When Nan Manzo’s husband Dom was diagnosed with multiple myeloma in 2008, their family doctor shared some advice about how to deal with the ups and downs of dealing with cancer. “Ants will show up at this picnic. Just brush them off, and keep focused.”

“I can’t begin to tell you how many times we laughed about the ants,” said Nan. “They certainly did show up – repeatedly!”

Many people find that humor can help ease the stress and worry associated with a cancer diagnosis, but caring for someone with multiple myeloma can certainly take an emotional and physical toll.

As your loved one battles cancer, you may experience a range of emotions such as anger, worry, fear, guilt, resentment, and grief. Under the constant stress of supporting your loved one, it is not uncommon to find yourself mentally and physically exhausted.

However, understanding the stress and emotions you are experiencing can help you cope with them.

Financial Implications

When Lori and Dave Puente found out that Dave had multiple myeloma in 2008, Lori quit her job to be his caregiver. She handled his treatment, the payment of medical bills, and communication with insurance providers. “It took a big hit on our finances even though we had insurance,” Lori said.

Chronic illnesses, such as multiple myeloma, can have a significant impact on a family’s finances. People with myeloma may be unable to work as consistently as they had before, and caregivers may leave their jobs to devote their time to caring for their loved one. At the same time, their bills grow due to hospital and treatment expenses. In many cases, it is the caregiver’s job to handle the payment of bills, insurance coverage, and resources that will ease the financial burden.

A study presented at the American Society of Hematology’s 2009 meeting evaluated the financial burden of different myeloma treatment options on patients and their caregivers. Out-of-pocket expenses were calculated to be at least $3,000 annually.

Luckily, aid is available in the forms of health insurance, pharmaceutical reimbursement programs, and other services. Consult with your insurance provider to determine what they cover. If your loved one receives coverage from Medicare, you can receive free one-on-one assistance and advice from the State Health Insurance Assistance Program or from the Medicare Rights Center.

Beyond health insurance, a number of pharmaceutical companies offer reimbursement programs. These include Celgene, the manufacturer of Revlimid (lenalidomide) and thalidomide (Thalomid), and Millennium, the manufacturer of Velcade (bortezomib). For a list of pharmaceutical reimbursement programs, visit the Beacon’s Drug Reimbursement Information links. A number of nonprofit organizations also offer reimbursement. For a list of nonprofit financial assistance programs, visit the Multiple Myeloma Research Foundation website.

Many chemotherapy agents and steroids are no longer patented, and generic versions are available at a fraction of a cost of the branded version. Ask a doctor if a less expensive generic option is available.

Participating in a clinical trial may be another way to reduce the financial burden of treatment and a way to be involved in the process of bettering myeloma treatment for the future. Ask your doctor or visit the Beacon’s list of Clinical Trials links.

Certain non-treatment expenses, such as home care assistance and medical supplies, may also be covered by Medicare or other insurance companies. Be sure to check with your insurance provider.

Mental Health Effects

Watching someone struggle with myeloma can be a very emotional and difficult time for a caregiver. Caregivers usually experience high levels of stress, and according to the Family Caregiver Alliance, between 40 to 70 percent of caregivers have symptoms of depression. These symptoms include changes in eating and sleeping habits, fatigue, loss of interest in people or activities, and ongoing physical symptoms that do not respond to treatment.

While it is natural to feel sad and anxious, if you think your symptoms are more severe, you should consult a doctor. It is important to treat depression properly so you are in the best condition possible to help your loved one.

Although Nan did not suffer from depression, she knew the devastating effects her sadness could have on Dom: “I tried to keep my chin up in his presence, but there were many times that I would cry. I tried to never let him see that. I always tried to remain completely positive.”

In addition to suffering from symptoms of depression, feelings of grief (the process of reacting to loss) are also normal. As a caregiver, you have been involved in all aspects of life with myeloma, so your grief may come and go with each loss and success. You may grieve more as the disease progresses.

Another type of grief – anticipatory grief – may also occur as the disease progresses. This is experienced when caregivers await and anticipate future grief. Grieving is a natural coping mechanism, but do not forget that there is still time to enjoy with your loved one.

Grief will vary from person to person. Bereavement (a state of sadness, grief, and mourning after the loss of someone you care about) may include physical as well as emotional pain. Each person will experience this pain for a different length of time. Some mourn for an extended period of time, others work through the grief process as their loved one’s health declines, and although others mourn, they may also feel a sense of relief that their loved one is no longer suffering.

Some people deal with grief by connecting with family and friends, by reaching out to other caregivers who have dealt with loss, or simply by working through things on their own.

Regardless of your coping strategy, help is available. Ask for advice from your doctor, family, friends, and a support group.

Coping With Lost Responsibility

Of course, the hope is that your loved one will respond favorably to treatment for their myeloma and ultimately be able to resume life as it was before their cancer diagnosis.

If your loved one responds to treatment and as their condition improves, he or she may want to have a more active role in their health care and retake control of some tasks that they passed to you soon after their diagnosis and during their treatment.

Despite being happy about your loved one’s improved condition, it can be difficult coping with the loss of responsibility as your loved one becomes less dependent on you.

Dave and Lori were lucky enough to learn that Dave responded well to multiple myeloma treatment and is in complete remission. As Dave regained strength, he started making his own decisions about his medicine and treatments, things Lori normally had done as his caregiver.

After Dave expressed his desire to take over, Lori found herself feeling lost and not needed. Over the course of a few months, Lori adapted to a new routine by reconnecting with childhood friends in California, visiting her children on the East coast, and thinking about working again. “Now I’m feeling a little bit more ready to go out and look for a job,” she said. “I feel really good now, but it took awhile. It took me months.”

At the same time, your loved one may experience feelings of abandonment if the switch from caregiver to companion is abrupt. Lori advised letting your loved one make their own decisions while continuing to offer support. “Make sure they don’t feel abandoned,” she said.

With Dave back at work, Lori makes sure that she is always available to help Dave when he asks. “It’s a delicate balance,” she said.

But Dave and Lori are thankful for Dave’s remission and that they can now move forward with their lives. “Since he’s being so closely monitored, we can put [myeloma] out of our minds and live our lives,” said Lori. “If it comes back, [the doctors] will tell us, and we’ll deal with it. If it’s not there, we’re not going to sit around worrying about it.”

For more information about caring for someone with multiple myeloma, please see Part 1 and Part 2 of this series.

When Lori Puente’s husband Dave was diagnosed with multiple myeloma in 2008, she decided that she would need to take time off from work and her activities in order to give Dave the best care possible. “It was a full-time job with a lot of down time,” she told the Beacon in a phone interview. “Dave would be up at 2 a.m. hungry, and then asleep from 10 a.m. until noon. Whatever his schedule was, my schedule was. It required major adjustments and flexibility.”

For many caregivers, taking time off from work is not feasible. Balancing work and other responsibilities with caregiving is no easy task, so the Beacon has provided practical tips to help busy caregivers manage their time, communicate with health care and health insurance professionals, and prepare for emergency situations.

Making Yourself A Priority

In order to fully perform your responsibilities as a caregiver, you must keep your body and mind healthy. While it may seem that the only option is to devote all your time and energy to combating myeloma, you must focus on yourself as well so that your loved one can continue to rely on you.

Balancing doctor appointments, treatment regimens, and household responsibilities on top of a full-time job may be overwhelming. Caregivers often take time off from work to focus on the patient’s needs. Dianna Allred was able to take nine and a half months off from work to care for her husband, Mark.

While taking time off from work may allow you to spend more time with your loved one, without a job, the illness may completely engulf all aspects of your life. It is important that you monitor your own health by visiting your doctor for routine check-ups and watching for stress-related symptoms.

Symptoms of stress include headaches, back or chest pain, high blood pressure or heart disease, upset stomach, difficulty sleeping, anxiety, depression, irritability, lack of focus, over- or under-eating, or increased smoking or drinking. These stress-related symptoms can make it difficult to concentrate and can make your body susceptible to viruses such as the common cold.

Other ways to stay healthy include eating a balanced diet; exercising for at least 30 minutes a day, four times a week; and striving to sleep eight hours a night. Nan Manzo tries to walk outside to stay healthy, so that she can take care of her husband Dom.

Taking breaks to walk outside, watching a few minutes of television, reading, or indulging in a hobby are useful ways to increase energy and concentration. Little breaks will help you clear your mind and refocus your energy on caring for your loved one. “I took up knitting, which I hadn’t done in years,” said Lori.

With its positive mental and physical aspects, yoga may be a valuable activity to adopt. It is said to improve balance and coordination, reduce stress, and improve concentration. Students of yoga are encouraged to be completely conscious of and love themselves in order to make challenging decisions and to help others. More information about yoga for caregivers can be found at the following sites: Empowering Caregivers and Yoga For Caregivers.

Delegating The Responsibility

Although many caregivers take on caregiving as their full time job, it does not need to be a job for just one person. If another family member or friend offers their assistance, accept it. Sometimes friends and family members may want to help, but may not offer because they are unsure of how to ask and how they can contribute. Have a one-on-one conversation with anyone you think may want to help to let them know what they could do; having a list of specific tasks is particularly helpful.

Delegate responsibility. For instance, as the primary caregiver, you can schedule and attend doctor appointments, research the disease and treatment options, and remind your loved one when to take their medications; Arrange for an assistant caregiver who takes care of the grocery shopping, laundry, house cleaning, lawn care, and other chores around the home.

When you allow and encourage others to help, everyone benefits. Most importantly, the practical and emotional support of others can help you feel less overwhelmed.

Another way to share the responsibility of caregiving is to hire help. At-home nurses or respite helpers can offer the valuable extra set of hands necessary for you to balance the many responsibilities in your life. However, finding a reliable person who gets along with you and your loved one can be difficult. Fortunately, there are many agencies that specialize in locating at-home nurses and aides. “If you’re not happy with the person, ask for someone else,” advised Dianna.

Find out how your loved one feels about receiving care from a hired aide, and ask friends or members of a local support group for references.

Communicating With Health Care Professionals

From diagnosis to treatment and follow-up, hospital visits become a routine part of life for people living with multiple myeloma. Interacting with hospital personnel can be intimidating, confusing, and exhausting. At times, myeloma patients may be too distracted by worry or fear to take control of the situation. Your role as caregiver includes advocating on behalf of the patient by coming to appointments, asking questions, and speaking up for them.

“One of the most important things a caregiver needs to realize is that they need to empower the patient as much as the patient wants to be empowered,” said Lori. During Dave’s treatment, Lori handled everything: filling prescriptions, contacting insurance companies, talking with health care providers, and more. She verified her actions with Dave at each step to ensure he was comfortable with her decisions.

To guarantee the best medical care, you should keep doctors and nurses informed and up to date on your loved one’s condition. Come prepared with lists of the patient’s allergies, recent side effects, and current medications, including dosages. If you are visiting a hospital or doctor for the first time, bring copies of your loved one’s medical history, including previous test records and results to help facilitate the administrative process. Feel free to ask the staff at your regular hospital for copies if you do not have these records.

If you have specific questions for the oncologist, write them down and prioritize them. Nan has found this strategy to be very useful when she goes to doctor appointments with her husband. “I go in with a list and take notes” she said.

If the doctor says something confusing or unclear, make sure to ask for clarification. One way to make sure you understand everything correctly is to state what you think the doctor said in your own words and see if he or she has anything to add. You can also ask for permission to use a recording device.

When the doctor finishes speaking, let him or her know that you have questions and begin with your most important concern. If the doctor does not have time to answer all of your questions, you can ask other medical staff. Nurses can be a great source of information and support, since they are usually responsible for implementing the doctor’s treatment plan.

If you are unsatisfied with a physician’s medical advice, say so. The patient-doctor relationship works best as a partnership; both the patient and the caregiver’s inputs are valuable. Be courteous, yet persistent, to successfully communicate with medical personnel on behalf of your loved one.

The same principles hold true when engaging with insurance providers. Prepare for the conversation by having the patient’s birth date and insurance policy number ready. If the question is about a specific bill, have ready the name and address of the organization that sent it, the total amount, and the diagnosis code listed on the bill. Writing down the questions you would like to ask ensures that you will not forget about any important inquiries.

When the conversation begins, be sure to take down the name and telephone extension of the person with whom you are speaking in case you need to call again. Present your question or case clearly and briefly, and tell the representative what you need and expect. Taking notes as they respond may be helpful. Dealing with health insurance providers is often complicated and time-consuming, so be patient, considerate, and assertive.

Emergency Situations

Multiple myeloma can cause a number of serious health complications such as kidney failure, bone fractures, reduced blood cell counts, and an increased susceptibility to infections. As a result, caregivers should be prepared to deal with emergency situations that require them to act quickly and confidently.

Dianna experienced such a situation after Mark’s second stem cell transplant. “I left [home], and I had only been gone for an hour. When I left he was fine,” she described. “When I got back, he was burning up with a fever. That’s how quickly it can come on.”

The first step is recognizing an emergency. For cancer patients, something as simple as a fever can warrant a trip to the emergency room. Dianna knew the warning signs of a serious problem, thanks to a booklet and a short educational class provided by her clinic. Ask your health care team if they offer any informational publications and classes.

The more information you can bring with you to the emergency room, the better. Be prepared with the same documents you would carry along to a normal doctor appointment: your loved one’s medical history and records and a list of their allergies and medications. Also include the contact information for your primary oncologist and treatment center. These documents contain sensitive information, so keep them in a private, yet accessible, location, such as a lockable drawer.

Another written document to consider bringing is a durable power of attorney. This gives you or whoever is designated the legal authority to make decisions on behalf of the patient in the event that the patient is no longer able to do so. A durable power of attorney form can be obtained at the hospital, from an attorney, or at a state attorney general’s office. Copies of the completed document should be provided to hospital personnel. If you or your loved one is unsure whether this is essential, speak to your doctor or lawyer. It is best to discuss and prepare for every situation beforehand in the event that a crisis occurs.

If you believe your loved one requires immediate medical attention, call 911. Upon arriving at the hospital, find out who the attending physician will be and collect his or her contact information. Make sure you understand what the doctors and nurses are proposing before making a decision. You can use some of the strategies presented above for talking with health care professionals, such as repeating what the doctor or nurse said in your own words.

Your loved one will probably be assigned a hospital social worker or case manager. When possible, sit down with this person and plan for your loved one’s discharge from the hospital. Be proactive about getting information from the physicians, nurses, and other personnel involved in your case.

Another thing to remember is that all situations are best dealt with calmly, and it is important to always keep the interests of your loved one in mind. Emphasizing the need for good communication between caregivers and patients, Lori said, “Everything I do with [Dave’s care], I have to keep in mind who he is.”

For more information about caring for someone with multiple myeloma, please see Part 1 of this series and check back for Part 3.

In October 2008, Dianna Allred’s husband, Mark, was diagnosed with multiple myeloma after suffering a severe spine fracture.

As Mark’s pain increased dramatically after the fracture, Dianna took action. “I called the doctor and told them we needed an MRI. Something was just not right,” she described in a phone interview with the Beacon. An MRI and a CAT scan later, Mark’s myeloma was diagnosed, and in Dianna’s words, “The ball started rolling from there.”

Immediately, Dianna assumed the role of Mark’s primary caregiver, the person who would help him cope with cancer.

A study by the National Alliance for Caregiving in collaboration with AARP, called Caregiving in the U.S. 2009, estimated that 65.7 million adults in the United States (29 percent) provide care for loved ones with a range of special needs.

While there is not a single specific type of caregiver, the study determined that the average age of a caregiver is 48 years old, and 66 percent are female. The study also found that caregivers provide an average of 20 hours of care a week. Constantly on call, a caregiver’s work varies from managing prescriptions to being a companion in times of emotional hardship. It can be an overwhelming task, especially if the caregiver has a full schedule of his or her own.

Fortunately, there are resources for caregivers who are looking for advice or wanting to connect with others in the same situation.

First Steps For Caregivers

Prior to diagnosis, most people have never heard of multiple myeloma. This was the case for Nan Manzo when her husband Dom was diagnosed in the spring of 2008.

“We had never heard of it,” Nan said in an interview with the Beacon. “All we knew was the big C: cancer. We were just absolutely shocked. And then [the doctor said], ‘All is not lost. You’re a good candidate for a stem cell transplant.’ Our mouths dropped even further, ‘What is a stem cell transplant?’ It was just so much information at once. Our heads are still spinning.”

For Nan and Dianna, the first step after learning of their husbands’ diagnoses was to educate themselves about the disease. Caregivers can learn more about multiple myeloma through physicians, nonprofit organizations and foundations, reputable websites, and blogs written by myeloma patients.

It is important to be careful when researching on the Internet because not all the information is credible. Keeping a journal of informative websites or questions to ask at the next doctor appointment may prove helpful. Important topics to research include treatment options, side effects, and clinical trials.

The amount of available information can be overwhelming and paralyzing, making it difficult to know where to begin. As a caregiver, remember that you do not have to know everything.

You can start by connecting with more experienced patients and caregivers, just as Mark and Dianna did. Through a chat line provided by their treatment center, they met Doug Carlsen, a multiple myeloma survivor.

“He was wonderful. He told us what to expect when we first found out about myeloma. We got his name from the hospital, and we just called him up and talked to him. He walked Mark through this. It calmed our nerves just to be able to talk to somebody who knew what we were in for,” Dianna explained.

While learning about multiple myeloma, it is also important to learn how to care for someone with cancer. Similar to learning about the disease itself, you can gather more information about being a caregiver from the Internet, brochures, and books.

As you educate yourself about the disease and your role as a caregiver, remember to take one webpage and one topic at a time. And take breaks! There is no possible way to learn it all in one day, so pace yourself. Although researching takes time and energy, information can be empowering and can contribute to greater peace of mind.

“Knowledge is power,” Nan advised. “Ask questions, take notes, and go home and research. It makes it a lot easier to comprehend and understand what they’re doing when you know how the whole thing works.”

Resources For Caregivers

There are a number of websites specifically for caregivers, such as the Family Caregiver Alliance, National Family Caregivers Association, and National Alliance for Caregiving, which provide information and advice, chances to connect with other caregivers, and research on caring for a loved one. Some websites for caregivers, such as Everyday Health, specifically provide information for multiple myeloma caregivers.

Check with local branches of patient advocacy groups for seminars and workshops offered to caregivers. The American Red Cross has a training program, called Family Caregiving, that covers topics such as caregiving skills, healthy eating, legal and financial issues, and caring for a caregiver.

While caregiving websites can provide general advice, blogs can provide insight into life as a caregiver. The Beacon’s Links section lists many blogs written by patients and caregivers, including Dianna and Nan and another caregiver Lori Puente. These patients and caregivers write about their progress, setbacks, treatments, emotions, and personal thoughts.

It is important to remember that you are not alone throughout this process. Connecting with other caregivers can help you learn more quickly about myeloma and being a caregiver, and it may be comforting to be able to share with others during the ups and downs of life with myeloma.

If you can, take a couple of hours each month to participate in a local support group. The Leukemia & Lymphoma Society, International Myeloma Foundation, and the Multiple Myeloma Research Foundation can connect you with support groups in your area.

If you do not have the time to attend support group meetings or if there are not any nearby, you can participate in Internet discussion boards, such as the Beacon forums, from the convenience of your home. This approach allows you to connect with other caregivers over great distances. There are also a number of forums and public chat groups for myeloma patients and caregivers available through the myeloma foundations, treatment centers, and also many e-mail servers, such as Yahoo!, AOL, and MSN.

For more information about caring for a loved one with multiple myeloma, please check back for Part 2 and Part 3 of this series.

Velcade has become a standard first-line treatment option for multiple myeloma, but more and more patients are developing resistance to or relapsing after it. Zolinza is a new cancer drug that is already approved for a certain form of lymphoma. Preclinical trials suggest that it enhances sensitivity to Velcade.

In a recent Phase 1 clinical trial, a combination of Zolinza and Velcade led to substantial response rates in patients with relapsed or refractory myeloma (see related Beacon news).

In this retrospective study, researchers investigated the effectiveness of Zolinza in combination with Velcade in six patients with persistent myeloma despite prior treatment with Velcade.

All patients had been heavily pretreated, and five had undergone stem cell transplants. They received treatment in 21-day cycles – 300 mg or 400 mg of Zolinza on days 1 to 14 and 1.3 mg/m² of Velcade on days 1, 4, 8, and 11.

Among the six patients, one (17 percent) achieved a very good partial response and four (67 percent) had a minimal response, for an overall response rate of 83 percent. One patient experienced stable disease. The treatment was well-tolerated, causing only mild to moderate nausea and diarrhea in three of the six participants.

The researchers concluded that the combination of Zolinza and Velcade may be a viable option for treating patients who have developed resistance to or relapsed after treatment with Velcade alone. They recommend more extensive research to verify their conclusions.

For more information, please see the journal Clinical Lymphoma, Myeloma & Leukemia (abstract).

Stem cell transplantation is the preferred treatment plan for multiple myeloma patients under the age of 65. When patients cannot produce enough of their own healthy stem cells for an autologous transplant, they undergo an allogeneic transplant, in which they receive stem cells from a donor.

A common complication of allogeneic stem cell transplantation, graft-versus-host disease, occurs when the body’s immune system flares in response to the donated stem cells. It often begins as a skin rash and is the leading cause of treatment-related death among patients who receive allogeneic stem cell transplants.

Currently, doctors can distinguish skin GVHD from other common skin rashes only by performing a skin biopsy, a labor-intensive and time-consuming procedure. Because skin GVHD can be life-threatening, doctors begin high-dose treatment in all patients developing skin rashes while waiting for the results of the procedure.

This one-size-fits-all protocol is problematic because patients whose results come back negative for skin GVHD are unnecessarily exposed to high-dose treatment which is associated with potentially fatal side effects.

In this study, researchers aimed to identify biomarkers for skin GVHD that would help in diagnosing the disease so doctors can develop treatment plans accordingly. A biomarker is a protein in the blood or tissue that can be used as an indicator for a disease.

“It [a biomarker] will help determine which rashes are caused by GVHD and need treatment with steroids,” explained Dr. James Ferrara, the study’s lead investigator, in an email to the Beacon, “as opposed to rashes from other causes which require a different treatment.”

To find biomarkers, researchers compared the blood samples of ten patients with skin GVHD and ten patients without it. They looked for proteins that had at least doubled in quantity in the blood samples of patients with GVHD and found fourteen such proteins, including elafin.

Because elafin is one of the easier proteins to screen for, researchers selected it as their top candidate for a biomarker. They found that on average, patients with skin GVHD had three times as much elafin in their blood as patients without GVHD.

Researchers also found that compared to other biomarkers for skin GVHD, elafin proved to be the most accurate for the diagnosis of skin GVHD.

Researchers also determined that in patients diagnosed with skin GVHD, those who had a high elafin concentration were three times more likely to die from the disease than those with a low elafin concentration. This indicates that elafin may be a prognostic indicator for a patient’s overall survival of GVHD.

They recommended that physicians use elafin concentration testing to develop individualized therapy for patients with skin GVHD. “In the long run, we hope using elafin levels will lead to more appropriate treatment, and therefore, reduce mortality,” said Ferrara.

For more information, please see the journal Science Translational Medicine (abstract).

Thalidomide and Velcade are among the many myeloma treatments that are neurotoxic, which means that they cause damage to the body’s nervous system. As a result, multiple myeloma patients commonly experience tingling and pain from nerve damage in their extremities as a side effect of treatment – this is called peripheral neuropathy, or peripheral nerve damage.

After reviewing numerous studies, researchers identified the characteristics of and differences between peripheral neuropathy induced by thalidomide and Velcade.

In patients treated with thalidomide, the risk of developing nerve damage in the limbs increased the longer they were exposed to the drug. In one study, patients who experienced peripheral neuropathy had received thalidomide for an average of about nine months, while patients who did not develop nerve damage were more likely to have received thalidomide for only about three months. Additionally, patients who receive thalidomide treatment for a year have a 70 percent chance of developing nerve damage. As a result, some of the studies recommended that patients be given thalidomide for no more than six months.

Thalidomide-based neuropathy often initially develops as stinging or numbness in the toes or sometimes the fingers, and then it spreads up the legs and arms. Patients may also experience trembling.

With Velcade, neuropathy is less common than with thalidomide. About 40 percent of patients receiving Velcade develop nerve dysfunction. However, patients typically developed it within the first few cycles of treatment, indicating that prolonged exposure to the drug is not the main cause of the nerve damage. Patients often feel pain, tingling, burning, or numbness in their feet rather than in their hands.

Researchers identified two key indicators for developing Velcade-induced peripheral neuropathy: treatment history and personal predisposition. They observed that patients who had received other neurotoxins like vincristine (Oncovin) or cisplatin in the past were more susceptible to nerve damage when treated with Velcade. Also, patients who had pre-existing nerve damage caused directly by their multiple myeloma were more likely to experience Velcade-induced peripheral neuropathy.

Velcade-related neuropathy can be reversed or alleviated by reducing the dosage given. Therefore, researchers recommended fast, simple, and accurate testing to identify when patients develop nerve dysfunction so that they can develop a treatment plan instead of completely discontinuing Velcade. They also noted that weekly Velcade infusions may alleviate nerve damage better than the current standard of biweekly infusions.

Other than the duration of treatment, no other indicators were identified as able to predict thalidomide-induced peripheral neuropathy. The authors concluded, however, that physicians must quickly reduce or stop thalidomide treatment in patients who develop tingling because (unlike Velcade-induced neuropathy) nerve damage caused by thalidomide has the tendency to become irreversible. Doctors are also advised to closely monitor their patients’ diabetes and vitamin B12 levels, since both are general risk factors for peripheral neuropathy.

For the general treatment of peripheral neuropathy, the review authors proposed Lyrica (pregabalin) or gabapentin (Neurontin) as a first line treatment, followed by Cymbalta (duloxetine) as a second line treatment. They also recommended tramadol (Ultram) for pain relief.

They also offered practical suggestions to help alleviate the discomfort, such as wearing loose socks and shoes or padded slippers; uncovering one’s feet in bed; walking to stimulate blood circulation; and soaking or massaging one’s feet in icy water.

For more information, please see the full review published in the journal Haematologica.

When myeloma patients are unresponsive to treatment or experience relapse, doctors implement their plan B, known generally as salvage therapy. Most salvage therapies consist of the same treatment drugs at an increased dosage or a combination treatment of the same and new drugs. However, in patients who have health complications or who encounter severe side effects, a dose increase or the addition of a new drug may lead to more problems, so doctors must attempt other salvage therapies.

In this study, researchers examined the effectiveness and safety of continuous, low-dose cyclophosphamide and prednisone as a salvage therapy in 27 multiple myeloma patients. All of the patients either had health complications (such as kidney impairment, diabetes, or heart failure) or had experienced repeated infection from conventional chemotherapy.

Patients received 50 mg of cyclophosphamide and 15 mg of prednisone orally each day without a treatment-free interval. The treatment was stopped only if the patients did not achieve partial response within the first three months. Doctors followed up every two months for a median of 11 months.

After three months of continuous treatment, 18 of the 27 patients (66.7 percent) responded to the salvage therapy. Two patients (7.4 percent) achieved complete response, two patients (7.4 percent) achieved very good partial response, and 14 patients (51.9 percent) achieved partial response. Seven patients (25.9 percent) remained stable, and two (7.4 percent) experienced progressive disease.

In patients who achieved partial response or better, the median overall survival was 22 months. Median progression-free survival had not been reached yet at the time of data analysis. Patients who remained stable or had disease progression experienced a median overall survival of seven months and a median progression-free survival of four months.

Treatment-associated side effects included pneumonia (25.9 percent); physical traits characteristic of Cushing’s syndrome (14.8 percent), a hormone disorder due to high levels of cortisol in the blood; upper respiratory infection (7.4 percent); secondary diabetes (7.4 percent); fatigue (3.7 percent); and water retention (3.7 percent). Most were mild and manageable.

Researchers concluded that in patients with health complications that lead to organ dysfunction, continuous, low-dose cyclophosphamide and prednisone is a safe, effective, and practical salvage therapy in terms of cost and use. They described the treatment as a “promising alternative” to conventional chemotherapy.

For more information, please see the journal Clinical Lymphoma, Myeloma & Leukemia (abstract).

In multiple myeloma patients under the age of 65, high-dose chemotherapy followed by an autologous stem cell transplant is the preferred and most effective treatment option. However, the high dose of chemotherapy often causes severe side effects such as oral mucositis, which occurs when the mucous lining inside the mouth becomes inflamed and develops ulcers.

Oral mucositis can become severe enough to require hospitalization so patients can receive pain killers or nutrition intravenously. Patients who develop inflammation and ulceration in the digestive tract also have a higher risk of infection and ultimately, treatment-related death.

Kepivance is a drug that prevents and treats inflammation and ulceration in the mouth by stimulating the activity of cells that line and protect the mouth and digestive tract. It is normally administered for three consecutive days before and three consecutive days after stem cell transplantation.

In this retrospective study, researchers evaluated the effect of a short-course treatment of Kepivance prior to high-dose chemotherapy and stem cell transplantation.  No Kepivance was administered after transplantation.

Researchers analyzed the data of 67 multiple myeloma patients who received 60 µg/kg Kepivance for three consecutive days starting a week before their transplantation. Patients then received high-dose melphalan (Alkeran) – 56 patients were given 200 mg/m², while the 11 patients with impaired kidney function received 140 mg/m². After their transplants, patients were given granulocyte colony-stimulating factor (G-CSF) to promote the circulation of the infused stem cells.

Sixteen patients (24 percent) developed severe oral mucositis. Researchers found that the rate of severe oral mucositis was significantly lower in patients with normal kidney function (16 percent) than in patients with impaired kidney function (64 percent). In addition, patients with impaired kidney function experienced mouth ulcers longer (nine days) than patients with normal kidney function (seven days).

Side effects associated with Kepivance included taste distortion and mild to moderate skin reactions.

Researchers also compared the results of this study with results of two prior studies that involved 21 patients who had been treated with G-CSF and 21 patients treated with supportive care only.

They found that patients treated with short-course Kepivance had a shorter hospital stay (median of 18 days) than patients treated with just G-CSF (21 days) and those treated with neither (22 days). In addition, patients who received short-course Kepivance did not need any intravenous pain killers, as compared to patients treated with G-CSF who needed them for a median of four days and patients treated with supportive care only who needed them for a median of eight days.

Researchers concluded that a three-day treatment with Kepivance prior to high-dose chemotherapy and stem cell transplantation may suffice to reduce oral mucositis effectively in patients with normal kidney function. They suggest that the short-course treatment has the potential to become the standard of care.

They added that their results show that the short-course Kepivance treatment does not reduce the rate of severe oral mucositis in patients with impaired kidney function. However, they pointed to another recent study that recommends treating oral mucositis in patients with impaired kidney function aggressively by intensifying the Kepivance doses.

They recommend prospective studies to confirm their results.

For more information, please see the journal Annals of Oncology (abstract) and the clinical trial description.

Non-marrow tumors, also known as extramedullary disease, occur when plasma cell tumors develop outside of the bone marrow in soft tissue or organs.

Coinciding with the use of high-dose therapy and targeted drugs such as Revlimid (lenalidomide), Velcade (bortezomib), or thalidomide (Thalomid), the rate of non-marrow myeloma has increased, and many researchers are concerned there may be a connection between the two events. In this study, researchers examined the relationship between treatment with high-dose therapy or novel agents and non-marrow tumors.

Researchers analyzed the data of 1003 patients treated at the University of Pavia in Italy between 1971 and 2007. Patients were divided into three groups according to the treatments that were available during their time period. Group 1 included patients treated between 1971 and 1993, when conventional dose chemotherapy was commonly used. Group 2 included patients treated between 1994 and 1999, when high-dose therapy was introduced as first-line therapy for patients under the age of 65 years. Group 3 included patients treated between 2000 and 2007, after the introduction of novel agents. Researchers followed up with patients for a median of 30 months.

Of the 1003 participants, 7 percent had already developed tumors outside the bone marrow at the time of their myeloma diagnosis, and 6 percent developed non-marrow tumors within the follow-up period, bringing the total to 13 percent.

Researchers noticed that the chance of a patient developing a non-marrow tumor increased over time – from an average of 1 out of 150 patients per year between 1971 and 1993 to 1 out of 65 patients per year between 1993 and 1999 and to 1 out of 20 patients per year between 2000 and 2007.

Among patients with non-marrow tumors at diagnosis, those who received high-dose therapy had survival similar to patients who never developed non-marrow tumors. However, patients with non-marrow tumors at diagnosis who did not receive high-dose therapy experienced a shorter progression free survival.

Patients who developed non-marrow tumors during the course of their myeloma experienced both shorter progression free and overall survival.

Despite the increase in non-marrow tumors in recent years, the researchers determined that treatment with high-dose therapy, Velcade, Revlimid or thalidomide did not increase the risk of developing non-marrow tumors.

Instead, the researchers found that more non-marrow tumors are being detected because patients are living longer and because detection methods are improving, allowing physicians to detect tumors that would have gone unnoticed in previous decades.

Over the three time periods studied, median overall survival increased from 32 months to 45 months to 54 months. From 2000 to 2007, the onset of tumors beyond the marrow occurred much later after multiple myeloma diagnosis than in previous years (an average of 34.6 months versus 18.9 months). Therefore, researchers concluded that as life expectancy for multiple myeloma lengthens, tumors outside the bone marrow have more time to develop, contributing to the sudden increase in non-marrow tumors.

The study authors wrote that they are unaware of any studies focusing on treatment for myeloma patients with non-marrow tumors. However, they stated that some studies have indicated that Velcade may be effective, while thalidomide appears to have low efficacy in this population of myeloma patients.

For more information, please see the journal Annals of Oncology (abstract).

Previous studies have shown a complementary, additive relationship between Velcade and other drugs, such as Doxil and dexamethasone. However, a three-fold combination has never been evaluated in patients over the age of 70, even though 70 is the median age at diagnosis of multiple myeloma.

In this study, doctors examined the effectiveness and safety of Velcade in combination with Doxil and dexamethasone (VDD) in elderly myeloma patients. Researchers recruited 25 patients over the age of 70 with relapsed or refractory myeloma. The patients had received a median number of two prior treatments.

For treatment, patients received Velcade (1.3 mg/m²  intravenously on days 1, 4, 8 and 11 every 21 days during cycles 1 and 2 and on days 1, 8, 15 and 22 every 32 days from cycle 3 on), Doxil (30 mg/m² intravenously on day 4 during cycles 1 and 2 and on day 8 from cycle 3 on), and dexamethasone (40 mg intravenously on days 1 to 4 during cycles 1 and 2 and 20 mg intravenously on days 1, 8, 15 and 22 from cycle 3 on). Patients underwent three to six cycles, depending on their responses. They also took a preventative antiviral medication twice each day. Doctors followed up with patients for a median of 12 months.

Of the 25 study participants, eight (32 percent) achieved complete response, eight (32 percent) reached very good partial response, one (4 percent) experienced partial response, and three (12 percent) had minor response. This added up to an overall response rate of 80 percent.

Overall, patients experienced a median progression-free survival of eight months. Researchers observed a difference between patients who had very good partial response (VGPR) or better and those who did not. Patients who had VGPR or better remained in remission for a median of 12 months, whereas patients who had less than VGPR experienced a median progression-free survival of four months. Eight of the 25 patients died due to disease progression. A median overall survival was not reached.

The treatment resulted in some severe side effects, including peripheral nerve damage (12 percent), low platelet count (12 percent), low white blood cell count (12 percent), and low red blood cell count (8 percent). More patients experienced the same side effects to a milder degree and others such as fatigue (20 percent) and diarrhea (16 percent).

Researchers concluded that the combination of Velcade, Doxil, and dexamethasone proved effective and safe in multiple myeloma patients over the age of 70 when administered weekly.

For more information, please see the journal Clinical Lymphoma, Myeloma & Leukemia (abstract).

Because of its effectiveness, the combination of Revlimid and dexamethasone (RD) has become a standard treatment option for patients with relapsed or refractory myeloma. However because Revlimid cannot be broken down effectively by the liver, it circulates throughout the body until it is filtered by the kidneys to be excreted in the urine.

Approximately 20 percent of multiple myeloma patients develop kidney failure, and in 2009, the US Food and Drug Administration (FDA) announced a revision to Revlimid’s prescribing information, warning patients with impaired kidney function to reduce their dosage of Revlimid accordingly (see related Beacon news).

In their study, researchers evaluated the effectiveness of RD therapy in patients with impaired kidney function. Kidney function is assessed by determining how quickly the kidneys filter creatinine, a waste product produced by the muscles. In this study, researchers defined impaired kidney function as creatinine clearance of less than 50 mL/minute.

Researchers recruited 50 patients with relapsed or refractory myeloma who had undergone a median of two therapies prior to the study. Patients were treated with 28-day cycles of Revlimid (days 1 to 21) and dexamethasone (40 mg on days 1 to 4 and 15 to 18 during the first four cycles and on days 1 to 4 from cycle 5 on).

In accordance with FDA safety guidelines, the dosage of Revlimid each patient received was determined based on their creatinine clearance. Patients with normal kidney function, defined in this study as a clearance of 50 mL/minute or greater received the standard dose of 25 mg per day.

Twelve participants (24 percent) had impaired kidney function at the start of the study. Patients with moderate kidney impairment (30 mL/minute to <50 mL/minute) received 10 mg of Revlimid per day. The three patients with severe kidney impairment (<30 mL/minute) who were not on dialysis received 15 mg every other day, and one patient on dialysis was given 15 mg three times a week.

Among the 50 participants, 16 (32 percent) achieved partial response, seven (14 percent) reached very good partial response, and seven (14 percent) complete response, for an overall response rate of 60 percent. There was no difference in overall response between patients with normal kidney function and patients with impaired kidney function (60.5 percent versus 58 percent).

Patients experienced remission for a median of 9 months and overall survival for a median of 16 months. Impaired kidney function did not result in any difference in progression-free and overall survival.

The most common side effects included a reduced white blood cell count (28 percent), fatigue (16 percent), infection (14 percent), a reduced platelet count (1o percent), diarrhea (2 percent) and blood clots in the body’s deep veins (2 percent). Once again, having reduced kidney function did not increase the occurrence of side effects.

Among the 12 patients with impaired kidney function, three achieved complete kidney response, defined as an increase in creatine clearance to 60 mL/minute or greater. Two experienced minor kidney response, defined as a 15 mL/minute to <30 mL/minute increase in the creatinine clearance of someone who has severe kidney impairment.

Researchers concluded that adjusting Revlimid dosage according to kidney function results in the same rate of response and does not negatively impact progression-free and overall survival or rate of side effects. Furthermore in some cases, the Revlimid-dexamethasone therapy improved kidney function. They recommended further studies examining RD therapy’s effectiveness in patients with severe kidney function and as an agent for improving kidney function.

For more information, please see the European Journal of Haematology (abstract).

Researchers also discovered that prior treatment with thalidomide (Thalomid) was associated with a decreased progression-free and overall survival.

Multiple myeloma patients with the chromosomal abnormalities del(13), t(4;14) or del(17p) are associated with a poorer prognosis in response to traditional chemotherapy. However, new drug and treatment options have the potential to overcome this poor prognosis. In particular, the relatively new combination of Revlimid and dexamethasone (RD) has proven highly effective in treating patients with relapsed or refractory myeloma.

Studies examining whether the RD combination can overcome the disadvantages associated with genetic risk factors like del(13), t(4;14), and del(17p) have given mixed results. In this retrospective study, researchers evaluated the impact of genetic risk factors and prior treatment on patient outcome in response to the RD combination therapy.

Researcher collected the medical records of 207 relapsed and refractory myeloma patients who had been treated with Revlimid and dexamethasone. Patients received a median of five 28-day cycles of Revlimid (25 mg/day on days 1 to 21) and dexamethasone (40 mg/day on days 1 to 4, 9 to 12, and 17 to 20 during cycles 1 to 4; days 1 to 4 from cycle 5 on).

Prior to Revlimid-dexamethasone therapy, patients had undergone a median of three treatments with drugs such as Velcade (bortezomib), thalidomide, or high-dose melphalan (Alkeran). Researchers also determined how many patients had genetic risk factors. Out of 191 patients tested for del(13), 41 percent had the abnormality. Out of the 184 patients tested for t(4;14), 14 percent had the abnormality, and seven percent of the 120 patients tested for del(17p) had the abnormality.

The overall response rate (ORR), defined as the rate of people achieving partial response or better, was 59 percent. Fourteen percent of patients reached very good partial response and seven percent showed a complete response. The median remission duration was 9.6 months, and the median overall survival was 15.1 months.

In patients with del(13), the overall response rate was significantly lower in comparison to patients without the risk factor (43 percent versus 71 percent). Median progression-free and overall survival were also significantly shorter (PFS: 5.0 months versus 12.5 months; OS: 10.4 months versus 17.4 months).

The same pattern was observed in patients with t(4;14). Patients with t(4;14) experienced a 39 percent overall response rate, a 5.5-month remission duration, and a 9.4-month overall survival’ whereas patients without t(4;14) had a 62-percent ORR, a 10.6-month PFS, and a 15.4-month OS.

There were too few del(17p) patients to perform a meaningful statistical analysis.

In terms of treatment history, patients who had previously been treated with Velcade had significantly lower overall response rates to the RD combination than those who had not (55.4 percent versus 74.3 percent). They also experienced shorter median progression-free survival (8.3 months) and overall survival time (12.2 months). In patients who had no prior Velcade history, median progression-free and overall survival periods had not been reached yet.

While no difference was observed between patients with thalidomide history and those without, researchers discovered that patients who had progressed after thalidomide treatment had a shorter progression-free and overall survival than those who had not progressed (PFS: 5.7 months versus 15.7 months; OS: 9.7 months versus 16.1 months).

The researchers determined that the del(13) abnormality could be used to predict overall response and remission duration, with the presence of del(13) correlating with lower response rates and shorter progression-free survival. The number of prior therapies a patient had undergone also proved to be a predictor of overall response rate, with more prior therapies correlating with lower response rates. They added that progression during thalidomide therapy may be a predictor of a shortened overall survival and reduced response duration.

For more information, please see the journal Leukemia (abstract).

To highlight the most important of these studies, the Myeloma Beacon surveyed leading physicians and researchers in the field. These physicians and researchers were asked to name the three peer reviewed journal articles published in 2009 and the three conference abstracts from 2009 that have the most important findings or implications relating to multiple myeloma.

The top three journal articles and conference abstracts that they chose are presented below.

Journal Articles

1: Pomalidomide Shows Remarkable Activity In Myeloma

According to the physicians surveyed, the most important study published in 2009 evaluated a combination of pomalidomide (Actimid, CC-4047) and low-dose dexamethasone (Decadron) in relapsed and refractory myeloma patients. In the study, 63 percent of patients, many of whom had been resistant to thalidomide (Thalomid), Revlimid (lenalidomide), and Velcade (bortezomib), responded favorably to the treatment.

The study confirmed earlier results indicating that pomalidomide is the most potent drug of its kind, a class of molecules, known as immunomodulatory agents, that includes thalidomide and Revlimid.

For more information, please see the Journal of Clinical Oncology (abstract) and the related Beacon news article.

2: MGUS Always Precedes Multiple Myeloma

In second place, a prospective study analyzed the blood samples taken from myeloma patients before their diagnosis. Researchers learned that in nearly every case, the patients had monoclonal gammopathy of undetermined significance (MGUS), a blood disorder present in three percent of Americans over the age of 50.

According to Dr. S. Vincent Rajkumar, a professor of medicine at the Rochester, Minnesota, Mayo Clinic and an author on the paper, the study’s findings settle a long-standing debate on whether MGUS is a consistent predecessor to myeloma. Researchers can now focus on identifying factors that increase the risk of MGUS progression.

“By studying mechanisms that are associated with progression, we will [ultimately] be able to develop earlier therapies that can be used to delay or prevent myeloma from happening,” wrote Dr. Ola Landgren, an investigator at the National Cancer Institute and lead author of the study, in an email to the Beacon.

For more information, see the journal Blood (abstract) and the related Beacon news article.

3: Maintenance Therapy After Transplantation Prolongs Life Expectancy

In a tie for third place is a study evaluating the post-transplantation benefits of either prednisone or a combination of prednisone and thalidomide, for patients treated with thalidomide and an autologous stem cell transplant. Patients in the combination therapy group experienced a longer remission duration and overall survival.

For more information, see the Journal of Clinical Oncology (abstract) and the related Beacon news article.

3: Very Good Partial Response Is A Good Indicator of Long-Term Outcome

The other third place study examined how patient response to treatment was associated with event-free and overall survival. Researchers followed up with patients who had undergone an autologous stem cell transplant for a median of 67 months. They discovered that patients who achieved very good partial response or better had significantly longer event-free and overall survival.

Based on their results, researchers recommended that very good partial response should become the standard treatment goal for patients since it is more attainable than complete response, yet offers similar benefits in event-free and overall survival.

For more information, see the Journal of Clinical Oncology (abstract) and the related Beacon news article.

Conference Abstracts

1: Velcade Treatment Options In Elderly Patients With Newly Diagnosed Myeloma

The surveyed physicians voted as most important a study presented at the American Society of Hematology (ASH) conference in early December in which researchers compared an induction therapy combination of Velcade, thalidomide and prednisone (VTP) with the already-popular regimen of Velcade, melphalan (Alkeran), and prednisone (VMP) in newly diagnosed elderly patients. Both treatments proved to be equally and highly effective.

Researchers also compared maintenance therapies of Velcade-thalidomide (VT) and Velcade-prednisone (VP), both of which improved patient responsiveness to the point of overcoming negative genetic risk factors.

For more information, please see ASH abstract 3 and the corresponding Beacon news article.

2: Revlimid Treatment Options In Elderly Patients With Newly Diagnosed Myeloma

For second place, the surveyed physicians chose a Phase 3 trial presented at the ASH conference that investigated Revlimid’s effectiveness as both an induction and maintenance therapy. Patients treated with a combination of melphalan, prednisone, and Revlimid followed by Revlimid maintenance had a decreased risk of disease progression than patients treated with melphalan and prednisone followed by a placebo.

Final results of the study are expected at the American Society of Clinical Oncology meeting later this year. The study’s findings offer substantial support for Celgene as it applies for FDA approval of Revlimid as a first-line treatment option in multiple myeloma.

For more information, please see ASH abstract 613 and the corresponding Beacon news article.

3: VMPT Effectively Treats Elderly Patients With Newly-Diagnosed Myeloma

In a tie for third place, another ASH conference study investigated the impact of adding thalidomide to the standard regimen of Velcade, melphalan, and prednisone (VMP). Patients treated with VMPT had a greater response rate than those treated with VMP, but they also encountered more blood-related side effects.

“VMPT represents the next generation,” wrote Dr. Antonio Palumbo, chief of the myeloma unit at the University of Torino in Italy and lead author of the study, in an email to the Beacon. “[The four drugs] improve response and progression-free survival with a higher toxicity, but this is [still] the first schema that is superior to VMP.”

For more information, please see ASH abstract 128 and the corresponding Beacon news article.

3: Elotuzumab Combination Produces Encouraging Results In Multiple Myeloma

Also tied for third place is another ASH presentation that provided positive results about the effectiveness of elotuzumab in combination with Revlimid and low-dose dexamethasone at treating multiple myeloma. The combination therapy led to a 92 percent response rate from patients, with manageable side effects.

A new antibody, elotuzumab targets proteins that are unique to myeloma cells and causes the cells to die.

“This is an important study because it represents the first evidence that an antibody can have efficacy in myeloma, and it confirms the suggestion that Revlimid enhances immunity and thus enhances the efficacy of an immune-mediated agent like elotuzomab,” wrote Dr. Sagar Lonial, an associate professor at Emory University’s School of Medicine and lead author of this study, in an email to the Beacon.

A multinational continuation of the trial is currently recruiting patients. For more information, please see the clinical trial description, ASH abstract 432, and the corresponding Beacon news article.

The Myeloma Beacon would like to thank the physicians who participated in the survey for their assistance and expertise:

S. Vincent Rajkumar, M.D.
Mayo Clinic, Rochester, MN

Sundar Jagannath, M.D.
St. Vincent’s Comprehensive Cancer Center, New York, NY

Sagar Lonial, M.D.
Winship Cancer Institute
Emory University School of Medicine, Atlanta, GA

Antonio Palumbo, M.D.
University of Torino, Italy

Jesus F. San Miguel, M.D.
University of Salamanca, Spain

“Very good partial response” is one of the terms defined by the International Myeloma Working Group (IMWG) to categorize how patients respond to treatment. According to IMWG criteria (see related Beacon news), patients reach very good partial response when the level of abnormal “M” proteins in their blood decreases by 90 percent.

Previous studies evaluating high-dose chemotherapy have shown that major tumor reduction as indicated by at least very good partial response is associated with increased progression-free and overall survival. In this study, researchers further examined the relationship between very good partial response and long-term prognosis.

Researchers analyzed the data of patients who participated in the 1999 trials conducted by Intergroupe Francophone du Myelome (IFM 99-02 and 00-04). In both trials, patients received a combination induction therapy of vincristine (Oncovin), doxorubicin (Adriamycin), and dexamethasone (Decadron), known as VAD.

Of the 680 patients evaluated for response to induction, 27 (4 percent) achieved complete response, 81 (12 percent) reached very good partial response, 337 (50 percent) achieved partial response, and 235 (34 percent) experienced less than partial response.

Next, patients underwent double autologous stem cell transplants, in which their own previously-collected stem cells were transplanted back into their bloodstream. Of the 802 patients included in the analysis, 445 (55 percent) achieved at least very good partial response, 288 (36 percent) reached partial response, and 69 (9 percent) experienced either stable disease or disease progression. The median follow-up time was 67 months.

Researchers observed that event-free survival – the time passed without disease progression, relapse, or death – was significantly longer in patients who had very good partial response or better than in those who achieved partial response (42 months versus 32 months, respectively). This translated into a five-year event-free survival rate of 34 percent in VGPR-or-better patients versus 26 percent in patients with partial response. Patients with very good partial response also experienced significantly greater five-year overall survival rate (74 percent versus 61 percent).

Researchers determined that as a single factor, partial response or less is an indicator of a shorter event-free and overall survival. Based on their results, researchers concluded that achieving very good partial response should serve as a major treatment goal for patients and their physicians – not only does it correlate with better short- and long-term event-free and overall survival, but it also encapsulates a larger population of patients than complete response.

For more information, please see the Journal of Clinical Oncology (abstract).

Currently, the standard treatment plan involving stem cell transplantation begins with induction therapy, which decreases the number of abnormal cells and proteins in a patient’s bone marrow before collection of stem cells for the transplant. Next, patients undergo high-dose chemotherapy and transplantation, after which, some patients receive consolidation or maintenance therapy.

Past studies have shown that regardless of how well a patient responds to induction, the transplant can still be performed and leads to the same remission duration. As a result, some researchers have questioned the need for induction therapy at all. However, those studies were conducted before new drugs were available as treatment options. Patient response rates have increased dramatically with Revlimid and thalidomide induction.

In this retrospective study, researchers evaluated the effectiveness of induction with Revlimid and thalidomide by examining patients’ progression-free and overall survival post-transplant.

Researchers looked back at the data of 286 patients diagnosed with multiple myeloma between 1998 and 2008 who had received either Revlimid or thalidomide-based induction prior to single or double autologous stem cell transplants, in which their own stem cells were collected before high-dose chemotherapy and then transplanted back afterward. Patients did not receive any consolidation or maintenance therapy.

Patients were grouped into three categories. The 232 patients (81 percent) who reached partial response after induction were placed in the “responsive” group. The 25 (9 percent) patients who initially responded, but then had disease progression, were known as “relapsed,” and the 29 patients (10 percent) who did not reach partial response were known as the “refractory” group.

Responsive patients had a significantly longer median progression-free survival after transplant than refractory or relapsed patients (22.1 months, 15.2 months, and 12.0 months, respectively). They also had a longer median overall survival than relapsed-refractory patients (73.5 months versus 30.4 months).

Post-transplant, 50 percent of responsive patients achieved at least a very good partial response (VGPR) in comparison to 22 percent of relapsed-refractory patients. Researchers observed that patients who achieved a very good partial response post-transplant had the same remission duration, regardless of how they responded to induction.

Researchers concluded that as induction therapies improve, patients who do not respond to induction therapy are also less likely to respond to stem cell transplant. However, they could not decisively state that transplants should not be performed in this patient group, since their study did not compare the results of transplant versus alternative treatment plans.

They also speculated that the biochemical activity responsible for a patient’s unresponsiveness to Revlimid or thalidomide induction may also contribute to their rapid disease progression after transplantation.

For more information, please see the journal Blood (abstract).

“[Revlimid] as maintenance has been evaluated in three independent randomized clinical trials. Results from each of these trials show improvements in time-to-progression,” the NCCN myeloma guidelines state. “The panel felt that this warranted inclusion; however, this recommendation remains Category 2A since these results have not undergone full peer review and safety/efficacy data are still preliminary.”

Recommendations labeled Category 2A are not as well supported by research as those in Category 1. However like Category 1 recommendations, they receive near unanimous approval from the panel, which in this case, consisted of 23 doctors from various institutions.

Currently, Revlimid is only approved by the United States Food and Drug Administration (FDA) in combination with dexamethasone (Decadron) as a second-line treatment. However, many academic medical centers use Revlimid for additional types of myeloma treatment.

“[The Mayo Clinic] has already been recommending maintenance therapy with [Revlimid] for certain patients for over a year, namely those who have failed to achieve a very good partial response after transplant and for those patients who have high-risk cytogenetic features,” wrote Dr. S. Vincent Rajkumar, a Professor of Medicine at the Mayo Clinic, in and email to The Myeloma Beacon.

Medicare uses NCCN guidelines, as well as several other sets of guidelines, to determine whether to pay for treatments if they are used differently than their FDA-approved use. Physicians can also refer to these guidelines when deciding among treatment options for patients.

“The NCCN recommendation may make more patients consider maintenance,” said Dr. Rajkumar.

Based on the preliminary results of MM-015 and other studies, Revlimid’s manufacturer, Celgene Corporation, plans to file for FDA approval of the drug as both an induction therapy in newly diagnosed myeloma and as a maintenance therapy after transplantation sometime this year (see related Beacon news).

Updated data from all three supporting trials are expected to be presented at the American Society of Clinical Oncology meeting in June of this year.

Despite the new NCCN guidelines, Dr. Rajkumar expressed some reservations about expanding the Mayo Clinic’s use of Revlimid maintenance therapy. “The evidence so far with Revlimid is still not definitive. We don’t have [evidence of overall survival benefit] for Revlimid as a maintenance therapy following transplant, so I am reluctant to recommend Revlimid maintenance based on evidence of progression free survival improvement alone.”

For more information, see the NCCN guidelines for multiple myeloma (free registration required) and related Beacon articles about the studies supporting Revlimid maintenance (MM-015, CALGB 100104, and IFM 2005-02).

Myeloma cells accelerate processes that degrade bone, resulting in bone lesions and fractures. Spinal fractures, in particular, are a common complication associated with multiple myeloma and can leave patients unable to walk. Treatment options include radiation therapy, medication, and a minimally invasive procedure called vertebroplasty (for further description, see related Beacon article).

In the study, researchers looked back at the recovery data of 11 patients, all of whom had undergone at least one vertebroplasty procedure at the Instituto Clinico Humanitas, a medical institution in Italy, over a two-year period. Three patients received an additional vertebroplasty later on, bringing the total number of procedures performed to 14. Doctors examined the procedure’s effectiveness and safety.

Despite the aid of medication and bed rest, all 11 patients still experienced pain and on a scale of 1 to 10, ranked their pain at an average value of 7 prior to surgery. After surgery, patient pain decreased to an average value of 2.

After 11 of the 14 procedures (79 percent), patients experienced pain relief almost immediately. The other three procedures (21 percent) required 24 to 36 hours for pain relief to occur. In all instances, patients were discharged two days after the treatment.

Of the eight patients who initially needed orthopedic devices to walk, five patients (63 percent) no longer required the aids two weeks after treatment. Two of the three patients who needed walking aids after surgery had initially been wheelchair-bound.

Pain relief remained consistent over follow-up periods ranging from 1 day to 25 months. However, three patients developed fractures at a new site in the spine and required a second vertebroplasty. In three procedures (21 percent), the bone cement leaked into nearby spaces in the spinal column, but the leaks were noted and repaired during surgery.

Leakage is the most common complication of vertebroplasty and can have serious implications if the cement travels into the spinal canal, home to the spinal cord. However, the risk of such a complication ranges from one to three percent.

Because patients experienced rapid and sustained pain relief and many no longer needed walking devices or medication, researchers described the study results as “excellent.” They concluded that vertebroplasty is an effective procedure in treating spinal fractures because it is relatively non-invasive, relieves pain rapidly, and has a low rate of complication. They also speculated that the surgery may be used to prevent vertebrae fractures in the future.

For more information, please see the journal Neurological Sciences (abstract).

Carfilzomib Phase 3 Clinical Trial Design Is Approved – Onyx Pharmaceuticals, Inc. announced that it has reached an agreement with the Food and Drug Administration on the design and analysis of a Phase 3 clinical trial evaluating carfilzomib in relapsed myeloma. The study follows up a Phase 1B trial that examined carfilzomib in combination with Revlimid (lenalidomide) and dexamethasone (Decadron) (see related Beacon news). The Phase 3 trial is expected to begin in early to mid 2010, and the Phase 1b/2 study of this combination regimen is still recruiting participants. For more information, please see the Onyx press release.

Cancer Vaccine Produces Positive Results In Multiple Myeloma Patient – Results from a study evaluating the effects of a high dose cancer vaccine in patients with multiple myeloma, myelodysplastic syndromes, and acute myeloid leukemia showed positive immune responses in several patients. The vaccine helps the immune system kill cancer cells by building up antibodies to a protein called RHAMM, which is associated with cancer progression. In one of the three myeloma patients, the vaccine led to a decrease of the patient’s free light chains, from 10.3 mg/L to 2.26 mg/L. Side effects were limited to mild redness and infection of the skin. For more information, please see the journal Haematologica (pdf).

Description:
Defibrotide is an anticoagulant (a drug that prevents blood clotting) that may make myeloma cells more susceptible to chemotherapy. It is not an anti-tumor drug and only has a significant effect on myeloma when combined with cancer-fighting drugs.  Defibrotide may decrease blood clotting and nerve damage caused by certain myeloma treatments. In combination with granulocyte colony-stimulating factor (G-CSF), defibrotide has been shown to significantly increase stem cell production. Defibrotide has also demonstrated an ability to treat hepatic veno-occulusive disease (VOD), a life-threatening complication of stem cell transplantation that is marked by blocked veins in the liver.

Clinical Trials:
For a list of clinical trials studying defibrotide for the treatment of multiple myeloma, see ClinicalTrials.gov.

Web site for defibrotide: http://www.gentium.it/Defibrotide.aspx

With the development of multiple myeloma therapies, the traditional melphalan-prednisone (MP) treatment regimen has been combined with substances such as Velcade (bortezomib) and thalidomide for more effective results. In particular, clinical trials have shown that these new combination treatments produce greater responses in patients than the traditional MP treatment regimen.

However, the presence of side effects, in particular clotting in the veins, also known as deep-vein thrombosis, and nerve damage in the limbs, also known as peripheral neuropathy, leaves room for improvement in these treatment options.

Defibrotide, an anti-clotting compound, has been shown to sensitize myeloma cells to chemotherapy in in vitro studies when combined with cancer-fighting drugs. In vitro studies are studies performed in controlled environments like test tubes or Petri dishes.

In this Phase 1 trial, researchers attempted to determine the dosage limit of defibrotide in combination with melphalan, prednisone and thalidomide while also evaluating the regimen’s effectiveness and toxicity.

The researchers recruited 24 patients with relapsed or refractory myeloma for their study. As initial treatment, patients received six 35-day cycles of melphalan (0.25 mg/kg on days 1 to 4), prednisone (1.5 mg/kg on days 1 to 4), thalidomide (50 to 100 mg on days 1 to 35), and any of three doses of defibrotide given either orally or intravenously (IV). Patients were then given 1.2 g/day of defibrotide orally and 50 mg/day of thalidomide as maintenance therapy until disease progression or excessive toxicity.

Forty-three percent of patients achieved partial response and nine percent experienced very good partial response or complete response, adding up to an overall response rate of 52 percent. The median progression free survival was 10 months, and at one year, 34 percent of patients remained progression-free. The overall survival rate after one year was 90 percent.

The most common side effects observed in patients included reduced white blood cell count (61 percent), reduced platelet count (39 percent), and fatigue (8 percent). Numerous participants required blood transfusions and the added support of granulocyte-colony stimulating factor (G-CSF), which stimulates stem cell production. One patient (4 percent) experienced clotting in the veins.

The researchers noted that there were no severe cases of peripheral neuropathy, a side effect that, like deep vein thrombosis, is commonly observed with thalidomide.

They did not observe any dose-limiting side effects. The highest dose of defibrotide administered during the trial (7.2 g/day orally on days 1 to 4 followed by 4.8 mg/day on days 5 to 35) was therefore defined as the maximum tolerated dose.

The study authors expressed enthusiasm about the significantly low rate of deep vein thrombosis and peripheral neuropathy attributable to defibrotide. They recommend further investigation of the drug, particularly in combination with thalidomide, Revlimid (lenalidomide), and pomalidomide.

For more information, please see the journal Haematologica (abstract).

“To get a cancer diagnosis when it seems like you’re doing everything right – you don’t smoke, you drink modestly, you exercise – it was quite shocking. But I don’t think it took more than a week or two for me to actually start realizing that we’re going to move beyond this, there’s a purpose in this, and we just have to figure out what it is.”

He and his wife Cassie began their research. They got advice from a friend in medical school and began searching for information online. “The blogs are phenomenal because you get the personal story, and it’s so much easier to connect with their words than with the oncologist. The oncologist will start talking, and all you hear is ‘wah wah wah.’”

The couple started their own blog called “Multiple Myeloma For Dummies” as a way of sharing the information they were learning about myeloma with their friends and family. “We felt like we didn’t know anything about multiple myeloma, so we started MM For Dummies to educate our family and friends. We knew it was a long journey, and we knew that as we were learning, we had to pass that information on to family and friends so that they could be comforted and feel like they were in the know.”

Brabbs considers himself fortunate that he did not require treatment until 15 months after his diagnosis, giving him and his wife time to learn about multiple myeloma, get a second medical opinion, seek advice from others living with myeloma, and reach out to helpful medical staff.

“I didn’t know about multiple myeloma before my diagnosis – like everyone else in the world. The health care system can be pretty intimidating, especially when you’re talking cancer because you expect your oncologist to know everything. [However,] I recommend people educate themselves on what’s out there.”

Because of Brabbs’s young age, he agreed with his oncologist that the five-year survival rate associated with myeloma was “just not good enough” and decided to pursue an aggressive line of treatment. His philosophy is to “dominate life and to grab it by the horns,” and he plans to do the same with his myeloma.

Brabbs is currently participating in a clinical trial at the University of Michigan that is combining Revlimid (lenalidomide), Velcade (bortezomib), dexamethasone (Decadron), and Doxil (doxorubicin liposomal). He recently completed his fifth round of chemotherapy and has achieved a good partial response. In round six, he hopes to reach a very good partial response before proceeding with the first of two stem cell transplants.

During recovery from his first stem cell transplant, which is due to take place in February or March, Brabbs hopes to begin a nonprofit program, Cancer Kicker, to raise awareness of and research funds for multiple myeloma.

Brabbs currently lives in Ann Arbor, Michigan, with his wife, two small children, and a baby girl on the way. He believes that living with cancer has enabled him to put things in perspective. “I think a lot of people are stressed out at their job, in their marriage, and with their kids. Cancer is a burden that is so much bigger than all that stuff that you’re actually able to drop everything and say, ‘I need to get perspective because if I’m gone tomorrow, am I going to be satisfied that I was yelling at my kids today or in a job that I don’t like?’ Cancer has allowed me to step back and have grace for myself and hopefully more grace for others as well.”

Based on his domination over myeloma, Brabbs has plenty of good advice for other myeloma patients. “I encourage them to be involved in the health care process. Don’t just take drugs because that’s what the doctor is saying. Understand, if you have the capacity, what’s going on, what the drugs are trying to do, what a transplant is, and what a tandem [transplant] could do.”

He also passed along advice that he found especially helpful from a gentleman in remission: “Be real with your emotions. When you’re sad, be sad. When you’re angry, be angry. When you’re furious, be furious. When you’re happy, be happy. When you want to laugh, laugh. Whatever you’re feeling, it’s okay. Especially when you’re newly diagnosed, there are so many thoughts and emotions running through your body that it’s hard to control. So don’t. Let it go.”

Brabbs also stressed the importance of combating physical sickness with mental and emotional health by leaning on a “support staff – whether it’s your faith, your family, your friends, or a combination of those.”

And “Keep dominating!”

For more information about Phil, please visit the Brabbs’ blog “Multiple Myeloma For Dummies.”

In mid-January, Celgene further announced that, based on an interim analysis reviewed by an independent committee, the Phase 3 trial has met an additional primary endpoint. Patients on Revlimid showed better progression-free survival than patients on a placebo. Final results will be presented at a major medical meeting later this year.

In recent years high-dose chemotherapy followed by an ASCT has become a standard treatment option for younger patients with newly diagnosed multiple myeloma. The patients receive high-dose chemotherapy which destroys both the myeloma cells and healthy stem cells. After chemotherapy, the patients receive an autologous stem cell transplant, in which the patients’ own stem cells that were collected before high-dose chemotherapy are transplanted back into the patients. In tandem transplantation, the entire process is repeated twice.

While high-dose chemotherapy followed by stem cell transplantation extends survival and improves response rate, many patients eventually relapse; thus, scientists are looking for new strategies to control the disease.

Post-transplant therapies, such as thalidomide (Thalomid) plus prednisone, have shown to increase both response rate and survival time; however, side effects, such as nerve damage in the limbs, were a major limitation of the thalidomide plus prednisone regimen. Because of its similarities to thalidomide, researchers decided Revlimid might offer the same benefits as a post-transplant therapy without the side effects associated with the thalidomide plus prednisone therapy.

For their study, researchers recruited 614 patients who had undergone an ASCT within the previous six months and treated all of them with two months of Revlimid (25 mg/day for 21 days each month), referred to as consolidation therapy, followed by either a lower dose Revlimid (10 to 15 mg/day) or a placebo, referred to as maintenance therapy, until relapse.

The researchers compared patient response rates before and after consolidation therapy. Of the 614 patients participating, 435 (80 percent) were able to receive the consolidation therapy at the dosage and schedule planned. Data for 412 patients were available for analysis.

Before receiving Revlimid consolidation therapy, 104 patients (25 percent) had achieved partial response; 206 (50 percent) achieved very good partial response; 90 (22 percent) achieved complete response; and nine (2.2 percent) achieved stringent complete response. Three participants (0.7 percent) remained stable.

Sixty patients (15 percent) improved their response after consolidation therapy. Eight patients (2 percent) advanced to stringent complete response, 33 (8.2 percent) to complete response, and 18 (4.5 percent) to very good complete response. The nine patients who had already reached stringent complete response before consolidation were not included in the post-consolidation analysis since they could not improve their response any further.

Seventy-four patients (12 percent) experienced severe side effects, such as blood disorders, allergic reactions, infections, fatigue, and clotting in the veins.

Researchers concluded that Revlimid can be administered as consolidation therapy for two cycles at the dose tested and that it significantly improves the rate of complete response or better.

For more information, please see abstract 529 at the ASH meeting Web site, the Celgene press release, and the clinical trial description.

Based on the significant difference in progression-free survival between the two treatment groups, the researchers concluded that high-dose (200 mg/m²) melphalan is more effective in preparing younger, medically fit multiple myeloma patients for stem cell transplants. However, reduced-intensity (100 mg/m²) melphalan may be safer in patients with other health-related complications.

The study investigators recommended further comparison of high- and reduced-intensity melphalan when used in combination with newer agents such as Velcade (bortezomib) or Revlimid (lenalidomide).

Although high-dose melphalan is the most common chemotherapy regimen used to kill residual myeloma cells just before stem cell transplantation, it often causes side effects such as diminished production of blood cells, gastrointestinal problems, and increased risk of infection. In the elderly and those suffering from other serious conditions, these effects are accented and may even be life-threatening.

The results of a prior, retrospective study comparing high-dose and reduced-intensity melphalan suggest that reduced-intensity melphalan may be as effective as high-dose melphalan in treating multiple myeloma while leading to fewer and less severe side effects.

Retrospective studies, which look back at the data of patients already treated, cannot control the execution of the trial and, therefore, may have more sources of bias than prospective studies that select a variable to investigate before treating patients accordingly.

In this prospective Phase 3 study, researchers compared the effectiveness and safety of high-dose and reduced-intensity melphalan regimens in patients with newly diagnosed myeloma.

Doctors randomly assigned 298 patients less than 65 years old to two treatment groups of 149 each, the high intensity group receiving 200 mg/m² melphalan and the reduced-intensity group receiving 100 mg/m² melphalan. Aside from the two different dosages of melphalan, both groups received the same induction treatment – two 28-day cycles of 1 mg/m² vincristine on day 1, 50 mg/m² doxorubin (Adriamycin) on day 1, and 40 mg dexamethasone (Decadron) on days 1 to 4.

Stem cells were collected from the blood stream after one or two cycles of cyclophosphamide and granulocyte colony-stimulating factor (G-CSF), which stimulates stem cell production.

At least one month after stem cell collection and two days before the transplant, patients received a melphalan dose of either 100 mg/m² (reduced intensity) or 200 mg/m² (high intensity).

Patients were given G-CSF to increase their white blood cell counts as well as medications to prevent infection.

The median follow-up time was 44.6 months. Researchers focused primarily on overall survival, and secondarily on progression-free survival and side effects.

Out of the 149 participants who received high-intensity melphalan, 117 (78 percent) achieved at least a partial response, 55 (37 percent) experienced at least a very good partial response, and 22 (15 percent) achieved a complete response. Twenty-seven patients (18 percent) remained stable, and one patient (1 percent) experienced disease progression.

In the reduced-intensity group, 107 patients (72 percent) reached at least a partial response, 32 (21 percent) achieved at least a very good partial response, and 12 (8 percent) achieved a complete response. Thirty-four participants (23 percent) had stable disease, and five (3 percent) progressed.

Overall survival was not significantly different for the two groups. The median overall survival for the reduced-intensity group of patients was 60 months. Based on the number of patients who were still living by the end of the follow-up, researchers could not determine a median overall survival in the high-intensity group. Doctors estimated that at five years, the survival rates would be 62 percent and 48 percent for patients receiving high- and reduced-intensity melphalan, respectively.

Participants in the high-intensity group experienced a significantly greater remission duration than those in the reduced-intensity group (31.4 months versus 26.2 months). The remission duration gap between the two doses was more pronounced in patients under 60 years old.

Patients receiving high-intensity melphalan were more likely to experience at least one serious or life-threatening side effect (45 percent versus 30 percent). Side effects included low white blood cell count (77 percent versus 67 percent), low platelet count (76 percent versus 49 percent), infection (40 percent versus 30 percent), inflammation of the digestive tract (17 percent versus 3 percent), and gastrointestinal problems (11 percent versus 1 percent).

In addition, more patients receiving high-intensity melphalan required platelet transfusions (56 percent versus 38 percent) and antibiotics (41 percent versus 29 percent). In each treatment group, three patients died of complications, including pneumonia, stroke, cardiac failure, brain hemorrhaging, and septic shock.

For more information, please see the study in the journal Blood (abstract) and the clinical trial description (NCT00950768).

While VMP without maintenance therapy currently is one of the standard treatments for elderly patients with newly diagnosed myeloma, the availability of new drugs has motivated researchers to search for more effective, less toxic combination treatments. In another study, also presented at the ASH 2009 conference, the addition of thalidomide to the VMP regimen, followed by maintenance therapy, resulted in greater response rates than VMP (see related Beacon news).

In this Phase 3 study, researchers compared VTP and VMP as induction therapies as well as Velcade-thalidomide (VT) and Velcade-prednisone (VP) as maintenance therapies, evaluating both efficacy and side effects of the combination therapies.

Researchers recruited 260 patients and randomly assigned them to either the VTP or VMP treatment group. In the VMP treatment, patients received 1.3 mg/m² of Velcade on days 1, 4, 8, 11, 22, 25, 29, and 32 of one six-week cycle, and then on days 1, 8, 15, and 22 of five five-week cycles. Melphalan, 9 mg/m² and prednisone, 60 mg/m² were given on days 1-4 of each of the six cycles. In the VTP treatment, patients received Velcade and prednisone at the same dosage and schedule, and 100 mg of thalidomide daily.

Maintenance therapy consisted of a three-month cycle of 1.3 mg/m² Velcade given on days 1, 4, 8, and 11, and either 50 mg of thalidomide daily (VT) or 50 mg of prednisone every other day (VP) for up to three years. Patients were randomly assigned to the two treatment options.

Of the 260 patients, 253 were included in the final analysis – 125 in the VMP group and 128 in the VTP group. Both treatments resulted in similar rates of at least partial response or better – 81 percent in the VMP group and 79 percent in the VTP group. Twenty-two percent of VMP patients and 27 percent of VTP patients achieved complete response, for an average of 25 percent.

Researchers did not observe any significant differences between the VMP and VTP groups in progression-free survival rates (71 percent versus 61 percent) or overall survival rates (81 percent versus 84 percent). In each treatment group, two patients experienced disease progression.

Of the 178 patients who participated in maintenance therapy, 143 were included in the final analysis. The addition of maintenance therapy increased the rate of complete response from 25 percent to 42 percent in both treatment groups. Both VT and VP maintenance resulted in similar overall survival rates after one year (92 percent versus 89 percent, respectively).

Out of 27 patients who exhibited high-risk genetic abnormalities, 26 percent achieved complete response after induction and 42 percent after maintenance. Both response rates were similar to the overall patient response, indicating that the maintenance regimens successfully combated the negative prognosis associated with patients’ genes.

Researchers observed differences in side effects between the two induction therapies. More patients in the VMP group than in the VTP group experienced decreased white blood cell counts, or neutropenia (37 percent versus 21 percent), and infection (7 percent versus <1 percent). However, eight VTP patients (5 percent) experienced serious heart problems not observed in any VMP patients. Nine percent of VTP patients also experienced peripheral neuropathy (nerve damage in the limbs), compared to five percent of VMP patients.

In both maintenance therapies, patients experienced few severe side effects. Two patients in the VT group and one patient in the VP group had severe heart problems, and four patients in the VT group and one patient in the VP group had severe gastrointestinal problems.

Researchers concluded that VMP and VTP work equally well as induction therapies. They added that the addition of VT or VP as maintenance therapies to VMP and VTP offer clear benefits by increasing response without compromising side effects..

For more information, see abstract 3 at the ASH Meeting Web site.

Sagent Pharma Launches Generic Alternative to Aredia – Sagent Pharma announced the launch of a generic alternative to Aredia (pamidronate disodium), a treatment for cancer-related osteoporosis marketed by Novartis Pharma. The injection will come in single-dose vials of 30 mg/10 mL and 90 mg/10 mL. For more information, please see the Sagent Pharma press release.

Terpenoid Therapeutics Raises $950,000 For Myeloma-Related Drug Development – Terpenoid Therapeutics has raised $950,000 of its intended $1.05 million for the development of two cancer drugs, one of which will treat bone disease associated with cancers such as multiple myeloma. Researchers anticipate the drug will cause fewer side effects than current treatment options. For more information, please visit the MedCity News Web site.

Phase 1 Study Of BioInvent’s Drug Candidate BI-505 Treats First Myeloma Patient – BioInvent announced treatment of the first patient with BI-505 in a Phase 1 study evaluating the drug for the treatment of advanced multiple myeloma. The study is recruiting 30 to 40 patients to receive BI-505 intravenously every second week for four weeks or longer. Researchers will evaluate the drug’s safety, activity, and dosage limits. For more information, please see the BioInvent press release and the clinical trial description.

LLS Seminar: Understanding Lab & Radiology Tests – On January 25, the Leukemia & Lymphoma Society (LLS) is holding an informational seminar on how to read and understand medical results, including CT scans, PETs, MRIs, and blood tests. The event will take place at the Katz Cancer Resource Center in Santa Cruz, CA from 11:30 a.m. to 12:30 p.m. For more information or to register, please visit the LLS Web site.

LLS Event: Living With Myeloma – On January 25, the Leukemia & Lymphoma Society (LLS) will host a free program on multiple myeloma from 5 p.m. to 6:30 p.m. at the Moffit Cancer Center in Tampa, FL. Dr. Melissa Alsina will give an overview of myeloma and cover the following topics: the latest in drug therapies, disease and treatment side effects, emotional repercussions and support resources, and clinical trial options. A question and answer session and complimentary dinner will be included. Pre-registration is required. For more information or to register, please visit the LLS Web site.

For a more detailed listing of myeloma related events, please check the Myeloma Beacon Events Calendar.

“Our objective is to make sure that the patients who have a fatal disease, a currently incurable disease, can take medicines that turn this into a chronic treatable disease,” said Celgene’s President and CEO Sol Barer during the announcement. “That is the mission in our hematology-oncology franchise.”

Revlimid is currently only approved to treat multiple myeloma in combination with dexamethasone (Decadron) for previously-treated myeloma patients. Despite the limited approval, Revlimid already has a 30 percent market share as an initial therapy for myeloma patients in the U.S. However, physicians in Europe rarely use Revlimid outside of its approved use.

Preliminary results from the clinical trial MM-015 offer strong support for extending Revlimid use to the treatment of newly diagnosed patients. The study tested the drug as both an induction and a maintenance therapy in elderly patients.

In the study, researchers compared the combination of melphalan (Alkeran) and prednisone followed by a placebo (MP-Pl) with the combination of melphalan, prednisone, and Revlimid followed by Revlimid maintenance (MPR-R). The researchers discovered that MPR-R decreased the risk of disease progression by 50 percent (see related Beacon news).

“The Revlimid arm was so superior the trial was unblinded early,” stated Barer. “We are incorporating the data for this trial into a [Food and Drug Administration] filing in the second half of 2010 for newly diagnosed and continuous treatment.”

In a conversation with The Myeloma Beacon, Celgene spokesperson Greg Geissman could not provide a specific timeline for the application, approval, and implementation of Revlimid as a treatment for newly diagnosed myeloma. Nonetheless, the drug’s approval would give patients and physicians another option when deciding how to begin treatment.

Celgene is also evaluating the drug’s effectiveness in treating smoldering myeloma patients (see related Beacon news) and patients who have undergone a stem cell transplant. Beyond multiple myeloma, Revlimid is already approved for a specific group of patients with myelodysplastic syndromes (disorders of the bone marrow and blood). Celgene has also launched clinical studies evaluating the drug for other myelodysplastic syndromes patients as well as non-Hodgkin’s lymphoma and chronic lymphocytic leukemia patients.

“Our objective is to make sure that Revlimid will become one of the most important hematology products,” said Barer.

The decision to apply for an extended approval in multiple myeloma was announced at JP Morgan’s 28th annual Healthcare Conference, an event that provides companies with the opportunity to present a summary of their activities to investors.

For more information, please see a related Dow Jones article or listen to the Celgene Web cast.

Papain is an enzyme that breaks down proteins. One such protein, called fibrin, makes up the protective layer of cancer cells. Papain degrades fibrin and damages this protective layer, making the cells more susceptible to immune response or chemotherapy. The compound also hinders tumor growth and prevents it from spreading to other parts of the body.

Papaya plants contain high concentrations of papain, not only in the fruit, but also in the stem, leaves, fruit skin, and seeds. The compound has a toxic effect on plant-eating insects, protecting the unripe papaya from the insects. It decreases naturally in concentration as the fruit ripens.

Synthetically, papain is combined with the enzymes trypsin and chymotrypsin in an oral enzyme product called Wobe-Mugos E. Wobe-Mugos E has been used in Europe to bolster chemotherapy since 1977.  Since then, studies have been conducted to verify the treatment efficacy of Wobe-Mugos E in multiple myeloma.

Scientists at the University of Brastislava’s Clinic of Hematology and Transfusion Medicine in the Slovak Republic determined that multiple myeloma patients undergoing chemotherapy achieved a greater remission response if they were supplemented with Wobe-Mugos E for more than six months, compared to patients who were not.

Patients in the Wobe-Mugos E group received two tablets of the oral enzyme daily for one year after starting chemotherapy, then one tablet daily for the remainder of their treatment. Supplementation with Wobe-Mugos E took place for a median of 41 months. Among patients who received Wobe-Mugos E, 97.6 percent achieved complete response, partial response, or disease stability after chemotherapy, compared to 69.7 percent of patients who received a placebo.

In addition, the median survival for Stage 3 patients nearly doubled with Wobe-Mugos E supplementation. The therapy proved safe, causing gastrointestinal symptoms in only 3.6 percent of patients. However, because group assignments were not random, the study’s results may have been influenced. Scientists expressed enthusiasm but recommended further evaluation. The journal Cancer Chemotherapy and Pharmacology (abstract) published their results in June 2001.

Several accounts from cancer survivors suggest that eating papaya offers the same antitumor benefits as synthetic forms of papain. In a book entitled Cancer: The Complete Recovery Guide, author John Chamberlain cites the story of a woman whose friend overcame stomach cancer in six months by juicing the skin of unripe papaya. He provides a recipe that explains how to do so.

In food, papain poses little to no health risk. Medicinal doses are also safe for most adults to consume, although patients may experience throat and stomach irritation. In instances of pregnancy, allergy to kiwi or figs, and blood clotting disorders, papain may pose a health risk and should be avoided. When in contact with the skin, raw papain may cause blistering or irritation.

Dietary supplements containing papain are available on the market. Patients should be advised that the Food and Drug Administration (FDA) does not require the manufacturers of dietary supplements to register their products before they enter the market. However, the FDA does monitor the supplements’ safety once they are on the market. Tips on how to choose supplements are available on the FDA’s Web site.

While little research has been done to illuminate the effects of papain in treating multiple myeloma, the enzyme and the fruit in which it is found offer a promising development in the fight against the disease, and their effects should be further evaluated.

In the meantime, patients should consult their physicians before taking papain supplements or changing their dietary patterns to include papaya fruit or juice.

In the process of treating multiple myeloma, patients often experience a weakening in their immune system which makes them more susceptible to infection. Serious infections can lower a patient’s quality of life, require doctors to reduce treatment to a less toxic but less effective level, and even cause death.

Doctors can treat infection as it occurs or anticipate and prevent it. Prophylaxis refers to any medication used to prevent illness from developing as opposed to fighting it once it has arisen.

In their analysis, researchers examined how effective antibacterial prophylaxes were in preventing infection in patients on various thalidomide combination regimens.

The researchers analyzed the data of 224 patients, 168 of whom received medication to prevent infections. Patients received any one of the following five thalidomide combination regimens: thalidomide, dexamethasone (Decadron), and Doxil (pegylated liposomal doxorubicin); thalidomide, dexamethasone, and Doxil plus Velcade (bortezomib); thalidomide and dexamethasone; thalidomide and dexamethasone plus Velcade; or a combination of Velcade, melphalan, prednisone, and thalidomide. Participants ranged in age from 31 to 90, with a median age of 70.

Of the 224 patients, 86 (38.5 percent) developed infection, and 39 (17.5 percent) experienced severe infections. Severe infections included pneumonia (59 percent), unidentifiable fevers (23 percent), bacteria in the blood (15 percent), and swelling of eye tissue (3 percent). One patient with bacteria in the blood died of septic shock.

Out of the 168 patients given prophylaxis, 15 percent developed infection. In contrast, 25 percent of the 56 patients not given preventative medication experienced infection.

Upon analysis of the patient data, researchers pinpointed factors that were associated with an increased risk of severe infection. These factors included having an increased monoclonal protein (M protein) count (> 2 g/mL of blood) and a decreased platelet count (< 130 cells/mL). Patients with neither of these factors were at a 4 percent chance of developing severe infection. Patients with one factor faced a 17 percent risk, and patients with both factors had a 32 percent chance of acquiring severe infection. Factors that did not affect risk of infection included type and stage of multiple myeloma; haemoglobin, albumin, and other protein levels; and prior experience with stem cell transplantation.

Patients who experienced severe infection were more likely to suffer from deep vein thrombosis, or blood clotting in the deep veins of the body.

Researchers concluded that antibacterial prophylaxis did not completely prevent the risk of developing infection, but antibiotic treatment could be used to fight infection once it occurred. They also recommended that patients with the two identified risk factors be treated with antimicrobial prophylaxes, which fight not only bacteria, but also fungi and viruses.

For more information, please see abstract 2828 at the ASH Meeting Web site.

Found in marine bacteria, NPI-0052 acts, like Velcade, as a proteasome inhibitor. Both compounds prevent enzymes in cancer cells that regulate growth from working properly, which eventually leads to cell death. NPI-0052 is structured differently than Velcade and other proteasome inhibitors to date, which changes its effects on the body.

In the study, scientists examined both the activity and toxicity of NPI-0052 at various doses in 27 patients with relapsed or refractory myeloma. Patients received an IV injection of NPI-0052 on days 1, 8 and 15 of a 28-day cycle. Researchers gradually increased the dosage in some participants, with the final range given to patients being 0.025 mg/m² to 0.7 mg/m².

At a dose of 0.7 mg/m², NPI-0052 inhibited 73 percent of a specific type of proteasome activity on day 1 and 99 percent on day 15. In comparison, Velcade is 65 percent effective in inhibiting that proteasome activity. Two patients who had relapsed after Velcade treatment achieved significant reductions in their M-protein levels (71 and nearly 50 percent). Eight other patients who participated in the study between 6 and 15 months arrived at disease stability. Two of them had been resistant to Velcade.

Out of the eight patients treated with 0.7 mg/m², two experienced severe fatigue, loss of balance and changes in mental status which required their doses to be reduced. Other serious side effects included nausea, vomiting, dizziness, and confusion. Patients were given medications to counter those effects.

Side effects associated with Velcade and other myeloma agents such as reduced blood cell count, neuropathy (tingling in the limbs as a result of nerve dysfunction), and clotting in the veins did not occur with NPI-0052.

Another study presented at the ASH conference evaluated NPI-0052 at doses up to 0.9 mg/m² in various forms of cancer. New side effects were observed, including a distorted sense of taste or smell, hallucinations with the eyes closed, and problems with memory, concentration or behavior. Some patients also encountered a reduction in their lymphocytes, a type of white blood cell. Researchers pinpointed the maximum tolerated dosage at 0.7 mg/m².

In both studies, scientists concluded that NPI-0052 shows promise in treating relapsed and refractory multiple myeloma without causing some of the serious effects that accompany standard treatments. Clinical trials evaluating the compound’s effects in other cancers are underway.

For more information, see abstracts 431 and 2693 at ASH Meeting Web site.

Currently, Revlimid is only approved in combination with dexamethasone (Decadron) to treat relapsed multiple myeloma patients, according to the United States Food and Drug Administration. This trial’s findings have the potential to gain Revlimid first-line treatment status, enabling its use in newly diagnosed patients.

In this study, researchers compared a combination regimen of melphalan (Alkeran), prednisone, and Revlimid (a regimen known as MPR) with a regimen of melphalan and prednisone alone (known as MP) in elderly patients with previously untreated myeloma.

The study organizers recruited 459 myeloma patients over the age of 65 years and assigned them to three treatment groups: nine cycles of MPR induction followed by Revlimid alone as maintenance (MPR-R), nine cycles of MPR followed by a placebo (MPR-Pl), and nine cycles of MP followed by a placebo (MP-Pl). All patients took aspirin daily to counter the formation of blood clots in the body’s deep veins, a side effect of Revlimid. Researchers focused primarily on the MPR-R and MP-Pl treatment groups and evaluated the two therapies on progression-free survival.

Interim results of the MM-015 study indicated the MPR-R treatment reduced the risk of disease progression by 50 percent, in comparison to the MP-Pl treatment. However, results from the MPR-Pl treatment group were similar to the MP-Pl treatment group. In both groups, patients lived about 13 months before their disease progressed. In the MPR-R group, in contrast, patients lived considerably longer before disease progression – long enough, in fact, that the study authors are not yet able to calculate the average survival time before disease progression for the group.

These findings suggest that Revlimid works effectively as a maintenance therapy and not as well in early treatment of myeloma. However, financial analysts attribute the MPR-R and MP-Pl similarities to the incomplete nature of the data and anticipate that the final results, to be presented some time next year, will reveal significant differences between induction with Revlimid and without it.

Researchers also evaluated the treatment groups’ response to the therapy and the therapy’s safety. They concluded that MPR-R is a safe and effective therapy that should be “considered a new standard” for treating multiple myeloma in elderly patients.

For more information, see abstract 613 at the ASH Meeting Web site.

The trial compared the Velcade-dexamethasone combination (VD) with a vincristine, doxorubicin (Adriamycin), and dexamethasone combination (VAD). As induction therapies, VD and VAD reduce the number of cancer cells in the body before a patient undergoes high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT).

In previous studies comparing the two treatments, a greater percentage of patients achieved at least very good partial response with VD induction. This trial examined the effects of VD and VAD induction therapies on progression-free survival.

Researchers randomly divided 482 patients into four treatment groups. Two groups of 121 patients each were treated with four 4-week cycles of VAD, one group with and one without dexamethasone, cyclophosphamide (Cytoxan), etoposide (Eposin), and cisplatin (DCEP) consolidation chemotherapy. The other two groups (121 and 119 patients, respectively) were treated with four 3-week cycles of VD, with or without cisplatin.

Researchers also made sure to divide high risk patients evenly among each group. High risk patients were defined as either in Stage 3 or having cytogenetic, or chromosomal, abnormalities such as t(4;14) or del17p. Responses to VD and VAD induction therapies were evaluated before and after HDT-ASCT. Patients who did not achieve at least a very good partial response after the first autologous stem cell transplant could opt to undergo a second HDT-ASCT or an allogeneic stem cell transplant where stem cells are collected from a healthy donor. The median follow-up was 32.2 months.

Patients treated with VD experienced an average progression-free survival of 36 months, while patients treated with VAD averaged 29.7 months. In addition, patients who achieved at least a very good partial response before and after their first HDT-ASCT experienced a longer progression-free survival, regardless of their treatment group. This indicates that reducing the number of cancer cells in the body early in treatment greatly influences progression-free survival.

Additionally, high risk patients in the VD group did not experience a significantly shorter progression-free survival than other VD patients. This indicates that VD induction therapy may counter the poor prognosis associated with Stage 3 multiple myeloma and a genetic profile including t(4;14) or del17p.

For more information, see abstract 353 at the ASH Meeting Web site.

Myeloma cells produce M proteins. Higher levels of M proteins are directly related to increased disease progression and severity.

Torisel, a drug already approved for use in advanced renal cell carcinoma, appears to reduce the amount of M protein in the blood and urine by targeting the myeloma cells that produce them.

While studies have shown that treatment with Torisel alone produces little effect in multiple myeloma patients (see related Beacon article), it seems to have potential in combination with other drugs. In this study, Torisel was combined with Velcade, a drug already approved for the treatment of multiple myeloma.

The study was spearheaded by Dr. Irene M. Ghobrial, M.D., at the Dana-Farber Cancer Institute in Boston. Dr. Ghobrial recruited 27 patients for treatment.

Every 35 days, the patients received four weekly IV infusions of 1.6 mg/m² Velcade and five of 25 mg Torisel.

Nineteen of the 27 patients were evaluated to determine how many achieved at least minor response, which is defined as a greater than 25 percent reduction in M protein levels. The study also examined the side effects of the drug combination.

Fifteen of the 19 patients evaluated (79 percent) achieved at least minor response; one (5 percent) achieved complete remission, three (16 percent) achieved very good partial remission, five (26 percent) achieved partial remission, and five (26 percent) achieved minor remission. For more information regarding the criteria set for each level of remission, please see this related Beacon article.

Two patients (10 percent) remained stable, while two (10 percent) experienced disease progression. One patient died from abnormal heart contractions that were determined to be unrelated to the treatment.

For seven patients (37 percent), doctors reduced the dosage given because of adverse side effects. These included: diarrhea, nausea, anorexia, pneumonia, hyperglycemia (high blood sugar levels), sepsis, gastrointestinal bleeding, and reduction in all blood cell types, especially platelet cells.

Despite the side effects, the study authors expressed excitement over the high response rate to the treatment.

For more details regarding the study, please see abstract 748 at the ASH Meeting Web site.

Despite recent advancement in treatment options, many myeloma patients relapse and experience disease progression. Therefore, the search continues for new alternatives to treat the disease, especially for patients where previous therapy has proved unsuccessful.

Torisel, a drug already approved for use in advanced renal cell carcinoma, shows potential for reducing the number of abnormal myeloma cells in the body by inhibiting the protein mTOR. mTOR is responsible for activating the proteins necessary for cell growth and division.

In multiple myeloma, mTOR’s activity enables myeloma cells to grow, increase in number, and resist normal cell death. By inhibiting mTOR, Torisel would prevent these cells from growing and make them more susceptible to chemotherapy. Myeloma cells produce “M” proteins, so by killing myeloma cells, Torisel would also reduce the amount of “M” protein in the blood and urine.

The study was spearheaded by Dr. Sherif Farag, Director of the Bone Marrow & Stem Cell Transplantation Program and Associate Director for Clinical Research at Indiana University Melvin and Bren Simon Cancer Center.

Sixteen multiple myeloma patients who had all relapsed after at least one treatment were recruited for the study. They received 25 milligrams of Torisel weekly by IV infusion until their disease progressed. Their blood and urine “M” protein levels were monitored every four weeks.

One of the 16 patients (6 percent) achieved partial response, which is defined by the International Myeloma Working Group as a greater than 50 percent reduction in “M” protein levels. Additionally, five patients achieved minor response, a greater than 25 percent reduction.  However, four patients experienced an increase in their “M” protein levels.

“The clinical trial did show some activity, but I think the activity is not as strong as the other modern agents like Revlimid (lenalidomide) and Velcade (bortezomib),” said Dr. Farag. “However, it did provide some understanding of how much activity [Torisel] has in its dosage, side effects, and toxicity and its potential for being used in combination with other drugs.”

Because fewer than 1o percent of the study participants achieved partial or complete response, the trial was not expanded. Eventually, all patients stopped the treatment for various reasons, including disease progression and adverse side effects.

During the trial, doctors reduced the dosage of Torisel given to 11 patients (69 percent) because of adverse side effects. These included fatigue, diarrhea, lung inflammation, and reduced white blood cell and platelet counts.

Doctors concluded that the dosage and treatment regimen of Torisel used in the study proved ineffective in treating multiple myeloma.

They recommend further studies that vary how much and how often Torisel is given. They also recommend combining Torisel with drugs that target myeloma cells through pathways other than mTOR for more effective results.

For more information, please see the study in Leukemia Research (abstract).