Through clinical trials, hematology-oncologist Hani Hassoun is working to improve stem cell transplantation for people newly diagnosed with multiple myeloma.
At the present time, no treatment approach is considered to be a cure for multiple myeloma. However, current treatment strategies are designed to slow the progression of disease, prolong survival, and alleviate symptoms.
Physicians caring for patients with smoldering myeloma — which generally causes few, if any, symptoms — usually decide that observation, rather than treatment, is the best course to follow. If the patient's protein levels rise or anemia occurs and there are signs that the disease has become active, his or her physician will likely begin treatment. Commonly used treatment regimens include dexamethasone — a potent corticosteroid — alone or in combination with other medicines such as doxorubicin, thalidomide, or lenolidamide.
Thalidomide, a medicine first used in the late 1950s as a sleeping pill and to combat the nausea some women experience in the first trimester of pregnancy, was found to cause birth defects and was later banned. In recent years, researchers began testing the drug on other diseases, and it was found to be an effective treatment for leprosy. In the late 1990s, cancer researchers discovered that thalidomide could be used to treat myeloma throughout the course of the disease as both first-line and maintenance treatment, and also for those whose disease has relapsed.
Newer versions of thalidomide, such as lenalidomide (Revlimid®), are designed to be more potent and also appear to have fewer side effects than thalidomide. Researchers theorize that thalidomide and lenalidomide act directly and indirectly in myeloma by promoting the death of cancer cells and by inhibiting myeloma cell growth and survival in bone marrow. Doctors use the combination of lenalidomide and low-dose dexamethasone for many newly diagnosed patients with myeloma who have limited organ damage and are candidates for stem cell transplant.
Bortezomib (Velcade®) is the first in a new class of medicines called proteasome inhibitors, and the first treatment in more than a decade to be approved by the Food and Drug Administration for patients with multiple myeloma. Proteasomes are protein complexes found within all cells that break down proteins and are essential for normal cellular processes like the cell cycle, signal transduction, and gene expression. Inhibiting proteasome activity in cancer cells seems to increase programmed cell death (a process called apoptosis), block proliferation, and inhibit the cell cycle, causing cancer cell death. In July 2008, the FDA approved bortezomib to treat patients who have not yet been treated for multiple myeloma. (Bortezomib is still approved in the relapsed setting).
Through clinical trials, our investigators are combining bortezomib with other agents as an initial treatment for patients with advanced myeloma (ISS stage II and ISS stage III) in order to achieve prompt disease control. More than half of the patients in the trial have achieved complete or near-complete responses, an outcome that makes stem cell transplant more effective because the target population of myeloma cells is smaller.
To help manage some myeloma symptoms, most patients with the disease are also prescribed bisphosphonates — such as pamidronate (Aredia®) or zoledronic acid (Zometa®) — which can slow bone loss and simultaneously help to alleviate bone pain. Bone disease and pain may also be treated with local radiation, and pathologic fractures can be treated through surgical approaches in which surgeons attach metal rods and plates to weight-bearing bones to provide support.
High-dose chemotherapy combined with stem cell transplantation is a standard therapy for patients with myeloma and has been shown to prolong survival. In this procedure, stem cells — blood-forming precursorcells — are obtained from the bloodstream or bone marrow during autologous or allogeneic transplantation and then frozen. (When the patient's own stem cells are collected before chemotherapy and returned after treatment it is called autologous stem cell transplantation. When the stem cells come from a donor it is called an allogeneic transplant.) The patient then receives a high dose of chemotherapy that destroys tumor cells and most or all of the stem cells in the patient's bone marrow. The harvested stem cells are then administered (transplanted) to help regenerate the patient's blood and immune systems.
Patients undergoing stem cell transplantation are hospitalized for about three weeks; recovery takes several months. In patients with myeloma, two consecutive transplants two to four months apart have been shown to prolong disease control.
Investigational Approaches
Researchers are developing new agents for cancer treatment at a faster rate than at any time since chemotherapeutic drugs were introduced in the late 1940s. Relying in part on information that is emerging about the genetic basis of the disease, investigators are pursuing a variety of strategies to control multiple myeloma — approaches that kill tumor cells directly, inhibit the body's production of substances that promote tumor cell growth and survival, inhibit the binding of tumor cells to bone marrow, or enhance the immune response against myeloma cells. Below are some of the therapies now approved and coming into regular use or being tested for their potential to treat myeloma.
New Chemotherapies
Researchers at Memorial Sloan-Kettering are studying the most effective agents and treatment combinations of agents and transplant approaches to treating myeloma. Through clinical trials, our investigators are assessing the optimal timing and combinations of immunomodulatory agents, including thalidomide and lenalidomide, proteasome inhibitors, including bortezomib (Velcade®), and traditional drugs for myeloma. For example, researchers here are studying the effectiveness of bortezomib in multiple myeloma patients who have not yet received any treatment. We are also studying the combination of lenalidomide and the monoclonal antibody rituximab for patients with the protein CD20 on the surface of their myeloma cells. The goal of this combination for rituximab to target the CD20 protein, and lenalidomide may make the immune system work better with rituximab.
Memorial Sloan-Kettering investigators are also studying a new proteasome inhibitor, carfilzomib, in multiple myeloma patients with relapsed disease.
Transplantation
Researchers here are studying the most effective ways to combine multiple stem cell transplantationin myeloma treatment. (When the patient's own stem cells are collected before chemotherapy and replaced after treatment, it is called autologous stem cell transplantation. When the stem cells come from a donor, it is called an allogeneic transplant.) We are currently comparing the outcomes of patients who undergo two consecutive autologous transplants with those who have an autologous transplant followed by an allogeneic transplant using stem cells from a sister or brother.
Researchers at Memorial Sloan-Kettering are starting to investigate whether stem cell transplant is still as necessary early in the course of treatment given the efficacy of new agents, such as lenalidomide and dexamethasone, in the treatment of myeloma.
In addition to testing new treatments, researchers are investigating tools such as microarray analysis (a test that reveals which genes are mutated) that will enable physicians to profile an individual patient's cancer and determine the therapy to which a patient is most likely to respond.
