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Increasingly Treatable: Advances in Multiple Myeloma

Conquest - Spring 2009

By Scott Merville

Alvaro Castro

Seven years ago, when Alvaro Castro discovered that he had multiple myeloma, treatment options were few, survival prospects were brief, and there hadn’t been a new drug approved for the disease in decades.

All of that was about to change.

Castro and his M. D. Anderson oncologist have since navigated a steady flow of novel drugs and new combination therapies that are extending survival for people with the still incurable, but increasingly treatable, cancer of the blood plasma cells.

“I’ve always, always been on some type of chemo or other therapy,” Castro notes.

Some worked for a while, others didn’t work at all, but there has always been another option to try. Three years ago, a clinical trial introduced him to a combination of new and old drugs that brought his disease under control.

“I’m thankful and I’m pleased,” the 63-year-old retired program analyst says. He volunteers at his church and at M. D. Anderson, teaches English as a second language and recently took a Caribbean cruise with his wife.

The clinical trial of a new drug and an old standby steroid was led by Castro’s physician, Donna Weber, M.D., associate professor in M. D. Anderson’s Department of Lymphoma and Myeloma.

The combination of lenalidomide, known commercially as Revlimid®, with dexamethasone was approved by the U.S. Food and Drug Administration for second-line therapy.

Shown here with postdoctoral fellow
Sally Hunsucker, Ph.D., Robert Orlowski,
M.D., Ph.D., developed the drug
carfilzomib, a second-generation
proteasome inhibitor that has advanced
to Phase II clinical trials. So far the drug
shows improved response rates and
reduced neuropathy, debilitating nerve
pain and numbness.

Lenalidomide and another new drug called bortezomib (Velcade®) have been instrumental in improving the prospects of myeloma patients. Each drug attacks the disease in a novel way and in combinations also enhances the impact of older drugs, further multiplying treatment options.

“Median survival now is about seven years. It used to be in the three-to-five-year range,” says Robert Orlowski, M.D., Ph.D., chief of the Myeloma Section and associate professor in the Department of Lymphoma and Myeloma. “There are many 10-year survivors now, which was incredibly rare not too long ago, and many patients can now enjoy long periods without ongoing treatment.”

In the push to make myeloma a chronic disease and develop potential cures,
M. D. Anderson researchers are:

  • Developing and evaluating new drugs, including immunotherapies, such as vaccines and antibodies, and new combinations.
  • Exploring ways to improve the impact of blood stem cell transplants, both from donors and with the patient’s own cells.

Alternatives to standard treatment emerge

Multiple myeloma is caused by the proliferation of abnormal plasma cells, an infection-fighting white blood cell. These rapidly multiplying cells crowd out normal blood cells and form tumors in the bone marrow. About 19,000 new cases are diagnosed annually.

Jeffrey Mallams, a multiple
myeloma patient, realized
his dream when he ran the
Rock ‘N’ Roll San Antonio
marathon in 3 hours, 25
minutes, 59 seconds.

Before new drugs arrived, the standard treatment was combination chemotherapy followed by an autologous blood stem cell transplant, in which eligible patients receive their own banked blood stem cells after high-dose chemotherapy destroys both their myeloma and their blood supply. Transplants were the only way to achieve a durable remission.

Combinations that include lenalidimide or bortezomib as frontline therapy are achieving durable complete remissions in some patients, Orlowski notes, presenting a new option of delaying transplant.

“We’ve presented data showing that complete remission is the most important goal and how you get there is less important. Whether by chemotherapy only or chemotherapy followed by transplant, the outcomes are similar,” Orlowski says. The question of when or whether to transplant will be sorted out by additional research.

“Even with these novel drugs and our excitement about them, until we start curing people with drugs alone, transplant remains important in managing multiple myeloma,” he says. “It adds to survival and lengthens time to disease progression. Patients in remission after transplant can be off therapy entirely, which is an added bonus.”

Research brings new combinations to trials

While at the University of North Carolina, Orlowski was instrumental in the preclinical and clinical development of the novel drug bortezomib, the first proteasome inhibitor of any kind. The proteasome destroys proteins that a cell no longer needs. When this useful destruction is blocked, cells die.

“Our Phase I clinical trial showed the drug had some beneficial activity in all nine patients in the study, all of whom had either relapsed or refractory (treatment-resistant) myeloma. One patient had a complete remission, which was very unusual at the time,” Orlowski says.

A series of clinical trials revealed a consistent advantage in response rates, time to disease progression and complete or partial remission, leading to FDA fast-track approval of the drug in 2003 for relapsed and resistant disease. Last year, the injectable drug marketed by Millenium Pharmaceuticals was approved for frontline therapy.

Orlowski and colleagues also showed that bortezomib with pegylated liposomal doxorubicin, an antibiotic chemotherapy drug packaged for efficient delivery, improves time to progression and overall response rates over bortezomib alone. The FDA approved the combination for previously treated patients who have not had bortezomib.

Thalidomide, a treatment for insomnia and morning sickness shown to cause birth defects in the 1960s, re-emerged in the late 1990s. It affects the immune system, and its precise mechanisms against multiple myeloma are not understood, but it attacks both the malignant cells directly and the environment that nurtures them.

Marketed as Thalomid® by Celgene Corp., the drug was thought to be the first truly new approach to multiple myeloma in 30 years. It was approved by the FDA as a frontline therapy in 2006. The company then developed lenalidimide, a thalidomide derivative designed to minimize the side effects of the original drug.

An open question now is which combination of drugs to use in newly diagnosed patients. Orlowski says a combination of bortezomib, and either thalidomide or lenalidimide and dexamethasone appears to be emerging as the best treatment.

Every patient in a recent clinical trial of bortezomib/lenalidimide/ dexamethasone had either partial or complete responses to the combination, he notes. “We’re not yet curing disease, but certainly, getting a 100 percentresponse rate is moving in the right direction.”

Tandem transplants help patient

As drug options proliferate, researchers also are exploring ways to optimize blood stem cell transplants.

Research at M. D. Anderson has eliminated age as a risk factor for having a transplant. “It used to be common to have an upper age limit, 55, then 65 or 70 years old, for patients to receive an autologous transplant,” says Muzaffar Qazilbash, M.D., associate professor in the Department of Stem Cell Transplantation and Cellular Therapy.

“Now, if you have adequate heart, lung, liver and kidney function and you’re reasonably active, you are eligible regardless of age,” he says. Patients into their 80s have received successful transplants at M. D. Anderson.

For matched donor transplants, M. D. Anderson pioneered the reduced-intensity chemotherapy, or mini-transplant, regimen that employs a lower dose of chemotherapy, which does not entirely destroy a patient’s blood cells. The matched donor stem cells gradually replace the patient’s remaining blood cells, while the cells of the donor’s immune system help destroy lingering myeloma cells. Lighter chemotherapy has greatly reduced transplant-related mortality.

At 34, Jerry Mallams is young for a multiple myeloma patient. He’s also in complete remission after receiving two consecutive transplants of his own blood stem cells in July and November 2006.

An avid runner, Mallams was feeling good enough in 2008 to ask Qazilbash whether he could train to run in a marathon, a longtime goal.

“He said, ‘If you feel like you can, do it. Just listen to your body,’ ” Mallams says. On Nov. 15, he completed the San Antonio marathon in 3 hours, 23 minutes, which was good for 306th place out of 4,070 male runners and 343rd overall.

“I ran cross-country in college and have always loved running,” Mallams says. “I found out about my multiple myeloma because I fractured a vertebra while I was running.”

Painful fractures of the ribs and backbone are often the first symptoms of myeloma. After the fractures are repaired, targeted radiation destroys the tumors in the bone, and patients are put on medication to strengthen their bones.

“This trial asks whether a second transplant within six months of the first will increase the complete remission rate, time to progression and overall survival,” Qazilbash says. “Preliminary data supports this approach. Results are expected in a year or so.”

After the tandem transplant, patients were randomized to maintenance chemotherapy or observation. Mallams is delighted to be in the observation group. “Since I went off antibiotics in May 2007, I haven’t been on any drugs.”

Qazilbash and Sergio Giralt, M.D., professor in the Department of Stem Cell Transplantation and Cellular Therapy, work with colleagues in myeloma to improve transplants by exploring new pre-transplant chemotherapy regimens and combinations to use when the disease returns.

A myeloma vaccine developed by Larry W. Kwak, M.D., Ph.D., professor and chair of the Department of Lymphoma and Myeloma, is in a clinical trial to improve donor transplants. The vaccine is given to donors to stimulate their immune system T cells against multiple myeloma. Patients then receive the enhanced immune response from the donated stem cells. Ten patients have been enrolled in the Phase I trial led by Giralt.

Moving from chronic to cured

The grooved pegboard is used by
symptom researchers to test a patient’s
upper extremity fine motor dexterity.

A major, multi-institutional clinical trial will soon be launched by the Blood and Marrow Transplant Clinical Trials Network, a federally funded alliance that plans and carries out the country’s transplant research agenda.

Giralt is chair-elect of the network and will begin a two-year term as chair in January 2010. The network advances promising results from single-institution trials to multiple-institution trials to enroll enough patients to conduct timely studies.

“We’re looking for a cure,” Giralt says. “Right now we’re really trying to make multiple myeloma a chronic disease. We’ve made progress, but we aren’t there yet.”

Greater molecular understanding of the disease is a key to progress. “We now know multiple myeloma is seven or eight different diseases based on chromosomal analysis,” Orlowski says.

As research progresses, more targeted approaches will develop.

If the time comes to change treatment, Alvaro Castro will consult Weber. "She's willing to work with you, suggests different possibilities, informs you of clinical trails, and reviews the possible outcome of any option," he says.

Castro spends his active retirement enjoying his family and continuing to learn. "I study French. I read the Gospel. Time flies."

Xin Shelley Wang, M.D., associate
professor in the Department of Symptom
Research, is project leader on one part
of the NCI program project grant looking
for the root causes of both cancer- and
treatment-related symptoms.

Targeting ‘Deranged’ Molecules

By Scott Merville

While M. D. Anderson researchers pursue a cure for multiple myeloma, a major new initiative focuses on relieving the debilitating symptoms caused by both the disease and its treatments.

Deep and persistent fatigue, relentless pain, loss of appetite and sleep disorders might all be rooted in a handful of deranged inflammatory signaling molecules that are themselves vulnerable to attack.

“We’re trying to understand the root causes of such symptoms, so that rather than throw an analgesic at someone to relieve their pain, or give a stimulant to somebody who is fatigued, we can treat or prevent symptoms by targeting the underlying cause,” says Charles Cleeland, Ph.D., professor and chair of M. D. Anderson’s Department of Symptom  Research.

Cleeland is principal investigator on an $8 million National Cancer Institute program project grant aimed at multiple myeloma’s symptom burden.

The prime suspects are inflammatory cytokines, signaling molecules that serve a useful purpose in response to injury or illness but “go crazy and become toxic” when distorted by cancer or cancer therapy, Cleeland explains. Cytokines play a major role in development of multiple myeloma and can be aggravated by aggressive cancer therapies.

The project studies will draw on preclinical research, clinical trials and a longitudinal study of patients’ symptoms and their correlation to circulating levels of three cytokines (IL-1, IL-6 and TNFα). NF-κB, a precursor protein capable of activating all three cytokines, also will be targeted.

Separate clinical trials will examine the effect of cytokine-inhibiting drugs on symptoms of patients undergoing either combination chemotherapy or autologous stem cell transplantation.

Another project focuses on curcumin, a component of a common spice known to have an inhibitory effect on NF-κB, including assessment of its effect on symptoms for patients undergoing combination chemotherapy.

© 2015 The University of Texas MD Anderson Cancer Center