High-dose melphalan (Alkeran) is the standard conditioning treatment for multiple myeloma patients who will receive an autologous stem cell transplant. Previous studies have shown that melphalan treatment elicits favorable complete response rates and overall survival. However, the possibility of achieving even better responses was investigated in this study by combining melphalan with other therapeutic agents: Hycamtin (topotecan), which inhibits the replication of DNA in cancer cells, and cyclophosphamide (Cytoxan), which works similarly to melphalan to slow or stop growth of cancer cells.

The study evaluated the safety and efficacy of the Hycamtin-cyclophosphamide-melphalan (HCM) combination in 60 patients with relapsed or refractory multiple myeloma or patients in first remission. HCM was administered intravenously over the course of six days preceding an autologous stem cell transplant.

The overall response rate for the HCM combination was 85 percent: 12 percent of participants achieved complete response, 32 percent very good partial response, and 30 percent partial response. Among the remaining participants, 13 percent had stable disease, and one patient progressed.

Very good partial response and complete response rates were higher in patients who underwent autologous stem cell transplantation within 12 months of their myeloma diagnosis; 68 percent of these patients achieved at least a very good partial response, whereas patients who received stem cell transplants more than 12 months after diagnosis achieved at least a very good partial response rate of 32 percent.

Additionally, very good partial response and complete response rates were higher in patients who achieved at least partial response to HCM therapy before stem cell transplantation. Of those who achieved this preliminary partial response, 63 percent went on to achieve very good partial response or complete response after transplantation. Of those who did not achieve an initial partial response, 31 percent achieved very good partial response or complete response after transplant.

After a median follow-up period of 32 months, the median progression-free survival time was 18.5 months. Five years after the completion of the study, 60 percent of the patients were still alive, and 33 percent were in remission.

Serious blood-related side effects were high, with all patients experiencing low white blood cell counts and low platelet counts. Most other side effects were mild and manageable; the most common were mucositis/stomatitis (inflammation and ulceration of the mouth and digestive tract, 65 percent), nausea (58 percent), and diarrhea (42 percent).

In comparison, past trials have shown that single-agent high-dose melphalan has a complete response rate of 22 to 44 percent, a progression-free survival time of 18 to 30 months, and a median overall survival time of five years, making the HCM combination comparable to, but not an improvement over, melphalan alone.

HCM yielded a lower complete response rate (12 percent) than the standard melphalan regimen, which may be due to a lower melphalan dose used in the combination treatment. Increasing the melphalan dose in HCM could raise the complete response rate, but at the risk of increasing side effects as well.

The side effects of HCM and high-dose melphalan were not directly compared in this study. Dr. Muzaffar Qazilbash of the University of Texas MD Anderson Cancer Center and an investigator of the study explained that side effects were comparable with only a small difference. “Subjectively we felt that the HCM regimen was slightly more toxic in terms of mucositis, diarrhea, and abdominal discomfort than melphalan alone,” said Dr. Qazilbash.

The HCM regimen is also administered over a course of six days, whereas the standard high-dose melphalan treatment is administered over one or two days. Therefore, the HCM treatment would likely be more costly and require longer hospital stays than the standard melphalan treatment.

Aside from complete response rates and treatment times, HCM is comparable to the standard melphalan regimen in terms of overall response rates, progression-free survival rates, and overall survival. However, researchers suggest that a Phase 3 trial directly comparing HCM to high-dose melphalan will be necessary in order to truly determine which treatment regimen is more beneficial.

“Until we can show unequivocal superiority of [HCM] or another regimen, melphalan should remain the standard of care,” suggested Dr. Qazilbash.

For more information, please see the study in Bone Marrow Transplantation (abstract).

These results suggest that adding cyclophosphamide as the fourth drug in the treatment therapy may be just as or more effective than traditional two- and three-drug combinations. The study also determined that 500 mg/m² cyclophosphamide, the highest dose tested, could safely be used in the RVCD drug combination.

Previous studies have shown that three-drug combinations can be very effective, including the Revlimid (lenalidomide)-Velcade (bortezomib)-dexamethasone (Decadron) (RVD) combination as well as cyclophosphamide and dexamethasone in combination with Revlimid or Velcade. In this study, researchers combined all four of the above mentioned drugs in hopes of further advancing combination therapies and responses to them.

Dr. Shaji Kumar of the Mayo Clinic explained, “The concept of four drug regimens was to examine if the natural history of the disease [could be altered] by producing deeper responses.”

The 25 myeloma participants in the study, all of whom were newly diagnosed and previously untreated, received 100, 200, 300, 400 or 500 mg/m² cyclophosphamide once a week along with maximum RVD doses for eight 21-day cycles. Starting with the lowest dose of cyclophosphamide, a couple of patients were enrolled at each dosage level until participants experienced severe side effects.

Of the 25 patients, 96 percent responded to treatment. Twenty percent achieved a stringent complete response, another 20 percent achieved a complete or near complete response, and 28 percent achieved a very good partial response. These responses are just as strong, or in some cases, stronger, than leading three-drug combination treatments.

The median time to the first response was 49 days, and the median time to best response was 95 days.

The time to disease progression, progression free survival, and overall survival rates have not yet been reached.

There was no significant difference in response that could be determined between groups that received different dosages of cyclophosphamide. “It is difficult to make any conclusions regarding differences between the different doses of cyclophosphamide, since only three to six patients were enrolled at each dose level. However, no obvious differences stood out,” explained Dr. Kumar.

In addition to investigating the efficacy of the RVCD regimen, the safety of the therapy was also determined.
Based on tolerability of the highest dose of cyclophosphamide tested, the researchers recommended that 500 mg/m² cyclophosphamide be used when administered with the RVD combination.

Dr. Kumar explained that raising the dose above 500 mg/m² would have made little-to-no difference in response rates at the expense of a higher rate of side events. “Increasing the dose of cyclophosphamide would not have made much impact on the response rate, but certainly could have compromised the doses of other drugs in terms of common toxicities,” Dr. Kumar stated.

Forty percent of study participants experienced at least one serious side effect. The most common severe side effects were low white blood cell counts (24 percent), peripheral neuropathy (pain or tingling in the extremities, 16 percent), low red blood cell counts (12 percent), low platelet counts (12 percent), and back pain (12 percent).

Two patients required dose reductions: One patient experienced fever and low white blood cell counts, requiring a dose reduction while on 400 mg/m² cyclophosphamide. Another patient developed severe herpes zoster and required a dose reduction while on 500 mg/m² cyclophosphamide.

Eight patients left the study due to side effects and personal decisions to decline further treatment. One patient died during the study due to disease progression.

Dr. Kumar concluded, “The response rates did not seem substantially different between the three and four drug regimens. So, at this point, it is hard to say that a four drug regimen is required. However, novel combinations of multiple drugs with different mechanisms of action should continue to be studied in trials.”

The Phase 2 portion of this study will compare RVCD with RVD and Velcade-cyclophosphamide-dexamethasone.

Further research also needs to address whether high response rates from multi-agent drug regimens lead to improved survival rates.

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

According to Dr. Michael Kauffman, Chief Medical Officer of Onyx Pharmaceuticals, the company’s newly released results demonstrate the potential for carfilzomib to significantly improve the outlook for relapsed and refractory multiple myeloma patients.

He cited a recent study conducted by the International Myeloma Working Group indicating that patients similar to those enrolled in this Phase 2 trial generally have an 11 percent chance of responding to further treatment and are predicted to survive for six to ten months.

Onyx Pharmaceuticals may file a new drug application for accelerated approval of carfilzomib by the end of the year.

Carfilzomib is a new drug currently being investigated as a potential multiple myeloma therapy. Similar to Velcade (bortezomib), it is a proteasome inhibitor that prevents the growth and spread of myeloma cells by interrupting their protein-related cellular processes. However, carfilzomib triggers this response by binding to different proteins than those bound by Velcade.

The Phase 2 trial included 266 relapsed and refractory patients who had received a median of five prior therapies. They were treated with 20 mg/m² of carfilzomib during the first treatment cycle. The dose was increased to 27 mg/m² during subsequent treatment cycles, and the maximum number of treatment cycles administered was 12.

Of the 266 study participants, 36 percent showed a minimal response or greater, and 24 percent achieved a partial response or better.

Carfilzomib was well tolerated, and the researchers did not observe any unexpected side effects.  Common side effects associated with carfilzomib include low blood cell counts, fatigue, nausea, shortness of breath, and diarrhea.

The full trial results will be presented at the American Society of Hematology meeting in Orlando in December.

The results of this study echo the positive data from a smaller-scale study presented at the American Society of Clinical Oncology Annual Meeting in early June. In that study, relapsed and refractory myeloma patients, including those who were Velcade-resistant, exhibited positive responses to single-agent carfilzomib treatment (see related Beacon news).

In comparison, results from a small Phase 2 trial showed that 26 percent of heavily pre-treated multiple myeloma patients responded to pomalidomide (Actimid, CC-4047) plus dexamethasone (Decadron), with an additional 28 percent achieving a minor response.  These trials indicated that both carfilzomib and pomalidomide hold promise for the treatment of relapsed and refractory myeloma patients.

Onyx Pharmaceuticals recently launched a Phase 3 trial evaluating the combination of Revlimid (lenalidomide) and low-dose dexamethasone with and without carfilzomib to further investigate carfilzomib’s potential in relapsed and refractory multiple myeloma patients.

For more information, please refer to the Onyx Pharmaceuticals press release.

In August 2008, Phil Brabbs was diagnosed with smoldering myeloma, which most physicians do not treat until symptoms begin and the disease progresses to multiple myeloma. After more than a year of physicians carefully reviewing his blood work, Phil’s smoldering myeloma progressed to multiple myeloma, and his physicians wanted to begin treatment.

Phil’s doctor suggested that he participate in a clinical trial that would test a new combination of myeloma treatments.

“My biggest concern was that I would be part of an unproven treatment that could have negative or dire effects on my health,” said Phil. “I was more concerned about taking the best known treatment for multiple myeloma, rather than signing up for something that was unproven.”

However, Phil’s doctor said that based on early results from the ongoing clinical trial, he recommended that Phil use the clinical trial treatment protocol, regardless of whether Phil qualified for the Phase 1/2 clinical trial at the University of Michigan Cancer Center.

The trial called for treatment with a combination of Revlimid (lenalidomide), Velcade (bortezomib), dexamethasone (Decadron), and Doxil (doxorubicin liposomal).

“Being young, I wanted to take on a treatment that was aggressive and could provide the most positive lasting effects,” said Phil, who is 29 years of age.

Once Phil realized that we would be using this new combination regardless of whether he participated in the clinical trial, the decision to participate was quite easy. Since the chemotherapy drugs were paid for in full as part of the trial, it was as Phil described, “A no brainer.”

In addition, Phil liked that participating in a clinical trial would benefit others as well as himself. “With treatment options for multiple myeloma still very limited, there is an opportunity to be part of the next big advancement of treatment options that could not only positively affect the patient’s outcome but also help all future patients and doctors,” he said.

Despite his initial reservations about participating in a trial, Phil decided that the pros of trying a new treatment outweighed the cons.

Signing up for the trial was quite easy. “It was a very simple process of looking over some documents, meeting with my physician’s assistant and oncologist, and signing the forms.” Additionally, several tests were required for the screening process.

“Most of my treatment is at home, but I do go in twice a week for two weeks, then one week off,” said Phil, conveying the convenience of the treatment. He saw his physician about as often as he did before joining the trial. Phil also explained that his lifestyle was not interrupted by the trial and that it allowed him to receive a new combination treatment that had a positive response.

Overall, Phil is happy with his choice to participate in a clinical trial, “The trial is proving to have a better response rate than previous therapies.”

Since completing the clinical trial protocol, Phil has undergone two autologous stem cell transplants. For each transplant, Phil received high-dose melphalan (Alkeran) chemotherapy to kill off the myeloma cells, and then his own stem cells were transplanted back into his blood steam. The Beacon wishes Phil a smooth recovery from his second transplant, which took place on Wednesday.

For more information about Phil and his clinical trial participation, please read a previous Beacon interview with Phil and visit his blog “Multiple Myeloma for Dummies.” To learn more about clinical trials, please read the previous articles in the series.

Don was diagnosed with multiple myeloma in 2004. At the age of 69 and despite living with a cancer that attacks his bones, Don inspires fellow myeloma patients by running in marathons. He has completed three marathons so far this year, is running in one tomorrow, and plans on participating in three to four more marathons just this year. Additionally, Don maintains a blog in which he shares his myeloma experiences with fellow patients, including details about his participation in a clinical trial.

With progressive stage 1 myeloma, Don decided to participate in a Phase 2 clinical trial at the Mayo Clinic Cancer Center that studied the effects of pomalidomide (Actimid, CC-4047) plus dexamethasone (Decadron) for patients with relapsed or refractory multiple myeloma. His doctor suggested this trial to him because it seemed to be less toxic and possibly more effective than other therapies he had tried, such as Revlimid (lenalidomide), thalidomide (Thalomid), and Velcade (bortezomib).

Despite the main advantage of trying a new therapy (that hopefully works), Don had some concerns about trying a relatively new treatment. In discussing his primary fear about the trial, Don said, “I have an ongoing concern that we may eventually discover a late-developing side effect from pomalidomide.”

Finding a clinical trial was an easy process for Don. The trial was recommended to him by his doctor at the Mayo Clinic who was also the principal investigator for the study. As Don’s myeloma specialist, she was able to recognize and recommend a trial best suited to Don’s needs.

In addition, Don did research about potential treatment options on his own that enabled him to make a more educated choice about his treatments.

“By then, I knew enough about the various treatments to believe in her choice,” said Don. “She gave me a choice between Revlimid and pomalidomide, and I chose pomalidomide.”

Enrolling in the trial was also an easy process. “I had no trouble getting into the trial,” he said. “At that time, eligibility required: at least one prior therapy, ‘measurable’ disease (any of several criteria), and otherwise being healthy enough to participate.”

The transition into the trial was also made smoother by the ease of determining eligibility through tests for myeloma. Myeloma patients are already frequently tested for several blood markers and other symptoms and given X-rays, bone marrow biopsies, and PET scans. Eligibility can be determined by the results of those tests.

Don’s tests confirmed his eligibility and also showed stage 1 bone lesions, which for many patients like Don, are reason enough to seek out new therapies in hope of relief or prevention of further bone damage.

Throughout the trial, Don has been fully aware of exactly what medications he is taking. “It would be hard to conceal it, actually, because I take the little pills every night, and I have the side effects that everyone attributes to pomalidomide and dexamethasone.”

The treatment regimen allows patients to take the pills by themselves, once a day, so Don never needed in-clinic treatment.

Don goes to the Mayo Clinic once a month for testing. He described the routine as follows: “I drive 90 minutes to the Mayo Clinic every 28 days. They do a blood draw at 6:30 a.m., followed by an electrocardiogram on every third visit. Sometimes there are more tests. Later that same morning I will see the doctor or her nurse practitioner, and most of the test results will be ready for that meeting. By about noon, usually, I will pick up the next 28-day supply of pomalidomide and head home or wherever we’re going.”

Don sees his doctor once a month during the trial. “If I were not in a trial, I suppose I might not see the doctor quite as often,” Don explained.

When asked about his experiences with the clinical trial, Don replied, “I am very glad that I am in this trial. The drug (pomalidomide) is free, and my insurance company doesn’t have to pay the very high price commanded by Revlimid, nor do I have to pay the co-pays. More important, I believe that pomalidomide is a better drug and has, for me, fewer side effects.”

Don pointed out that no myeloma treatment is without serious side effects. However, in Don’s case, the pros outweighed the potential cons. “Pomalidomide with dexamethasone brought my M-Spike down from 2.7 to 1.0 g/dL within a few months, holding it mostly stable since then. I have been on the drugs for two years now. I discontinued dexamethasone in December because of current side effects and other potential effects of long-term treatment.”

Don described the side effects he experienced from pomalidomide as “modest” and “fewer than most.” They included:

• Slight neuropathy in feet (tingling and numbness)
• Slightly reduced heart rate
• Declining white blood cell count, especially neutrophils (this is the primary reason why a blood check is done every 28 days).

The pomalidomide trial has changed Don’s life by providing a new treatment for him that allows him to experience a pretty high quality of life. “I am a runner. Running stops when a runner breaks a bone. Because of my Mayo Clinic doctors and pomalidomide [and dexamethasone], I have continued running, with no broken bones,” he added.

Don had the following advice for fellow myeloma patients looking into clinical trials, “If I hadn’t participated in the trial, I would have gone with Revlimid. But Revlimid is only available because other people participated in trials for it. My most immediate concern is my own health, of course, but I’m glad to be able to ‘pay it forward’ in this way. It’s a good feeling.”

For more information about Don and his clinical trial participation, please visit his blog, “Myeloma Hope: Don’s Myeloma Diary.” To learn more about clinical trials, please read the previous articles in the series and check The Myeloma Beacon in the coming weeks for the final article in this series.

More than 30,000 clinical specialists from all over the world are expected to attend the five day meeting to discuss the most current research in cancer treatment and care. This year’s meeting, which will feature more than 4,000 presentations and posters, will primarily focus on the theme of “Advancing Quality through Innovation.”

The ASCO meeting will include many presentations and seminars focused on multiple myeloma. The ASCO website currently lists over 70 myeloma-based abstracts. The Myeloma Beacon will be covering some of the meeting’s key myeloma presentations in the coming weeks.

Treatments Under Development

Several of this year’s ASCO presentations will unveil results from Phase 1 and Phase 2 clinical trials of drugs under development for treatment of multiple myeloma. In particular, there will be many presentations on pomalidomide (Actimid, CC-4047), carfilzomib, and elotuzumab.

On June 5 Dr. Ravi Vij will present the results of an ongoing Phase 2 clinical trial of carfilzomib in patients with relapsed and/or refractory (resistant) myeloma. Dr. William Bensinger will present a poster on June 4 on the results of a dose-escalation study of carfilzomib plus Revlimid (lenalidomide) and low-dose dexamethasone (Decadron) in relapsed/refractory myeloma patients. Dr. Ashraf Z. Badros will present a poster on June 5 on the results of carfilzomib in relapsed/refractory myeloma patients with impaired kidney function.

On June 5 Dr. Martha Lacy will present a poster on a study that found the combination of pomalidomide and dexamethasone to be active in patients who are refractory to both Revlimid and Velcade (bortezomib).

Dr. Andrzej Jakubowiak will present on a poster on June 5 on the results of a Phase 1 study that evaluated the combination of elotuzumab and Velcade in relapsed/refractory myeloma patients. A second presentation on June 6 by Dr. Sagar Lonial will discuss the results of a Phase 1/2 trial that investigated the combination of elotuzumab, Velcade, and low-dose dexamethasone in relapsed/refractory patients.

Maintenance Therapy

This year’s ASCO Annual Meeting will feature several sessions on maintenance therapy after stem cell transplantation. The preliminary data from two major studies indicates that even if a patient achieves a “complete response,” it is still important to continue treatment with targeted, tolerable drugs.

Highlights include a report by Dr. Philip McCarthy on June 6 about the results of a Phase 3 study that compared maintenance therapy with Revlimid versus a placebo in patients who received single autologous stem cell transplantation. Results will also be reported for other maintenance therapies that include Velcade, melphalan (Alkeran), prednisone, and thalidomide (Thalomid); Velcade and dexamethasone; and Revlimid alone.

Long-Term Survivors Of Multiple Myeloma

As research continues to advance, doctors can look further in the future for their patients. This year’s ASCO meeting will include presentations on the few people —less than two percent of people with multiple myeloma, according to some University of Texas researchers— who have lived with multiple myeloma for more than 10 years. ASCO Meeting presenters will try to characterize long-term survivors and how they were treated, in hopes of increasing that two percent figure in the future.

Elderly Myeloma Patients

Several of the presentations will discuss treatment management and patient care for elderly myeloma patients.

On June 4 Dr. Vicki A. Morrison will host an educational session on the treatment management for older patients with leukemia and myeloma. In a separate presentation, Dr. Jesus San-Miguel will also discuss new treatment regimens for older myeloma patients.

For more information on ASCO’s 46th Annual Meeting, including presentation abstracts, the final schedules, and information on attending, please see the American Society of Clinical Oncology website.

If you have decided to participate in a clinical trial, then you will need to select a clinical trial that is right for you. This process may be very easy if your physician has already recommended a specific trial, or this process may require research and careful consideration if you are trying to find a trial on your own. This article provides a list of resources for finding a clinical trial as well as describes the things you will want to consider and questions you will want to ask when deciding between several trials.

How To Search For Myeloma Clinical Trials In Your Area

Fortunately, there are many ways to find myeloma clinical trials. One of the easiest ways is often by word of mouth. Ask your doctor about clinical trials that are currently recruiting participants. Your doctor is familiar with your case and can recommend a clinical trial that will be right for you. Also, you can inquire at your cancer treatment center about ongoing trials.

If you want to search on your own for clinical trial options, there are a number of websites and organizations that can help you find suitable trials based on your stage of myeloma, your location, and treatments that you are interested in trying.

The United States National Institutes of Health’s website, www.ClinicalTrials.gov, allows you to search by disease or treatment and also allows you to refine your search by location, clinical phase, enrollment status, and much more. The entry for each trial also provides information about the purpose of the trial, eligibility criteria, and who is sponsoring and conducting the trial.

The U.S. National Cancer Institute also maintains a website, www.cancer.gov/clinicaltrials, for searching clinical trials based on disease, location, treatment type, clinical phase, and trial sponsors or investigators. The entry for each trial also provides detailed information about eligibility criteria. Additionally, if you have questions about clinical trials, you can call their toll-free hotline at 1-800-4-CANCER (1-800-422-6237).

The clinical trial matching service, found on the Multiple Myeloma Research Foundation website, is also another online tool for finding clinical trials. It enables you to view all myeloma trials or to build a personal profile and to narrow down your search for a trial based on your specific case. Their registry provides detailed information about eligibility and the treatment protocol but does not provide information about the locations where the trial is being conducted or who the sponsor or investigator is. They also have a toll-free hotline at 1-866-603-MMCT.

You can also find a treatment center near you by using The Myeloma Beacon’s treatment center directory. You may wish to check with local treatment centers if they are conducting any ongoing clinical trials.

Criteria For Joining

Once you have found a few clinical trials that you are interested in, you will also need to determine whether you are eligible to participate in any of those trials.

Because each trial has a specific purpose, only certain patients are eligible to participate. Each clinical trial protocol clearly states who can or cannot join the trial. These criteria reduce variability in the study so that the results can be accurately analyzed to determine whether the treatment being studied is effective.

Common criteria for entering a trial include:

• Having a certain type or stage of cancer
• Having received a certain kind of therapy in the past
• Other health problems
• Current medications
• Being in a certain age group

For myeloma patients, criteria for entering a trial include:

• Newly diagnosed myeloma
• Refractory/relapsed myeloma
• Patients with a certain treatment history

For more information about eligibility criteria, see the eligibility sections of Part 3 in this series.

These criteria help ensure safety as well as accurate and meaningful study results. Some people have health problems besides cancer that could be made worse by the treatments in a study. If you are interested in joining a trial, you will receive medical tests to assure that you are healthy enough to participate.

You may not be able to join certain clinical trials if you already have had another kind of treatment for your cancer. There are a number of reasons for this type of restriction: the purpose of the trial may be to investigate the drug in newly diagnosed patients, it may already be known that the drug is not effective if you relapsed or are refractory to a certain drug, or the researchers may want to be sure that your response to the new treatment is not being affected by a previous treatment.

Also, it is wise to discuss with your physician all medications that you take, including any you may not take on an ongoing basis. Some medications may interfere with the protocol being studied and, therefore, may need to be stopped. Clinical trials often require a washout period of two to six weeks before the start of the trial in which you are not allowed to take any medications. The purpose is to allow all current drugs to leave your system, so that the researchers can accurately determine whether the new drug is effective.

If you are required to stop any of your medications, please discuss this carefully with your physician to determine the risks and to make sure this would be safe for you.

Important Questions To Ask

While you are deciding which clinical trial in which to participate, there are a number of questions that you want to ask about each trial. Many of the questions can be answered by the entry for the trial in a clinical trials database, such as www.ClinicalTrials.gov.

Once you have selected a clinical trial in which you most likely want to participate, you will begin the informed consent process in which you will meet with the principle investigator of the study as well as the research coordinator at your treatment center to discuss the trial. This is an opportunity to find out all of the details of the trial, to ask the remaining questions you have about the trial, and to make your final decision about whether you want to participate in the trial.

It is important to communicate with your physician and your research coordinator, both while you are deciding whether to participate in a clinical trial and also during your participation in the trial. If you have questions, do not be afraid to ask them.

It can be useful to write down and take your questions with you when you go to visit the doctor. It is also helpful to take a writing pad with you to jot down notes during your conversation. This way, if you get nervous or flustered, you have your questions right in front of you.

It also helps to bring along a family member or a friend for moral support and as a second set of ears. Some people prefer to bring an audio recorder with them to record the conversation so they can replay it later.

During the day of the appointment, it will be helpful to clear your schedule for a couple of hours or even the whole day. The informative process itself takes a while, and you do not want to have to rush through it. For some people, a day is needed to fully process the information as it sinks in.

Here are some questions to keep in mind as you consider your clinical trial options:

About this trial:

• Why is this trial being done?
• Why do the doctors who designed the trial believe that the treatment being studied may be better than the standard treatments? Why might it not be better?
• How long will I be in the trial?
• What kinds of tests and treatments are involved?
• What are the possible short and long-term side effects or risks of the new treatment?
• What side effects have been seen in patients who took this treatment previously?
• What are the possible benefits?
• How will the doctor know if the treatment is working?
• What happens if the treatment is found to be ineffective or harmful?

Costs:

• Will I have to pay for any of the treatments or tests?
• What costs will my health insurance cover?
• Are there any other costs that I need to worry about such as travel expenses, overnight stays, hospital parking, etc.?

Daily life:

• How might the trial affect my daily life?
• How often will I have to come to the hospital or clinic?
• How often do I have to make appointments with my doctor/research coordinator?
• How often do I have to be tested during the trial?
• Will I have to travel long distances?

Comparing choices:

• What are my other treatment choices, including standard treatments?
• Have I exhausted all other options?
• How does the treatment I would receive in this trial compare with the other treatment choices?

To learn more about clinical trials, please read the previous articles in the series and check The Myeloma Beacon in the coming weeks for subsequent articles.

There are many issues that patients worry about when considering whether to join a clinical trial, and there are many myths surrounding those issues. This article will try to separate the myths from the facts about clinical trial participation.

Participating in a multiple myeloma clinical trial

MYTH: There are already enough myeloma patients participating in clinical trials.
FACT: Approximately 5 percent of cancer patients are currently participating in clinical trials. However, with 66,529 people currently living with myeloma in the United States and with an estimated 20,580 new cases of myeloma expected to be diagnosed this year, there is a strong need for more people to participate in research to find more treatment options.

Purpose of myeloma clinical trials

MYTH: Myeloma clinical trials only benefit doctors and corporations who are testing out new medications.
FACT: Myeloma clinical trials try to achieve many goals beneficial to the patient. These goals include:

• Discover new therapies/treatments to eradicate or slow the growth of myeloma cells
• Provide long periods of remission
• Help patients feel better if they have bone pain, fatigue, or other difficult symptoms
• Adjust and test dosages of current treatments for myeloma
• Test combinations of current treatments for myeloma
• Test combinations of a new treatment in addition to current treatments for myeloma
• Improve safety and efficacy of stem cell transplantations
• Research how myeloma progresses in different ages, races, and genders of myeloma patients
• Develop novel therapies designed to delay/prevent multiple myeloma progression in smoldering myeloma patients
• Study mechanisms for multiple myeloma progression to aid in the design of future therapies to prevent progression

Eligibility / criteria for joining clinical trials

MYTH: Only terminally ill cancer patients or patients with no other treatment options left should take part in a clinical trial.
FACT: Clinical trials are open to all types of patients, including those who have exhausted all other treatment options as well as those who are newly diagnosed with myeloma.

A myeloma patient may fulfill any of these criteria to be able to participate in a clinical trial:

• Newly diagnosed
• Did not achieve a good response to established treatments
• Relapsed after treatment
• Continuing treatment after remission (maintenance)

Eligibility is also based on:

• Type and stage of myeloma
• Age
• Overall health
• Medications you have taken in the past and how long ago (wash-out period)

Common questions on criteria/eligibility:

Is there a screening period during which doctors decide the patient’s eligibility? If so, how long does this period last?
Yes. Patients’ eligibility is determined by their physician who is monitoring their health and response to standard treatment. If a patient is relapsing, a physician may suggest trying other standard therapies or a clinical trial. In the case of trying a trial, the screening period or washout period, during which the patient is monitored and is supposed to be off any other therapy for myeloma (to be able to determine efficacy of the drug being tested in the trial and so that there is only one variable in the trial), varies from two to four weeks to up to six weeks, depending on each individual case.

Do patients need to be concerned about their disease getting worse during the washout period?
There is a possibility that the disease could worsen without any treatment for two to four weeks. If you and your physician feel that this much time without any treatment is detrimental to your health, then another option should be considered. Waiting would only be beneficial if your case is not too severe or aggressive and allows leeway of that much time.

Are patients allowed to remain on maintenance medication throughout the washout period and trial?
This depends on the protocol. Generally, maintenance drugs and vitamin supplements, when approved by your physician, are okay. However, supplements with “natural” ingredients or unknown ingredients are not allowed due to doctors not knowing what they contain (which could cause a reaction with the tested drugs).

Testing for eligibility for a myeloma clinical trial

MYTH: Most patients who participate in clinical trials are “preselected” and are a certain “type,” so there is no such thing as truly being eligible for a trial.
FACT: Testing to determine eligibility for a myeloma clinical trial is very thorough and precise – much like the tests done when a patient is diagnosed. Each patient is unique, so to best determine what trial will be most effective, different tests are conducted. Some of the tests are done before the trial, and some are done to watch and track progress during the trial.

According to Dr. William Bensinger, a myeloma specialist at the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, “If a patient meets the general eligibility criteria, they must undergo a series of baseline tests that will confirm eligibility. These usually include a bone marrow aspiration, skeletal survey, serum and urine protein electrophoresis, complete blood count, and chemistry labs including kidney and liver functions tests.”

Specific age of candidates required for enrollment in a clinical trial

MYTH: Older cancer patients are ineligible for clinical trials.
FACT: Enrollment of older patients in clinical trials is low, but not because they are ineligible but due to their low participation. Older patients are encouraged to join, especially since 63 percent of all cancer patients are 65 or older.

More information on best types of candidates for myeloma trials:

Specific minorities or age groups that are candidates:

According to Dr. Ola Landgren, a clinical trial investigator at the National Cancer Institute, “Myeloma is two-fold more common in African-Americans (versus Caucasians). We have ongoing studies looking into the underlying mechanisms of these patterns. Our data suggest that African-Americans have more precursor disease, monoclonal gammopathy of undetermined significance (MGUS), while the rate of progression from MGUS to myeloma is the same for the two races.”

Also, while myeloma is still quite rare in the general population, the elderly (above 60) have higher rates of myeloma.

“There are data to suggest that family members of myeloma patients are at a two-fold higher risk of myeloma, which supports a role for genetic factors,” said Dr. Landgren.

Specific types of patients that are best candidates for clinical trials:

• Smoldering myeloma patients with certain adverse clinical features (a higher risk of developing myeloma)
• Active myeloma patients who are not responding to established treatment
• Relapsed/refractory multiple myeloma patients who are willing to try new drugs
• Newly diagnosed patients are also good candidates for studies that develop new treatment strategies.

Explanation of risks

MYTH: Researchers and doctors may not spell out all of the risks associated with a clinical trial.
FACT: All aspects of a clinical trial, including the risks, potential short and long-term side effects, financial aspects, confidentiality, and protocol, are part of the informed consent process and are carefully explained to the patient in the beginning.

Treatment of people during clinical trials

MYTH: Patients in clinical studies are human guinea pigs.
FACT: Patients participating in clinical trials may be tested more frequently than patients treated at standard cancer centers. Frequent tests are necessary to monitor the patients’ safety. Patients participating in clinical trials are treated with the same care and respect as everybody else.

Quality of care received during a clinical trial

MYTH: I will receive poorer medical treatment in a clinical trial.
FACT: Patients in clinical trials receive either the best standard treatment or a new treatment that researchers believe is at least as good as the standard treatment. Patients in clinical trials are very closely monitored.

MYTH: I will get better medical treatment in a clinical study.
FACT: Medical treatment in a clinical study is as good as standard treatment. In addition, patients are receiving constant care and are being closely monitored. Also, they receive treatments from doctors who are leaders in their fields.

Chances of getting a placebo

MYTH: Cancer patients may be given a placebo in a clinical trial and thus not receive any real treatment.
FACT: Some multiple myeloma clinical trials may use a placebo as part of the treatment regimen, but myeloma patients always receive at least the standard of care. For instance, some trials may compare the addition of a drug to standard of care. In those trials, some patients will receive the new combination while others will receive the standard of care plus placebo. Also, since maintenance therapy is still being investigated, trials testing maintenance therapy may have an arm that receives maintenance therapy and another arm that receives a placebo maintenance therapy. In trials investigating how to prevent cancer, some participants may receive a placebo only.

Success of myeloma clinical trials

MYTH: Because drugs being tested in myeloma trials are relatively new, their success rates may be lower, and patients may not respond positively.
FACT: Patient response varies from trial to trial based on the treatment being tested and also on the patients. Trials for newly diagnosed myeloma patients typically have a higher rate of success than those for relapsed/refractory myeloma. At the same time, advances in the treatment of multiple myeloma are being made, and response rates are increasing. If a patient does not respond positively to a trial, they have the option to opt out.

Safety of clinical trials

MYTH: Clinical trials are not safe.
FACT: With clinical trials, there are many unknowns, including short-term and long-term side effects of the drug and how well you will respond to the treatment.

However, new treatments are tested on humans only after they have been lab tested and there is valid scientific evidence that the treatment is likely to be effective and safe. Patient safety is a top priority in clinical trials. Patients in clinical trials are therefore monitored very closely. However, the treatment may not be effective in some patients, or patients may develop serious side effects.

“If there is any doubt the drug does not work for that individual patient and the side effects are bad – then the drug is immediately stopped,” said Dr. Landgren. “The patient always comes first – in every trial!”

More information on safety:

Other options for patients afraid of unknown side effects:
If you are worried about the safety or efficacy of a new treatment, you may want to consider a later phase trial. With each phase of testing, more is known about the safety and efficacy of the treatment. Before signing up to receive a new treatment, you can read results of previous trials that tested the drug.

Additionally, you may want to consider a clinical trial that tests a new way of using drugs that have already been approved – the trial may test new dosages of a drug or a new combination of treatments. Also, there are myeloma clinical trials that are studying new procedures for stem cell transplants.

Side effects that can be experienced during myeloma clinical trials:
(These side effects are also seen in common myeloma treatment practices and are not specific to clinical trials. Side effects vary depending on the treatments being used. It is also possible for patients to experience side effects not yet associated with myeloma treatments. Side effects often vary from patient to patient.)

• Upset stomach, nausea, and/or vomiting
• Mouth sores
• Constipation
• Extreme tiredness/exhaustion
• Infections
• Low red blood cell count (anemia)
• Low white blood cell count
• Low platelet count
• Achy feeling
• Numbness in arms, hands, legs, or feet
• Neuropathy in hands and/or feet

Finances

MYTH: My health insurance will not pay for treatment provided through a clinical trial, and it is not an affordable option.
FACT: Many people are afraid to consider a clinical trial, fearing that their health insurance may not cover treatment. However, most trials are not financially burdensome, and sometimes physicians recommend participation in clinical trials to reduce costs for the patient. In many cases, private organizations or pharmaceutical companies conduct trials at no expense to the patient (this includes covering costs for tests, treatment, etc).

In the event that the cost of treatment during the trial is not covered by the sponsoring agency, your physician/research coordinator will need to speak with your insurance company to work out the details. Generally, insurance companies do not cover experimental clinical trials, unless it can be proven that it is a necessity or that the approach is especially safe and effective. For specific coverage, a doctor would have to prove the necessity of the drug.

If your health insurance does offer a possibility of covering it, there are certain criteria that need to be met, such as a specific cost threshold (it cannot cost more than a similar drug used to treat your disease).

Beneficiaries of Medicare, TRICARE, or the Department of Veterans Affairs are encouraged to participate in clinical trials designed to diagnose or treat cancer and are often reimbursed.

For more information, visit the National Cancer Institute’s Clinical Trials and Insurance Coverage website

Ability to drop out of a clinical trial

MYTH: If I join a clinical trial, I will not be able to drop out.
FACT: You may quit a clinical study at any time.

A common concern or reason why a patient might want to drop out of a clinical trial is if they experience serious side effects or get ill from an infection during the trial. Based on the protocol, in the event of a serious side effect or infection, the drug is either stopped or the dosage is reduced. The patient is always monitored very closely, so an infection would be taken care of promptly with antibiotics, anti-viral, or anti-fungal medication.

Length of myeloma trials and how long patients are monitored for

MYTH: Myeloma trials last only as long as the sponsor can afford to pay for the drug being tested, which cannot be very long.
FACT: The length of each trial varies depending on the protocol. It depends on how many cycles of treatment the protocol includes and also on the response of the patient. Treatment may continue as long as the patient responds positively to treatment, or it will end sooner if there is no response or symptoms get worse. Some trials may last for several years.

Life after the clinical trial

MYTH: I will not be able to continue treatment after the clinical trial is over.
FACT: After treatment during the clinical trial has been completed, a patient will often be studied for a while afterward to monitor progress and to see if any other side effects or changes occur. There are many treatment options for participants during this time, whether they responded to the experimental treatment or not.

If a patient responds positively
There are several options that allow the patient to continue receiving the experimental treatment:

• If the drug is FDA approved and commercially available for another disease or therapeutic use, the patient may purchase the drug. Payment methods/insurance coverage needs to be worked out between the physician/research coordinator, the insurance company, and the drug company.
• If the drug is not commercially available, many trials offer an “extension arm” that enables the patient to continue taking the drug under an extension of the trial, sponsored by the corporation or organization that sponsored the trial. Availability of an extension arm varies with each study, and the length of the extension arm also varies. Be sure to check with your physician.
• In the case that the drug is not commercially available and there is no extension arm of the trial, physicians and research coordinators can arrange for the drug to be used under “compassionate use,” which enables the patient to continue receiving the experimental therapy after the end of the clinical trial.

If a patient does not respond
The patient has the options to go back to a treatment that had previously worked, try another established treatment plan, or opt to try another clinical trial.

To learn more about clinical trials, please read Part 1 and Part 2 and check The Myeloma Beacon in the coming weeks for the other articles in the series.

If you are considering participating in a clinical trial, it is important to be entirely comfortable with your decision. Here are some benefits and risks associated with clinical trial participation that should help you during the decision process. The most important thing, however, is whether the treatment regimen being studied is the best option for you. Your physician can help you determine this.

Why are clinical trials important?

Not only do clinical trials offer new treatment options for you, but they are also (in the long run) helping further research for the benefit of many patients in the future. It takes a significant number of people who are willing to participate in order for disease research and treatment development to move forward, but every person counts and adds to the culmination of knowledge.

It takes years of preparation and research for one treatment to reach the market. Without the help of clinical trial participants, advances in treatment could not be made.

By taking part in a clinical trial, you can try a new treatment that may or may not be better than those that already exist. But in addition to receiving the treatment that you have decided is best for you, you can also help doctors and researchers better understand how the treatment works in people of different races, genders, ages, and stages of disease.

Potential benefits of participating in a clinical trial

• Health care provided by leading physicians in the field of cancer research
• Access to new drugs and interventions before they are widely available
• Close monitoring of your health care and any side effects
• A more active role in your own health care
• You may be among the first to benefit from a new treatment
• An opportunity to make a valuable contribution to cancer research.

Clinical trials are known for their meticulous detail and observation. So you will get the same, if not better, care and attention that you would get during regular treatment. There are frequent visits with your physician to provide thorough examinations. There are also various ways to record your everyday symptoms and to track your progress, such as diaries and hotlines. This allows the research coordinator and physician to physically see the progression of your symptoms and whether the treatment is having any effect.

Common reasons to participate in a myeloma trial

Relapsed or refractory patients are most likely to participate in a myeloma clinical trial because they are not responding to established therapies and are looking for new methods of relief.

If a patient is not responding to standard treatment and their quality of life is poor, there may not be many options left to exhaust. For those who have tried various treatments without results, clinical trials and their treatments offer new hope.

Potential risks of participating in a clinical trial

• New drugs and procedures may have side effects or risks unknown to the doctors
• New drugs and procedures may be ineffective, or less effective, than current approaches
• Even if a new approach has benefits, it may not work for you.

Common reasons patients choose not to participate in a myeloma trial

Some patients may choose to continue trying established treatments that have been proven to work on other patients because those treatments have already been assessed for efficacy and safety factors. Unknown short term and long term side effects are one of the many reasons that patients choose not to participate in trials.

There is also a lifestyle factor. Participating in a clinical trial may not suit some patients’ lifestyles (i.e. too much traveling, too many doctor’s visits, unexpected financial troubles, etc.).

Another reason is a comfort level that patients feel with their doctors in a more private environment and a nervousness associated with switching to a different doctor and to a new environment. Additionally, local physicians may not be inclined to refer their patients to clinical trials at research institutions.

“Because of the infrastructure of clinical medicine in the United States, many patients are treated by local oncologist/hematologists in their private practice. The incentives for these physicians to keep their patients in their clinics (rather than referring them to trials elsewhere) are quite strong,” said Dr. Ola Landgren, a clinical trial investigator at the National Cancer Institute.

“Patients diagnosed and treated at larger research institutions have a different situation; i.e. the number of available trials is larger.” Physicians at research institutions may be eager to suggest clinical trials to their patients.

To learn more about clinical trials, please read Part 1 and check The Myeloma Beacon in the coming weeks for the other articles in the series.

Taking part in a clinical trial is a huge decision for both patients and their families, and it is one that should be made with careful consideration.

This guide, which will be published as a series of articles over the next couple of weeks, is intended to help clarify the clinical trial process and to answer common questions so that you can decide whether a clinical trial is the right option for you. The guide will explain the different types of clinical trials in this first article, and subsequent articles will address common myths, provide answers from physicians to common questions, describe patients’ clinical trial experiences, and provide resources for finding a clinical trial.

What are clinical trials?

Simply put, clinical trials are research studies that involve people. Often, they are meant to help those who do not respond to standard treatments and are looking for other options.

Clinical trials test new drugs, procedures, treatment combinations, and medical devices to improve the diagnosis of the disease, patients’ responses to treatment, and the quality of life of patients. Trials may also try to find methods to prevent certain cancers.

Even though these clinical trials are exploring “new” treatments and procedures, they are actually the final step in a long process that begins with lab research and animal testing. All treatments and drugs used today are the result of successful clinical trials conducted in the past.

Types of clinical trials

• Treatment trials – test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.
• Quality of Life trials (or Supportive Care trials) – explore ways to improve comfort and the quality of life for individuals with a chronic illness.
• Diagnostic trials – are conducted to find better tests or procedures for diagnosing a particular disease or condition.
• Screening trials – test the best way to detect certain diseases or health conditions.
• Prevention trials – look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vaccines, vitamins, minerals, or lifestyle changes.

Phases of Clinical Trials

In order for a treatment to be officially approved for use, it must pass through at least the first three phases of clinical trials. Each phase corresponds to a stage in the testing of the drug on humans. It is also a good way for patients to tell how well tested the drug is.

The following table summarizes the purpose of each phase and the estimated number of people who take part in each phase.

The phase of the trial is important for patients to consider. Most patients feel more comfortable with a clinical trial in a later phase because more information about the therapy is already known (such as short-term side effects and initial efficacy results). However, physicians may suggest early phase clinical trials to patients who are particularly good candidates for responding favorably to the treatment.

Clinical Trial Terminology

Randomized Trials – Randomization is a process used in some clinical trials to prevent bias. Bias occurs when a trial’s results are affected by human choices or other outside factors. Randomization helps ensure that unknown factors do not affect trial results.

If you participate in a randomized trial, you will be assigned by chance to either an investigational group or a control group. Your assignment will be determined by a computer program or table of random numbers.

• If you are assigned to the control group, you will get the most widely accepted treatment (standard treatment) for your cancer.
• If you are assigned to the investigational group, you will get the new treatment being tested.

Comparing these groups to each other often shows which treatment is more effective or has fewer side effects. If you are thinking about joining a randomized clinical trial, you need to understand that you have an equal chance of being assigned to either one of the groups. The doctor does not choose the group for you.

Placebo – In certain randomized trials, there is a chance that the patient is given a placebo, a drug that is designed to look like the medicine being tested but which is actually inactive. This is done to account for a “placebo effect,” which is a perceived psychological effect that does not reflect the efficacy of the actual drug.

Fortunately, for the safety of the patients, placebos are almost never used in cancer treatment trials.

Blinding – “Blind” (or “masked”) studies are designed to prevent members of the research team or study participants from influencing the results. This allows scientifically accurate conclusions.

• In single-blind (or “single-masked”) studies, only the patient is unaware of what is being administered.
• In a double-blind study, only the pharmacist knows what is being administered; members of the research team are not told which patients are getting which medication, so that their observations will not be biased. If medically necessary, however, it is always possible to find out what the patient is taking.

Clinical Trial Protocols

Clinical trials are meticulously conducted under and observed by doctors, nurses, social workers, and a devoted research staff that includes a head research coordinator, who is your liaison between your medical institution, the United States National Institutes of Health, U.S. Food and Drug Administration, the National Cancer Institute, and the pharmaceutical company or private corporation funding the trial.

The protocol, prepared by the principal investigator (the physician in charge) is a strict guideline that explains what the trial will do, how the study will be carried out, and why each part of the study is important. The protocol includes:

• The reason for conducting the study
• Who can join the study
• How many people are needed for the study
• Any drugs the participants will take, including the dose, and how often
• Potential side effects
• What medical tests the participants will take and how often
• What information will be gathered about the participants.

Research involving people is conducted according to strict scientific and ethical principles. These trials and procedures are all put through a rigorous review and approval process by the Institutional Review Board. The patient’s safety is always top priority.

Informed Consent And Confidentiality

An important part of the clinical trial process is the informed consent. It is easy to be confused about what exactly you are giving consent to, but rest assured – you are only giving consent to participating in the trial and that it is only to your benefit.

Your identity remains safe throughout the process as you are put through a system and given an ID number with which you will be identified (this is useful for confidentiality, but there is no need to worry about not being properly identified in an emergency). Confidentiality and personal details, including the data collected during your trial, are kept safe by the Data Safety Monitoring Board.

There are two parts to the informed consent that a patient should be aware of: the informed consent document and the informed consent process.

The informed consent document is to be read by the patient. Always ask for a copy to keep for yourself in case you want to look it over again or have further questions later. The document informs you of the purpose of the trial, the treatment procedures, risks, benefits, etc. Most importantly, it explains to you your right as a participant and affirms that by signing, you consent to participating in this trial but that you have the right to withdraw from the study at any time.

The informed consent process is simply an ongoing process during which you and your research coordinator or physician will discuss the trial. Its purpose is to inform you about everything you will be doing and receiving. Before signing any document, it is mandatory that your physician or research coordinator explains every aspect of the trial to you. The document should be in written form, but the details of the trial should first be explained to you verbally. Do not hesitate to have things repeated or to ask questions. It takes many people time and multiple explanations to understand everything properly and to feel comfortable with the process.

Be sure to look out for specifics in the documents such as side effects, rules that you should be aware of (i.e. no alcohol, pregnancy, etc.), and cost coverage. Again, if you are ever confused or unsure about any part, feel free to ask a doctor to clarify – it is his or her job. And remember, this is not a binding contract.

Check The Myeloma Beacon in the coming weeks for the other articles in the series that will address common myths about clinical trials, provide answers from physicians to common questions, describe patients’ clinical trial experiences, and provide resources for finding a clinical trial.