is the cause for this fatigue. Thyroid changes can result from some cancer treatments and can also cause fatigue. Some chemotherapy and newer targeted therapies can cause low levels of magnesium, which might be responsible for fatigue. Other issues that can make fatigue worse during treatment are poor nutrition, not drinking enough fluids, and stress and anxiety.

As far as treatment options, again, exercise has the best evidence of efficacy. The other drugs discussed above are also of possible benefit. Studies done to date have shown that different types of therapies, such as radiation therapy or different cancer drugs, result in similar fatigue. One option, for patients with advanced cancer whereby chemotherapy may have limited benefit, is to take a temporary break from the chemotherapy.

Q: What are some tips for patients on talking with their doctors about fatigue?

A: As with most things, patients should be honest with their doctors and tell them the symptoms that are bothering them. Likewise, they should tell their doctors about others issues, discussed above, which might relate to fatigue. This includes issues with depression, pain, and trouble sleeping. They should tell their doctors whether they’re on a regular exercise routine and, if not, the reasons for not exercising.

Q: What research is ongoing with fatigue in people with cancer?

A: Ongoing studies to reduce fatigue are looking at additional exercise programs, including yoga and resistance exercise. Other ongoing clinical trials are evaluating acupuncture and sleep interventions to try to help with fatigue. Also, studies are addressing the utility of medicinal substances, such as ginseng and psycho-stimulants. Much of the current research is trying to understand the physiologic (physical and chemical) changes in the body from cancer and cancer treatment that can lead to fatigue, so that better treatments can be developed to help this important symptom.

Dr. Loprinzi is Professor, Oncology, at Mayo Clinic in Rochester, Minnesota.

Dr. Barton, also at Mayo Clinic in Rochester, is a PhD-trained nurse scientist who conducts extensive research on fatigue.

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MM Update 9/16/08

Posted by Eve on January 3, 2009

JOURNAL EDITORIAL DOCUMENTS DRAMATIC INCREASE IN SURVIVAL SINCE THE 1980’S
9.11.08
—Treatment Advances in Myeloma Now Benefiting Other Blood Cancers—
North Hollywood, CA – September 11, 2008 – The International Myeloma Foundation (IMF)—supporting research and providing education, advocacy and support for myeloma patients, families, researchers and physicians—today said survival outcomes have improved dramatically for patients with multiple myeloma, cancer in the bone marrow that affects blood cell production. Writing in the October 10th edition of the Journal of Clinical Oncology, IMF chairman Brian G.M. Durie, M.D., notes that 25 years ago only 48 percent to 66 percent of myeloma patients survived two years, depending on which treatment was used. By contrast today, two-year survival rates are around 90 percent.
“What has changed is not the research capability, it is the availability of potent new classes of drugs without the side effects typically associated with chemotherapy,” says Dr. Durie. “The successful agents in myeloma are multifunctional with a diverse impact on cell function and pathways. This may well be the secret of success.”
The editorial explains that drug design was spurred by the discovery that thalidomide, originally developed as a sedative, was effective against myeloma through multiple mechanisms of action. As a result we have potent, targeted drugs such as Revlimid® and Velcade®, with improved outcomes.
“The benefits and comparisons are particularly interesting looking at the results with lenalidomide (Revlimid) plus low-dose dexamethasone (steroid) compared with prior results with interferon and levamisole. There is essentially a doubling of survival at two years, with preliminary evidence that this survival will be maintained for at least three to four years.”
Dr. Durie notes these achievements with myeloma are now benefiting a wide range of blood cancers as these drugs are being tested in non-Hodgkin’s lymphoma, chronic lymphocytic leukemia and other blood cancers. In the editorial he says the next step is to identify new agents with “greater efficacy or lesser toxicities” in this setting of already high response rates.
Dr. Durie is also affiliated with Aptium Oncology, and Cedars-Sinai Medical Center, and he is chairman of the Myeloma Committee of the Southwest Oncology Group (SWOG).
ABOUT THE INTERNATIONAL MYELOMA FOUNDATION
The International Myeloma Foundation is the oldest and largest myeloma organization, reaching more than 165,000 members in 113 countries worldwide. A 501 (c) 3 non-profit organization dedicated to improving the quality of life of myeloma patients and their families, the IMF focuses in four key areas: research, education, support and advocacy. To date, the IMF has conducted more than 120 educational seminars worldwide, maintains a world-renowned hotline, and operates Bank on a Cure®, a unique gene bank to advance myeloma research. The IMF was rated as the number one resource for patients in an independent survey by the Target Research Group. The IMF can be reached at (800) 452-CURE, or out of the United States at +1-818-487-7455. More information is available at www.myeloma.org.
Media Contact: Stephen Gendel or Jennifer Anderson +1-212-918-4650

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MM Update 9/16/08

Posted by Eve on January 3, 2009

Study Finds European SNP Data Precisely Reflects Geography
September 1, 2008
By Andrea Anderson,
a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – New research is revealing just how well genetics and geography mesh in European populations.

In a paper appearing online yesterday in Nature, a team of American and Swiss researchers assessed SNPs in the genes of individuals from across Europe and used the data to construct two-dimensional genetic maps. They found that genes were closely tied to geography. In fact, genetics pinpointed most individuals’ geographic origin within a few hundred miles. The results highlight the importance of accounting for geography in genetic studies and suggest precise genetic ancestry tests may not be far off.

“The surprise was just how well and clearly it relates to geography,” University of California at Los Angeles evolutionary biologist John Novembre, who recently completed his post-doctoral research in the University of Chicago’s department of human genetics and was lead author on the paper, told GenomeWeb Daily News. “At the broadest level, it means that geography matters.”

The samples tested were collected as part of a larger study of about 6,000 individuals called the Population Reference Sample, or POPRES, project, Novembre explained. That study, led by GlaxoSmithKline and collaborators, was aimed at developing a reference sample for genetic and pharmacogenetic studies.

Novembre and his colleagues took advantage of this rich data set to ask questions about genetic history, genetic variation, and human population structures.

They initially genotyped 3,192 Europeans at 500,568 loci using Affymetrix 500K SNP chips. After filtering out specific SNPs to minimize linkage disequilibrium patterns and limiting their analysis to individuals with well-defined ancestry, they were left with data on 197,146 loci in 1,387 individuals.

They then created two-dimensional maps revealing genetic patterns in the samples. Although the overall genetic variation across Europe was miniscule, Novembre explained, there were still enough differences to distinguish between geographic populations. Indeed, the two-dimensional genetic map closely resembled a map of Europe.

For half of the individuals tested, the researchers could place them within about 193 miles of their reported geographic origin. When they stretched that to about 435 miles, they could place 90 percent of the individuals.

Moreover, the team was able to distinguish incredibly subtle population effects, including genetic differences between French-, German-, and Italian-speaking individuals in Switzerland. As such, the results are providing new insights into the genetics associated with population structure.

That, in turn, brings a new level of information to genome-wide association studies, suggesting that there may be certain population-related traits that could create false-positive associations in these studies. Being aware of such population stratification effects should help researchers avoid such problems, Novembre said.

In the future, he predicted, whole-genome re-sequencing projects will likely add even greater resolution to this sort of gene-geography study. For the time being, though, Novembre and his colleagues are continuing to tap the POPRES data for more information about populations in other parts of the world, including South Asia, East Asia, and Latin America.

Although the current approach very closely linked most people’s genetics with their origin, Novembre noted, it is much less accurate for individuals who have ancestors from more than one part of the world. That means precise genetic ancestry tests are likely still a ways off. “But the promise is there,” Novembre said, “and it’s very exciting.”

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MM Update 9/16/08

Posted by Eve on January 3, 2009

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2008 Aug;16(4):943-5. Links
[Clinical study of bortezomib in combination with dexamethasone for the treatment of multiple myeloma.]
[Article in Chinese]
Wang LX, Lu H, Shen WY, Qian SX, Qiu HX, Wu HX, Zhang JF, Wu YJ, Li JY.
Department of Hematology, The First Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
The objective of study was to evaluate the efficiency and safety of bortezomib for the treatment of multiple myeloma. Bortezomib in combination with dexamethasone was administered as first-line treatment in all 7 newly diagnosed patients with multiple myeloma. The patients with refractory myeloma were treated with bortezomib in combination with dexamethasone or with other traditional agents such as mitoxantrone and thalidomide. The results showed that according to the EMBT criteria, out of 7 patients one achieved complete response (CR), five achived partial response (PR) and one achived minor response (MR). The 3 patients with refractory/relapsed myeloma achieved PR (2/3) and MR (1/3). The overall response rate (CR + PR) was 80%. The most frequent adverse events observed were thrombocytopenia in three patients, diarrhea and peripheral neuropathy in one respectively. In conclusion, bortezomib demonstrates efficiency in the treatment of new-diagnosed and refractory/relapsed multiple myeloma, and the side effects from treatment are acceptable and manageable.
PMID: 18718096 [PubMed - in process]
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Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2008 Aug;16(4):829-32. Links
[Measurement of serum free light chains and its clinical significance in 20 newly diagnosed patients of multiple myeloma.]
[Article in Chinese]
Mao XB, Chen XQ, Zhai YP, Liang R, Gao GX, Ma GG, Yu YP, Li F.
Department of Hematology, Xijing Hospital, The Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China; Department of Hematology, Nanjing General Hospital of Nanjing Military Area, Nanjing 210002, Jiangsu Province, China.
The objective of this study was to explore the clinical significance of measuring serum free light chains (sFLC) and to compare with serum total light chains (free and binded) in multiple myeloma (MM). sFLC in 20 newly diagnosed MM patients and 20 cases of healthy people as control were measured by immuno-nephelometric assays; the serum light chains and kappa/lambda ratio were measured in all patients, while immunofixation electrophoresis (IFE) tests were carried out at the same time in 18 out of 20 patients. The results showed that the abnormality of serum free light chains and kappa/lambda ratio were found in all of the 20 newly diagnosed MM patients (p < 0.01). The measurement of sFLC showed higher sensitivity than the total serum chains (p < 0.01). It is concluded that the method testing sFLC by immuno-nephelometric assay combined with kappa/lambda ratio is valuable for MM diagnosis, and the measurement of sFLC can be used as one of indicators for MM diagnosis.
PMID: 18718070 [PubMed - in process]
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N Engl J Med. 2008 Aug 28;359(9):906-17. Links
Comment in:
N Engl J Med. 2008 Aug 28;359(9):964-6.
Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma.
San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG; VISTA Trial Investigators.
Collaborators (144)
Corrado C, Fantl D, Garcia J, Klein G, Riveros D, Hermann R, Hertzberg M, Horvath N, Marlton P, Spencer A, Drach J, Gisslinger H, Greil R, Gunsilius E, Linkisch W, Petzer A, Thaler J, Andre M, Beguin Y, Bron D, Demuynck H, De Prijck B, Delforge M, Doyen C, Ferrant A, Feremans W, Janssens A, Van de Velde A, Van Droogenbroeck J, Vermeulen P, Zachee P, Bahlis N, Belch A, Dolan S, Fox S, Lavoie A, Voralia M, Ai H, Hou J, Meng F, Shen Z, Zhao Y, Hajek R, Maisnar V, Koivunen E, Remes K, Sikiö A, Vanhatalo S, Attal M, Harousseau J, Hulin C, Michallet M, Salles G, Durk H, Engelhardt M, Gabor C, Goldschmidt H, Haenel M, Hess G, Knauf W, Schlag M, Welslau M, Zervas K, Zoumbos N, Borbényi Z, Fekete S, Illes A, Masszi T, Radvanyi G, Tarkovacs G, Ben-Yehuda D, Berrebi A, Nagler A, Rowe J, Boccadoro M, Cavo M, De Fabritiis P, Foa R, Lazzarino M, Liberati A, Morra E, Musto P, Pinto A, Kim K, Min C, Min Y, Suh C, Yoon S, Gibbons S, Hellmann A, Holowiecki J, Kloczko J, Kuliczkowski K, Komarnicki M, Robak T, Sulek K, Alexeeva J, Biakhov M, Domnikova N, Dunaev Y, Gaisarova G, Golenkov A, Loginov A, Patrin V, Pavlov V, Rossiev V, Rukavitsyn O, Savchenko V, Suvorov A, Yablokova V, Alegre A, Bladé J, De la Rubia J, Diaz-Mediavilla J, Hernandez J, Palomera L, Sureda A, Björkstrand B, Gruber A, Chao T, Huang S, Kuan-Der Lee C, Kuo C, Shih L, Cavet J, Kazmi M, Littlewood T, O’Dwyer M, Rule S, Russell N, Berdeja J, Bruetman D, Butler F, Callander N, Glass J, Gurtler J, Hanna W, Holladay C, Irwin D, Lewis R, Morrison V, Noga S, Roberts T, Schiller G.
Hospital Universitario Salamanca, CIC, IBMCC (USAL-CSIC), Salamanca, Spain. sanmigiz@usal.es
BACKGROUND: The standard treatment for patients with multiple myeloma who are not candidates for high-dose therapy is melphalan and prednisone. This phase 3 study compared the use of melphalan and prednisone with or without bortezomib in previously untreated patients with multiple myeloma who were ineligible for high-dose therapy. METHODS: We randomly assigned 682 patients to receive nine 6-week cycles of melphalan (at a dose of 9 mg per square meter of body-surface area) and prednisone (at a dose of 60 mg per square meter) on days 1 to 4, either alone or with bortezomib (at a dose of 1.3 mg per square meter) on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. The primary end point was the time to disease progression. RESULTS: The time to progression among patients receiving bortezomib plus melphalan-prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan-prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P 0.05), whereas the combination of bortezomib and cetuximab had highly significant antitumoral activity (p < 0.043). CONCLUSION: Our results indicate that cetuximab increases the cytotoxic activity of bortezomib in EGF-stimulated HNSCC cell lines. A combination treatment of HNSCC with bortezomib and cetuximab may allow a therapeutical regimen to be developed that is less toxic than the conventional drugs used for these tumors.
PMID: 18751401 [PubMed – in process

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Various Updates 09/12/08

Posted by Eve on September 16, 2008

Using Velcade as part of initial treatment for myeloma improves outcomes: http://rarediseases.about.com/b/2008/09/03/using-velcade-as-part-of-initial-treatment-for-myeloma-improves-outcomes.htm
Human Genome shares fall on trial results report: http://www.forbes.com/feeds/ap/2008/09/03/ap5385158.html
Biogen to test Tysabri as a cancer treatment: http://www.bizjournals.com/triangle/stories/2008/09/01/daily34.html
We Fought Cancer…And Cancer Won: http://www.newsweek.com/id/157548
He Won His Battle With Cancer: http://www.time.com/time/magazine/article/0,9171,1838776,00.html
Genomic Variation in Myeloma: Design: http://7thspace.com/headlines/292135/genomic_variation_in_myeloma_design_content_and_initial_application_of_the_bank_on_a_cure_snp_panel_to_detect_associations_with_progression_free_survival.html
Germline Polymorphisms as Modulators of Cancer Phenotypes: http://7thspace.com/headlines/292134/germline_polymorphisms_as_modulators_of_cancer_phenotypes.html
The IMF Says Journal Editorial Documents Dramatic Increase in Survival since the 1980’s: http://www.businesswire.com/portal/site/google/?ndmViewId=news_view&newsId=20080911005222&newsLang=en

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Med Updates 09-11-08

Posted by Eve on September 16, 2008

AACR Seeks Cancer Research Ideas and “Dream Teams”

Zosia Chustecka
Medscape Medical News 2008. © 2008 Medscape
August 14, 2008 — The cancer community has a few more weeks in which to respond to the call from the American Association for Cancer Research (AACR) for ideas for cancer-research projects that promise rapid translation into clinical realities. The call for ideas went out July 15, and the deadline for submitting them to the AACR has been extended to Wednesday, September 10.
This initiative is part of the Stand Up To Cancer (SU2C) program, a huge ongoing effort to raise awareness of and funds for cancer research. The AACR is the scientific partner for this program, and it will be allocating and administering the funds raised by the campaign, under the guidance of a scientific advisory committee.
The plan is to build up collaborative research “dream teams” that will use the new tools of molecular biology and systems biology to work on research questions that are most likely to bring near-term patient benefit. The AACR envisages teams, made up of the most talented and promising researchers across institutions and disciplines, sharing information in a goal-orientated way to focus on key problems in cancer. The aim is to advance research quickly “in the interests of both today’s cancer patients and those who may develop cancer in the future.”
The number of dream teams to be formed will depend on the total amount of money raised by SU2C. The amount each team receives will depend on the scope of the project, but support could reach $20 million.
Research projects could address critical problems in patient care, including prevention strategies for those at risk, the AACR explains. Or they could focus on particular organ sites/tumor types or on specialized research areas. Proposals should be based on perceived opportunities for success and should focus on high-priority areas with a critical need for rapid progress beyond current medical care.
Researchers should submit ideas electronically, using the form on the AACR Web site. Submissions, no longer than 2 pages, should consist of a project summary statement that includes background, rationale, a description of the expertise and key personnel needed for the dream team, an explanation of clinical impact, and key literature references. The proposals will be considered by the SU2C Scientific Advisory Committee, which is headed by Nobel Laureate Phillip Sharp, PhD, from the David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, in Cambridge. Acting as vice-chairs are Arnold Levine, PhD, from the Institute for Advanced Study, in Princeton, and the Cancer Institute of New Jersey, in New Brunswick, and Brian Druker, MD, professor of medicine at the Oregon Health & Science University Cancer Institute, in Portland.
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Cancer News
Cancer Researchers And Oncologists Offer A Clinical Trial For Multiple Myeloma Patients
NewsRx.com
August 14, 2008
Cancer researchers at George Mason University’s Center for Applied Proteomics and Molecular Medicine are studying the effects of experimental treatments on living tumor cells taken from multiple myeloma patients who are undergoing a routine diagnostic process.
The trial may result in the discovery of novel therapeutic targets for treatment of this incurable form of blood cancer expected to strike nearly 20,000 men and women this year.
CAPMM co-directors Lance Liotta and Emanuel Petricoin III are partnering with oncologists at Fairfax-Northern Virginia Hematology Oncology in a clinical program for multiple myeloma patients to examine protein signal pathway activity in diseased cells and determine what type of drug intervention is needed to prevent further growth of the disease.
“This is not a patient treatment trial,” explains Liotta. “Instead, living cells from a biopsy are treated in culture immediately after being removed from the patient.”
Trial participants will undergo a bone marrow biopsy, which is part of the routine standard of care practices for an existing or suspected multiple myeloma diagnosis. Once the office procedure is performed, extra material not required for diagnosis is immediately preserved and taken to the CAPMM laboratories for analysis.
“Our data indicate that the protein signaling pathways that control cellular activity are different in each patient’s tumor,” Liotta says. “This novel trial will test a large series of targeted inhibitors, alone and in unique combinations, which block key signaling pathways in the tumor cells. This is a key first step toward true individualized therapy for multiple myeloma.”
Currently, treatment of multiple myeloma is based on a one-size-fits-all approach that fails to consider the protein signaling information, Petricoin adds. “Since this information underpins the growth and survival of the cancer cells, we hypothesize that turning patient-specific signaling activation off will kill the tumor cells more effectively than the current treatment,” he says. “In this initial study, we will test promising new treatments that may be candidates for Phase I or II clinical treatment research trials.”
The research is funded by local philanthropist Chris Walker. “This is an example of serendipity and opportunity, and that is what makes America a special place — where good people and good ideas garner support from pluralistic sources,” he says. “Cancer, in particular, needs some new ideas since the old approaches aren’t working.”
Multiple myeloma is a treatable progressive disease that attacks the plasma cell, a vital part of the immune system that produces antibodies to fight infection and disease. One of the leading causes of cancer death among African Americans, it is the second most prevalent blood cancer in the United States and strikes more frequently in men than women.
Patients interested in participating in this multiple myeloma trial must be referred by their physicians for an eligibility screening. For additional information contact Denise Campbell, Fairfax-Northern Virginia Hematology Oncology, at 703-280-5390.
Copyright 2008, Physician Law Weekly via NewsRx.com
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Cancer News
Spice-Based Compound May Kill Cancer Cells
United Press International
August 18, 2008
COLUMBUS, Ohio — U.S. scientists say they’ve used a spice-based compound as a starting point to develop synthetic molecules able to kill cancer cells.
The Ohio State University researchers said they combined organic chemistry, computer-aided design and molecular biological techniques to develop and test pharmaceutical compounds that, in lab settings, are able to kill breast and prostate cancer cells and stop them from spreading.
Assistant Professor James Fuchs said the synthetic molecules are derived from curcumin, a naturally occurring compound found in the spice turmeric.
“Newer evidence describes how curcumin interacts with certain proteins to generate anti-cancer activity inside the body,” said Fuchs. “We’re focusing on the pathways that are most involved in cancer and trying to optimize for those properties.”
Fuchs presented the research Sunday in Philadelphia during the annual meeting of the American Chemical Society.
Copyright 2008 by United Press International
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U.S. Medicare to Weigh Easing Some PET Scan Limits

From the PharmaLive.com News Archive – Aug. 27, 2008

- Patients in the VELCADE, melphalan and prednisone arm demonstrated a significant survival benefit as well as a 30 percent complete response -
CAMBRIDGE, Mass., August 27, 2008 /PRNewswire/ — Millennium: The Takeda Oncology Company today announced the publication of results from the 682 patient, randomized, Phase III VISTA(1) trial in this week’s edition of the New England Journal of Medicine. The results showed a significant survival benefit and a 30 percent complete remission (CR) rate with VELCADE, melphalan and prednisone (VcMP) compared to 4 percent for melaphalan and prednisone (MP) alone in previously untreated multiple myeloma patients. Multiple myeloma is the second most common blood cancer.

“These data demonstrate that treatment with VELCADE plus melphalan and prednisone leads to a survival benefit and a high complete remission in previously untreated patients with multiple myeloma,” said Professor Jesus San Miguel, M.D., Ph.D., Hematology Department Head, University Hospital of Salamanca and Principal Investigator of the trial. “The combination of VELCADE plus melphalan and prednisone is an important new option for these patients.”
These data originally were presented at the 2007 American Society of Hematology (ASH) Annual Meeting. Based on these positive trial results, the U.S. Food and Drug Administration approved VELCADE for patients with previously untreated multiple myeloma on June 20, 2008. The Phase III VISTA trial was conducted by Millennium and its co-development partner Johnson & Johnson Pharmaceutical Research & Development, L.L.C. in 151 centers worldwide.
“We are proud to have these data published in such a highly esteemed journal,” said Nancy Simonian, M.D., Chief Medical Officer, Millennium. “We’re delighted that previously untreated multiple myeloma patients now can benefit from this VELCADE based therapy as have patients in the relapsed and refractory settings since 2003.”
(1) VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone
VISTA Trial Results
Patient responses were evaluated by the stringent European Group for Blood and Marrow Transplantation (EBMT) criteria:
– A CR rate of 30 percent in the VcMP arm compared to 4 percent with MP (p<0.001)
– VcMP demonstrated statistical significance in overall survival with a 39 percent reduction in risk of death (Hazard ratio= 0.61; p=0.008) with a follow-up of 16.3 months
– The median treatment duration was 46 weeks for the VcMP arm compared to 39 weeks for the control arm and discontinuation due to adverse events was similar in both arms
Patients in the VcMP arm received VELCADE at 1.3 mg/m2 twice weekly in weeks one, two, four and five for four six-week cycles (eight doses per cycle), followed by once weekly on weeks one, two, four and five for up to five six-week cycles (four doses per cycle) in combination with melphalan at 9 mg/m2 and prednisone at 60 mg/m2 once daily on days 1 through 4 of each cycle for up to nine six-week cycles. For both groups, treatment continued for a maximum of 54 weeks.
“The tolerability of VcMP also was encouraging and side effects were generally manageable with appropriate supportive care and dose reduction as needed,” commented Paul Richardson, M.D., Clinical Director of the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Senior Investigator on the study.
The safety profile of VELCADE in combination with MP is consistent with the known safety profiles of both VELCADE and MP. In VISTA, the most commonly reported adverse events for VELCADE in combination with MP vs MP, respectively, were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).
Important Safety Information
In the U.S., VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE also is indicated for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron or mannitol. VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy.
Risks associated with VELCADE therapy include new or worsening peripheral neuropathy, hypotension throughout therapy, cardiac and pulmonary disorders, reversible posterior leukoencephalopathy syndrome, gastrointestinal adverse events, thrombocytopenia, neutropenia, tumor lysis syndrome and hepatic events. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Nursing mothers are advised not to breastfeed while receiving VELCADE. Cases of severe sensory and motor peripheral neuropathy have been reported. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Acute development or exacerbation of congestive heart failure, and new onset of decreased left ventricular ejection fraction has been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome in patients receiving VELCADE. Some of these events have been fatal. There have been reports of Reversible Posterior Leukoencephalopathy Syndrome (RPLS) in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. VELCADE is associated with thrombocytopenia and neutropenia. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. Complete blood counts (CBC) should be frequently monitored during treatment with VELCADE. Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. Patients on oral antidiabetic medication while receiving VELCADE should check blood sugar levels frequently.
Adverse Reaction Data
Safety data from Phase II and III studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the Phase III, VELCADE plus DOXIL(R) [doxorubicin HCl liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.
In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise and weakness) (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated) (39%), thrombocytopenia and appetite decreased (including anorexia) (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia and headache (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo) (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of greater than or equal to Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).
About Multiple Myeloma
Multiple myeloma is the second most common hematological malignancy. Between 2001 – 2005, the median age of diagnosis was 70 years. In 2007, there were 110,000 patients living with multiple myeloma across the United States, Europe and Japan. It is estimated that this number will increase by 5.6 % annually over the next few years due to new therapies extending the lives of multiple myeloma patients.
About VELCADE
VELCADE is being co-developed by Millennium: The Takeda Oncology Company and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Millennium is responsible for commercialization of VELCADE in the U.S. and Janssen-Cilag is responsible for commercialization in Europe and the rest of the world. Janssen Pharmaceutical K.K. is responsible for commercialization in Japan. For more information about VELCADE clinical trials, patients and physicians can contact the Millennium Medical Product Information Department at 1-866-VELCADE (1-866-835-2233).
About Millennium
Millennium: The Takeda Oncology Company, and a leading biopharmaceutical company based in Cambridge, Mass., markets VELCADE, a novel cancer product, and has a robust clinical development pipeline of product candidates. Millennium research, development and commercialization activities are focused in oncology. Additional information about Millennium is available through its website, www.millennium.com.
Media Contact:
    Karen Gobler
    (617) 444-1392
    karen.gobler@mpi.com
CONTACT: Karen Gobler, +1-617-444-1392, karen.gobler@mpi.com Web site: http://www.millennium.com/ Company News On-Call: http://www.prnewswire.com/comp/114562.html /
Terms and conditions of use apply
Copyright © 2008 PR Newswire Association LLC. All rights reserved.
A United Business Media Company

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Posted in MM Updates | Leave a Comment »

MM Med Updates 09-05-08

Posted by Eve on September 16, 2008

DSM and MorphoSys add MOR202 to Ab deal: http://www.in-pharmatechnologist.com/Materials-Formulation/DSM-and-MorphoSys-add-MOR202-to-Ab-deal
UAMS Tackling Bone Cancer with Landmark Clinical Trials: http://arkansasmatters.com/content/fulltext/news/?cid=104511

Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma: http://content.nejm.org/cgi/content/short/359/9/906
New England Journal of Medicine Publishes Phase III Results of VELCADE(R) (Bortezomib) for Injection in Previously Untreated Multiple Myeloma Patients: http://www.marketwatch.com/news/story/new-england-journal-medicine-publishes/story.aspx?guid=%7BD36F175D-52D1-4172-A274-35D1FA97594C%7D&dist=hppr
Local cancer study gains national attention: http://leadernewspapers.net/modules.php?name=News&file=article&sid=8038&new_topic=18
Bortezomib Added to Melphalan Improves Myeloma Response: http://www.cancerpage.com/news/article.asp?id=12590
Innovative back treatment available at PVH: http://www.mydailyregister.com/articles/2008/08/30/news/news02.txt

Researchers can view genetic information from multiple databases with a specially designed Web portal: http://www.computerworld.com/action/article.do?command=viewArticleBasic&taxonomyName=Data+Mining&articleId=323811&taxonomyId=54&pageNumber=1
Human Genome Sciences Reports Initial Results of Randomized Phase 2 Trial of HGS-ETR1 in Combination With Bortezomib in Advanced Multiple Myeloma: http://www.earthtimes.org/articles/show/human-genome-sciences-reports-initial,524267.shtml#
Tysabri clinical study underway: http://www.hayspharma.com/news/news-item/18765851
Human Genome Sciences reports initial results from Phase II myeloma trial: http://www.pharmaceutical-business-review.com/article_news.asp?guid=F6AC5ED3-BBF7-4371-BFA8-80F116A02D91

Posted in MM Updates | Leave a Comment »

Various MM related articles

Posted by Eve on September 16, 2008

Survival Benefit of Palliative Chemotherapy Often Not Discussed With Patient.
Roxanne Nelson
Medscape Medical News 2008. © 2008 Medscape
August 1, 2008 — Patients with incurable cancer are frequently offered the option of palliative chemotherapy, an intervention that is unlikely to result in a major survival advantage but that can improve tumor-related symptoms. However, most patients receiving treatment in the United Kingdom are not given clear information about the survival gain of palliative chemotherapy, according to a report published online July 31 in BMJ.
Life expectancy in patients with metastatic cancer is often short, and despite improvements in treatment options, survival benefits tend to be modest. Treatment can also be highly toxic, but chemotherapy is increasingly being given closer to the end of life, note Daniel F Munday, MD, a consultant in palliative medicine at Warwick Myton Hamlet Hospice, in the United Kingdom, and E. Jane Maher, MD, consulting oncologist at Mount Vernon Hospital, in Middlesex, United Kingdom, in an editorial that accompanied the study.
“To make informed choices, patients need up-to-date consistent information and comprehensive and expert communication from their oncologists and supportive care teams,” write the editorialists.
How information on prognosis and chemotherapy is shared probably influences decisions about palliative care, but it can be difficult to obtain reliable information about prognosis and treatment options in advanced disease, and there is no nationally agreed-upon information about prognosis or risks for palliative chemotherapy, they write. “Most patients say they want full information about diagnosis and prognosis, but do not always receive such information from their oncologist. But they may not necessarily want the whole truth all of the time or want to be fully involved in decision making once information has been received.”
Survival benefit is frequently the primary outcome measure in studies concerning palliative chemotherapy, and many patients do place a priority on survival, as opposed to quality of life. “From our results, we found that patients were clearly told that their cancer could not be cured, but it was the actual survival benefit that might be gained from palliative chemotherapy that was not discussed with them,” coauthor Jane M. Blazeby, MD, FRCS, professor of surgery and honorary consultant surgeon at the University of Bristol, United Kingdom, told Medscape Oncology.
“We think that for patients to make an informed decision about whether to undergo or not undergo palliative chemotherapy, they need the information about survival benefit, alongside the information about treatment side effects and toxicity and the alternative to receiving supportive treatment alone,” said Dr. Blazeby.
The survival gain from palliative chemotherapy is often modest, and tends to be measured in months rather than years, the authors write. Although an offer of active intervention with palliation can support patients as they adjust to their diagnosis, there can be a considerable gap between patient hopes and what is achievable if the survival benefit is not clearly discussed when treatment decisions are being made.
Dr. Blazeby and colleagues undertook this study to evaluate how much information oncologists give their patients about the survival benefit of palliative chemotherapy during consultations at which decisions about treatment are made. Nine oncologists participated in the study, as did 37 patients with advanced non-small cell lung cancer (n = 12), pancreatic cancer (n = 13), and colorectal cancer (n = 12).
Current guidelines in the United Kingdom state that palliative chemotherapy in non-small-cell lung cancer can extend survival by up to 2 months; in pancreatic cancer, it can extend survival from 3 or 4 months to 5 or 6 months; and in colorectal cancer, it can extend median survival of 5 to 9 months to 7.5 to 14 months with single-agent chemotherapy, and 3 to 5 months beyond that with combination therapy.
The consultations between patient and oncologist were digitally recorded, and a researcher observed the office visit to capture nonverbal communication. The recordings were transcribed but kept anonymous to protect privacy and confidentiality.
After analyzing the data, the researchers noted that although there was consistency in informing patients that their disease was not curable and that a cure was not being sought, the amount of information given the patient concerning survival benefits of palliative chemotherapy varied considerably.
The information given to patients about survival benefits included numerical data (“about 4 weeks”), timescales (“a few months extra”), vague references (“buy you some time”), or they weren’t mentioned at all. Of the 37 patients, only 6 were given numerical data about the survival benefits of treatment. In 26 of 37 cases, survival benefits were either not mentioned during the visit or the discussion was vague.
Researchers were also able to pinpoint some specific triggers and barriers to discussion of survival benefit. For example, a trigger to discuss survival benefits would be when a patient or relative asked a direct question about it, or the oncologist volunteered the information and gave realistic expectations. The patient might then refuse treatment but at least he or she was aware of the potential benefits of therapy that included extended survival.
Barriers to discussing survival benefits tended to undermine informed consent. As an example, if patients declined the offer of palliative chemotherapy without a thorough discussion of benefits, which included a gain in survival, their decision might be based on inaccurate or incomplete information.
“In our opinion, the reason the survival benefit is not discussed is because oncologists do not want to further upset patients who are already in a vulnerable position,” said Dr. Blazbey. “The audio recordings of the consultations showed that in two thirds of consultations, there was no information about survival benefit communicated from the oncologist.”
The researchers believe that training for oncologists should include guidance on how to discuss the survival benefits of palliative chemotherapy with their patients. “We think that doctors need to receive advanced-level training in communicating these significant issues,” explained Dr. Blazbey. “In the UK, this is part of the latest Department of Health Cancer Reform Strategy.”
The study was funded by Cancer Research UK. The researchers have disclosed no relevant financial relationships.
BMJ. Published online before print July 31, 2008.
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Study Clarifies Glycoprotein’s Role in Bone Damage of Multiple Myeloma

Reuters Health Information 2008. © 2008 Reuters Ltd.
Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
By Scott Baltic
NEW YORK (Reuters Health) Aug 01 – Overexpression of the glycoprotein Wnt-3a in bone significantly inhibits osteolytic bone lesions and tumor growth in multiple myeloma (MM) in the microenvironment of bone marrow, but activation of Wnt signaling does not affect MM cell growth in vitro or subcutaneously in a mouse model, according to a report by University of Arkansas researchers in the July 15 issue of Blood.
Wnts (pronounced “wents”) make up a highly conserved family of secreted glycoproteins that are part of various signaling cascades, including coupled bone turnover, an ongoing balance between osteoblasts and osteoclasts that maintains healthy bone. In MM, however, the disease-causing malignant cells destroy bone by secreting a Wnt signaling inhibitor, DKK1 (Dickkopf-1).
The loss of the Wnt signaling cascade, Dr. John D. Shaughnessy Jr. told Reuters, not only slows the creation of osteoblasts, but indirectly increases the production of osteoclasts, inducing bone loss. In addition, DKK1’s suppression of the Wnt signal increases production of interleukin-6, which is a growth factor for tumor cells, creating a vicious circle that leads to more DKK1.
“Our hypothesis has been that re-establishing normal Wnt signaling in the bone should suppress bone destruction and tumor growth, all in one shot,” Dr. Shaughnessy said.
“Remarkably,” the authors write, “we found that, although increasing Wnt signaling in MM tumors had no effect on cell growth in vitro or when cells were grown in subcutaneous locations, tumor growth was attenuated when grown in bone.” This reduced tumor growth, and the associated reduced bone destruction, suggest that “Wnt-3a-induced alteration of the bone marrow microenvironment has antimyeloma effects,” the investigators say.
“It is important to note,” Dr. Shaughnessy pointed out, “that in addition to multiple myeloma, recent data … show that osteolytic bone destruction associated with rheumatoid arthritis, osteolytic bone metastases of breast cancer and neuroblastomas, glucocorticoid-induced osteoporosis, and even the osteoblastic metastases of prostate cancer, all appear to be linked to DKK1-mediated suppression of the Wnt signaling cascade.”
He added that a neutralizing antibody against DKK1 is now in clinical development.
Blood 2008;112:374-382.
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Bortezomib, Doxorubicin and Dexamethasone in Advanced Multiple Myeloma

A. Palumbo; F. Gay; S. Bringhen; A. Falcone; N. Pescosta; V. Callea; T. Caravita; F. Morabito; V. Magarotto; M. Ruggeri; I. Avonto; P. Musto; N. Cascavilla; B. Bruno; M. Boccadoro
Ann Oncol. 2008;19(6):1160-1165. ©2008 Oxford University Press
Copyright 2008 European Society for Medical Oncology. Published by Oxford University Press. All rights reserved.
Posted 08/01/2008

Abstract and Introduction
Abstract
Background: Bortezomib has shown significant activity in myeloma. In this multicenter trial, we assessed for the first time the combination of bortezomib, doxorubicin and low-dose dexamethasone (PAd) in the treatment of relapsed/refractory myeloma.
Patients and methods:Sixty-four patients were treated for a median of four 28-day cycles (1–6). Bortezomib was given at 1.3 mg/m2 (days 1, 4, 8, 11) and dexamethasone at 40 mg (days 1–4); 34 patients receive doxorubicin at 20 mg/m2 (days 1, 4) while 30 patients pegylated liposomal doxorubicin at 30 mg/m2 (day 1).
Results:Fifty-eight percent of patients had undergone prior autologous transplantation, 70% prior anthracycline and 27% prior bortezomib-based regimens. Forty-three patients (67%) achieved at least a partial response including 16 (25%) with at least a very good partial response. One-year event-free survival was 34% after PAd and 31% after the previous line of therapy (hazard ratio 1.20, 95% confidence interval 0.76–1.90, P = 0.43). One-year overall survival from the start of PAd was 66%. Grade 3–4 toxic effects included thrombocytopenia (48%), neutropenia (36%), infections (15%), anemia (13%), gastrointestinal disturbances (11%) and peripheral neuropathy (10%). Two patients had grade 3–4 cardiac heart failure.
Conclusions: PAd is an active salvage therapy with manageable toxicity in patients with relapsed/refractory myeloma.
Introduction
Multiple myeloma (MM) is a malignant plasma cell disorder. In 2004, its incidence was estimated for >13 700 new diagnoses in men and 15 000 in women in the European Union.[1] It is considered incurable and conventional salvage therapy in relapsed and refractory disease has traditionally been disappointing with progression-free survival (PFS) usually not exceeding 6 months and median overall survival (OS) of 1 year after relapse.[2,3]The recent introduction of novel agents, including thalidomide, lenalidomide and bortezomib, has transformed the treatment paradigm for MM. Bortezomib, a specific inhibitor of the 26S proteasome, is associated with profound antimyeloma activity against both MM cells and their microenvironment.[4] Bortezomib has also shown in vitro synergistic activity with several agents with enhanced sensitivity to doxorubicin or melphalan shown in drug-sensitive and chemoresistant MM cell lines as well as primary MM cells derived from patients.[5]
Clinical trials employing bortezomib in combination with other agents have shown additive or synergistic activity. Partial response (PR) rates have ranged from 27% to 50% in relapsed/refractory MM.[2,6-8] The combination of bortezomib and pegylated liposomal doxorubicin (PLD) in patients with advanced disease has further increased the PR rate up to 48%–73%.[9,10]In a large study, 646 patients with advanced myeloma were randomized to receive bortezomib either alone or with PLD and a final analysis showed a significant benefit in terms of time to progression in the bortezomib/PLD arm (P < 0.0001).[10]In newly diagnosed MM patients, the combination of bortezomib, doxorubicin and dexamethasone has been encouraging. The intensity of dexamethasone and the use of 21-day regimen have, however, been associated with a high incidence of infections and peripheral neuropathy.[11] These observations provide the rationale for the evaluation of safety and efficacy of the combination of bortezomib with doxorubicin or PLD and low-dose dexamethasone (PAd), repeated every 28 days, in patients with relapsed/refractory MM.
Patients and Methods
Patients
Between March 2005 and November 2006, 64 consecutive MM patients were treated at seven Italian centers. Inclusion criteria were as follows: patients in first relapse or higher or refractory to salvage treatment defined as progression during treatment or within 60 days after its completion; age >18 years; adequate cardiac, hepatic, renal and pulmonary functions; measurable disease.[12] The Durie and Salmon staging system was used.[13]Previous treatment with bortezomib or anthracycline was permitted. Exclusion criteria included grade 3–4 peripheral neuropathy, the presence of another cancer or uncontrolled medical problems or conditions at the discretion of the attending physicians, psychiatric disease and hypersensitivity to bortezomib, boron or mannitol. Pre-exiting grade 1–2 peripheral neuropathy was not an exclusion criteria. Patients agreed to use effective contraception and women of childbearing age had a pregnancy test before enrollment. All patients gave written informed consent to participation in the study in accordance with the Declaration of Helsinki.
Treatment Plan
Bortezomib, at a dose of 1.3 mg/m2, was given as an i.v. bolus injection on days 1, 4, 8 and 11. Intravenous doxorubicin was administered at a dose of 20 mg/m2on days 1 and 4 while i.v. PLD was administered at a dose of 30 mg/m2on day 1. Thirty-four patients received doxorubicin and 30 patients received PLD. The use of doxorubicin or PLD depended on drug availability at each participating center. Oral dexamethasone was given at a dose of 40 mg/day on days 1 through 4. Each cycle was repeated every 28 days for up to six cycles. Treatment was withheld if drug-related grade 4 hematological toxic effects or grade 3–4 non-hematological toxic effects occurred. After their resolution, bortezomib could be resumed with a 25% dose reduction (from 1.3 to 1.0 mg/m2 and, if needed, from 1.0 to 0.7 mg/m2). If two or more doses of bortezomib were skipped because of hematological toxicity, a dose reduction of 25% was performed during the following cycle. A 25% dose reduction was required for symptomatic grade 2 neuropathy, whereas bortezomib was interrupted for symptomatic grade 3 neuropathy and resumed with a 50% dose reduction upon complete resolution or reduction of severity to grade 1 neuropathy. Oral antibiotic prophylaxis (ciprofloxacin 250 mg b.i.d.), acyclovir (400 mg b.i.d) and gastroprotection were recommended. No prophylaxis for thromboembolism was instituted. The use of bisphosphonates, erythropoietic and myeloid growth factors was allowed as accepted standard of care.
Efficacy and Safety Assessments
Treatment response was evaluated according to the recently published International uniform response criteria. Briefly, complete response (CR) was defined as undetectable serum and urine monoclonal paraproteins (M-protein) by immunofixation, disappearance of any soft tissue plasmacytomas and marrow plasma cells ≤ 5%. Very good partial response (VGPR) required serum and urine M-proteins detectable by immunofixation but not by standard electrophoresis or a ≥ 90% reduction in serum M-protein with urinary M-protein excretion <100 mg/24 h. Partial response (PR) was defined as a ≥ 50% reduction of serum M-protein, reduction in 24-h urinary M-protein by ≥ 90% or to <200 mg/24 h, a ≥ 50% reduction in bone marrow plasma cells. Progressive disease was defined as a ≥ 25% increase of serum and/or urinary M-protein or bone marrow plasma cells (absolute amount ≥ 10%), an increase in the size or development of new bone lesions or soft tissue plasmacytomas or development of hypercalcemia. The disease was defined as stable if the criteria for CR, VGPR, PR or progressive disease were not met.[12] All adverse events were graded according to the National Cancer Institute Common Terminology Criteria (version 3).[14]
FISH analyses were performed on bone marrow plasma cells that were purified using anti-CD138-coated magnetic beads (Miltenyi Biotech GmbH, Germany). FISH was performed on fixed plasma cells, as previously described.[15,16]
Statistical Analysis
OS was calculated from the time of enrollment until the date of death or the date the patient was last known to be alive. Event-free survival (EFS) was calculated from the time of enrollment until the date of progression, relapse, death or the date the patient was last known to be in remission. Time-to-event analyses were performed with the Kaplan–Meier method.[17] Subgroup analyses were carried using the Cox model to estimate the hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) to detect clinically relevant interactions between treatment and clinical variables. The incidences of adverse events were compared by the chi-square test. The analyses were performed with SAS (version 8.2).
Results
Patients’ Characteristics
The patients’ characteristics are reported in Table 1 . At study entry, the median time from diagnosis was 31 months (range 2–181 months) and the median number of prior therapy lines was 2 (range 1–7). Fifteen patients (23%) received PAd as second-line therapy, 24 patients (38%) as third line and 25 patients (39%) beyond third line. Thirty-seven patients (58%) had previously undergone autologous stem-cell transplantation, 17 (27%) had received prior bortezomib-based regimens, 45 (70%) prior anthracycline, 48 (75%) prior thalidomide and 6 (9%) prior conventional chemotherapy. The median number of PAd cycles administered was 4 (range 1–6). The assigned treatment was discontinued in 27 patients: 6 patients stopped treatment because of toxic effects (one case each of grade 3 neurological toxicity, grade 3 acute heart failure, grade 4 acute heart failure and grade 3 infection and two cases of grade 4 infections) and 21 patients because of disease progression.
Efficacy
Disease response is illustrated in Table 2. CR or VGPR was achieved in 16 of the 64 patients (25%) and at least PR in 43 (67%). The median time to the best response was 2 months (range 1–6 months). The best response occurred within the first three cycles (3 months) in 76% of responding patients. Response was higher or equal to that induced by the previous therapy line in 69% of patients. In those patients who received PAd as second-line therapy, 4 (27%) achieved a CR or VGPR and 12 (80%) had at least a PR.
Response rates were similar in both patients who had received previous bortezomib-based regimens and those who had not (the CR or VGPR rates were 18% versus 28% and the PR rates 41% versus 38%, respectively). Response rates were higher or equal to those induced by the previous bortezomib-based regimen in 65%. In the 12 patients who achieved at least a PR in response to previous bortezomib, one CR, one VGPR, six PR were reported in response to retreatment with PAd. In the five patients who did not reach PR in response to previous bortezomib, one CR and one PR were achieved after PAd. In the 34 patients who received doxorubicin, 10 (29%) had a CR or VGPR and 17 (50%) had a PR, while in the 30 patients who received PLD, CR or VGPR was achieved in 6 (20%) and PR in 10 (33%). The PR rate was significantly higher in patients who received doxorubicin (P = 0.03). The median follow-up from study entry was 8 months (range 1–21 months) for survivors. Progression, relapse or death occurred in 29 patients (45%). Overall, the 1-year EFS was 34% which was similar to that reported after the previous line of therapy (HR 1.20, 95% CI 0.76–1.90, P = 0.43; Figure 1A). At the time of this analysis, 16 deaths had been reported, 13 due to disease progression and 3 due to treatment-related causes (two infections and one case of acute heart failure). Overall, the 1-year OS from the start of therapy was 66% (Figure 1B).

Figure 1.
Event-free survival and overall survival. Panel A shows EFS in patients treated with PAd and in the same patients during the last treatment before study entry. Panel B shows overall survival from start of therapy for all patients.

A subgroup analysis showed a 1-year EFS of 57% in patients who received PAd as second-line therapy as compared with 30% in those who received PAd beyond the second line (HR 1.91, 95% CI 0.67–5.49, P = 0.23). One-year EFS was 39% in those who had never received bortezomib and 16% in those who had received prior bortezomib-based regimens (HR 1.79, 95% CI 0.83–3.88, P = 0.14). No differences in EFS were reported between patients who received doxorubicin and patients who received PLD (HR 1.30, 95% CI 0.62–2.74, P= 0.49). One-year EFS in patients who achieved VGPR or CR was 83% and 16% in those who achieved only a PR (HR 4.90, 95% CI 1.31–18.34, P= 0.02). The landmark analysis at 6 months showed a similar trend (HR 2.85, 95% CI 0.68–11.97, P= 0.12). One-year OS from the start of therapy was 90% in patients who achieved VGPR or CR and 63% in those who achieved only a PR (HR 7.09, 95% CI 0.88–56.91, P= 0.06). The landmark analysis at 6 months also showed a similar trend (HR 3.50, 95% CI 0.49–24.96, P = 0.24). No differences in EFS were reported between patients with chromosome 13 deletion and without such abnormality (HR 1.32, 95% CI 0.13–13.0, P = 0.8). One-year EFS among patients with β2-microglobulin levels ≤ 4.0 mg/dl was 32% and 41% in those with higher β2-microglobulin levels (HR 1.07, 95% CI 0.51–2.20, P = 0.86). Similarly, OS from the start of therapy was not different between these two groups (HR 1.79, 95% CI 0.56–3.81, P = 0.43).
Safety
Adverse events are shown in Table 3 . The most common grade 1–2 adverse events were anemia (42%), neutropenia (30%), thrombocytopenia (27%), peripheral neuropathy (27%), nausea (14%), diarrhea (11%) and fever of unknown origin (11%). Three patients, who were not on acyclovir, developed grade 2 herpes zoster infections; no patient treated with prophylactic acyclovir developed viral infections. The most common grade 3 adverse events were thrombocytopenia (23%), neutropenia (20%), anemia (11%), peripheral neuropathy (10%) and pneumonia (9%). The incidence of all other grade 3 adverse events was <5%. Deep vein thrombosis was reported in only two patients (3%). Grade 4 adverse events included hematological toxic effects [thrombocytopenia (25%), neutropenia (16%) and anemia (2%)], one episode of acute heart failure (2%) and two cases of pneumonia (3%). No patient experienced grade 4 peripheral neuropathy. Fifteen patients received support with granulocyte colony-stimulating factor.
Among the 50 patients who had no evidence of neuropathy before study entry, grade 1 sensory neuropathy developed in 11 patients, grade 2 in 5 patients (three sensory and two painful neuropathy) and grade 3 sensory neuropathy in 3 patients. Sensory neuropathy remained stable in eight patients and worsened to grade 2 in one patient and to grade 3 in another, among the 10 patients with pre-existing grade 1 neuropathy, whereas it remained stable in two patients and worsened to grade 3 in two of the four patients with pre-existing grade 2 neuropathy.
The dose of bortezomib was reduced from 1.3 to 1.0 mg/m2 because of hematological toxicity (five patients), grade 2 neuropathy (n = 5), grade 3 infections (n = 5), grade 3 gastrointestinal toxicity (n = 4) and grade 3 fatigue (n = 1). Among these patients, the dose of bortezomib was further reduced to 0.7 mg/m2 because of worsening neuropathy (n = 2) and grade 3 gastrointestinal toxicity (n = 2). Two patients with pre-existing grade 2 neuropathy reduced from 1.3 to 0.7 mg/m2because of grade 3 neuropathy. Both hematological and non-hematological toxic effects were similar between patients younger and older than 65 years. Patients treated with doxorubicin showed a higher incidence of grade 3–4 hematological toxicity (85%) than patients treated with PLD (23%) (P < 0.001); non-hematological toxicity was not significantly different in the two groups (50% and 27%, respectively, P < 0.1). The patient who experienced grade 3 acute heart failure was treated with doxorubicin, whereas the patient who died from acute heart failure received PLD.
Discussion
In this study, we evaluated the efficacy and safety profile of PAd combination in patients with relapsed or refractory myeloma. The median EFS of 9 months after PAd was similar to that observed after the previous line of therapy, suggesting an efficacious combination with tangible clinical benefit. Importantly, the achievement of VGPR appears to be associated with a significantly longer survival than that of patients who attained only PR. Severe non-hematologic adverse events included infections (15%), gastrointestinal disturbances (11%) and peripheral neuropathy (10%).
In relapsed myeloma, bortezomib as a single agent induced at least a PR in 43% of patients including CR in 6%.[6,8] The addition of dexamethasone increased response rates in patients with suboptimal response to bortezomib alone.[18]In a large study, 646 patients with advanced myeloma were randomized to receive bortezomib either alone or with PLD: in the bortezomib/PLD group the PR rate was 44% including 9% near CRs.[10]In our study, PAd induced at least a PR in 67% of patients, including a CR rate of 9% and a VGPR rate of 16%. CR or VGPR are considered important surrogates for remission duration and survival.[19-22]Despite the relatively small number of patients, the achievement of at least VGPR or CR improved both EFS and OS. These findings further suggest that effective cytoreduction should be considered a primary treatment goal.
During the first 2 years of follow-up, in each individual patient the time to disease progression after PAd was similar to that observed after the previous line of chemotherapy. This provides evidence of the efficacy of PAd, as the remission duration usually becomes progressively shorter after each line of salvage therapy. These results have been achieved despite 58% of patients had previously undergone autologous transplant and 75% of them had already received thalidomide. Moreover, PAd activity was similar in both patients treated with PAd as second-line treatment and those treated as fourth-line treatment. EFS and OS were not affected by serum β2-microglubulin levels; this finding is consistent with observations on the use of thalidomide as maintenance therapy after autologous stem-cell transplantation or in combination with dexamethasone as salvage treatment.[23,24]Similarly, EFS was not modified by the presence of chromosome 13 deletion. In a previous report, elevated β2-microglubulin levels and presence of chromosome 13 deletion, generally considered poor prognostic factors for conventional chemotherapy, were not predictive of poor outcome in patients treated with bortezomib.[25] As shown in other studies,[25-28] in our trial, bortezomib also overcomes the adverse prognostic effects of both β2-microglobulin and chromosome 13 deletion. Moreover, patients who were retreated with bortezomib after prior exposure still showed an EFS similar to that of patients who had never received the drug, encouraging its use in multiple lines of salvage therapy.
Most adverse events reported were rather expected and were managed with standard supportive care. Doxorubicin was delivered on days 1 and 4 and not by continuous infusion. This was a very convenient outpatient infusion regimen that allowed the simultaneous administration of doxorubicin with bortezomib. The incidences of grade 3–4 neutropenia and thrombocytopenia were 36% and 48%, respectively. In relapsed patients treated with bortezomib and dexamethasone, the rates of both neutropenia (13%) and thrombocytopenia (33%) were lower[18] as compared with regimens containing bortezomib and doxorubicin.[9,10]Despite this hematological toxicity, a higher incidence of bleeding or infections was not reported.
Grade 3–4 infections occurred in 15% of patients after PAd, in 15% after bortezomib as a single agent,[7] in 24% after bortezomib and PLD[9] and in 33% after bortezomib doxorubicin and high-dose dexamethasone.[11]Low-dose dexamethasone markedly reduced the risk of infections in comparison with a regimen including both doxorubicin and high-dose dexamethasone.
Severe grade 3 peripheral neuropathy has been reported in 8%–15% of patients who received bortezomib alone,[2,6,7] and in 17% of those who received the combination of bortezomib, melphalan and prednisone.[26] In relapsed patients treated with bortezomib, melphalan, prednisone and thalidomide, the incidence of grade 3–4 peripheral neuropathy was 7% only, despite the concomitant administration of thalidomide:[29]the weekly administration of bortezomib at a dose of 1.3 mg/m2may have contributed to the reduced rate of peripheral neuropathy. In our PAd regimen, a 28-day cycle instead of 21-day cycle may have contributed to the reduced neurotoxicity of 10% as suggested by Berenson et al..[30] Only two episodes of deep vein thrombosis and no pulmonary embolism were recorded, whereas these complications were frequently reported in patients treated with drug combinations including doxorubicin.[31,32]
No differences in non-hematological toxic effects between patients treated with doxorubicin or PLD were reported. The incidence of cardiac toxicity was inferior to that recently reported[10] and was equally distributed between the two cohorts of patients. When the study was designed, the use of doxorubicin or PLD was on the basis of the Institutional guidelines of each participating center as data comparing the two drugs were not available. Our data show that there are no significant differences in terms of toxicity profile and clinical efficacy. However, it should be noted that the recent approval of the combination bortezomib/PLD by the Food and Drug Administration and the European Medicines Evaluation Agency has provided an important treatment option for relapsed/refractory MM patients.
In conclusion, PAd induces clinically significant responses and prolonged remission duration in patients with relapsed and refractory myeloma. Adverse events are reduced by the administration of low-dose dexamethasone and the 28-day schedule of bortezomib.
Table 1. Patient and Disease Characteristics

Patient characteristicsn (%)
Age at PAd, median (range), years65 (41–85)
Sex
   Male34 (53)
   Female30 (47)
Disease characteristics at diagnosis
   Stage
   IA–IIA22 (34)
   IIIA37 (58)
   IIIB5 (8)
   Myeloma protein class
      IgG39 (61)
      IgA18 (28)
      Bence-Jones protein7 (11)
   β2-microglobulin, median (range), mg/l4.0 (0.2–71.0)a
      <3.522 (34)
      ≥3.5 to <5.510 (16)
      ≥5.521 (33)
      Data missing11 (17)
   Cytogenetic abnormalities
      Deletion of chromosome 1316 (25)
      Data missing36 (56)
Treatment at diagnosis
   High-dose therapy with PBSC rescue35 (55)
   Conventional chemotherapy21 (33)
   Thalidomide-based regimen8 (12)
Median time from diagnosis of PAd (range), months31 (2–181)
Prior lines of treatment
   115 (23)
   224 (38)
   3–725 (39)
Prior treatments
   High-dose therapy with PBSC rescue37 (58)
   Thalidomide-based regimen48 (75)
   Bortezomib-based regimen17 (27)

a Three patients with high values (18, 20 and 71 mg/l), all with renal failure.
Table 2. Response of Patients With Relapsed/refractory Multiple Myeloma Receiving Bortezomib, Doxorubicin and Dexamethasone (PAd)

ResponseAll patients, N = 64 (%)PAd as second-line therapy, N = 15 (%)PAd as third-line therapy, N = 24 (%)PAd as fourth- to eighth-line therapy, N = 25 (%)
CR or VGPR
   >90% protein reduction16 (25)4 (27)6 (25)6 (24)
CR
   Immunofixation negative6 (9)2 (13.5)1 (4)3 (12)
VGPR
   90%–99% myeloma protein reduction10 (16)2 (13.5)5 (21)3 (12)
PR
   50%–89% myeloma protein reduction27 (42)8 (53)9 (38)10 (40)
Stable disease15 (24)3 (20)6 (25)6 (24)
Progressive disease6 (9)03 (12)3 (12)

CR, complete response; VGPR, very good partial response; PR, partial response.
Table 3. Grade 1–2 Adverse Events Occurring in at Least Three Patients and All Grade 3–4 Adverse Events in Patients Receiving Bortezomib, Doxorubicin and Dexamethasone (PAd)

Grade 1–2, n (%)Grade 3, n (%)Grade 4, n (%)
Hematological
   Neutropenia19 (30)13 (20)10 (16)
   Thrombocytopenia17 (27)15 (23)16 (25)
   Anemia27 (42)7 (11)1 (2)
Infectious
   Pneumonia06 (9)2 (3)
   Febrile neutropenia02 (3)0
   Herpes zoster3 (5)00
   Fever of unknown origin7 (11)00
   Upper respiratory tract3 (5)00
   Others4 (6)00
Constitutional
   Fatigue

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MM Updates

Posted by Eve on September 16, 2008

DSM Biologics and MorphoSys AG to Manufacture Fully Human Antibody: http://www.marketwatch.com/news/story/dsm-biologics-morphosys-ag-manufacture/story.aspx?guid=%7B1BF6C754-14E5-4DBE-8907-ABA88A76B76A%7D&dist=hppr
ESAs cut survival by more than half in multiple myeloma: http://www.hemonctoday.com/article.aspx?rid=30210
Treatment with Plerixafor Shown to Improve Mobilization of Cells in Donors During Bone Marrow Stem Cell Collection Procedures: http://www.medadnews.com/News/Index.cfm?articleid=564403
SymBio Pharmaceuticals and Eisai Sign License Agreement for bendamustine hydrochloride (SyB L-0501): http://www.pharmalive.com/News/index.cfm?articleid=564544&categoryid=10

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