Recurrent multiple myeloma has persisted or returned following treatment initial treatment. About one-quarter of patients with relapsed disease will experience a remission of their cancer after several cycles of chemotherapy. Treatment with newer “targeted” therapies or high-dose therapy followed by a stem cell transplant appears to produce better outcomes.
The following is a general overview of conventional and investigative treatments for recurrent multiple myeloma. Cancer treatment may consist of targeted therapy, high-dose therapy and stem cell transplantation, supportive care, or a combination of these treatment techniques. Combining two or more of these treatment techniques has become an important approach for increasing a patient’s chance of cure and prolonging survival.
In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Treatments that may be available through clinical trials are discussed in the section titled Strategies to Improve Treatment.
Circumstances unique to each patient’s situation influence which treatment or treatments are utilized. The potential benefits of combination treatment, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.
The introduction of three new drugs for multiple myeloma — Velcade® (bortezomib), Revlimid® (lenalidomide), and Thalomid® (thalidomide) – has improved outcomes among patients with newly-diagnosed multiple myeloma as well as patients with relapsed or refractory multiple myeloma.
Velcade® (bortezomib): Velcade is a targeted therapy that inhibits the activities of a group of proteins, called proteasomes. These proteins are found in virtually all cells, but are particularly important for allowing myeloma cancer cells to survive and grow. By inhibiting the proteasomes, Velcade kills cancer cells and reduced overall cancer growth.
Important support for the use of Velcade in the treatment of relapsed multiple myeloma came from a phase III clinical trial known as the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial. The study enrolled more than 600 patients with relapsed multiple myeloma. Half the patients were treated with Velcade and half were treated with high-dose dexamethasone. Compared to the patients treated with dexamethasone, patients treated with Velcade had longer time to cancer progression (6.2 months versus 3.5 months), higher response rate (38% versus 18%), and better one-year survival (80% versus 66%). Serious side effects, however, tended to be more common in patients treated with bortezomib than patients treated with dexamethasone1
Studies have also evaluated Velcade in combination with other therapies, and several of these combinations have produced promising results.2 In a phase III clinical trial, the combination of Velcade with pegylated liposomal doxorubicin resulted in longer survival than Velcade alone among patients with relapsed or refractory multiple myeloma.3 Fifteen-month survival was 76% among patients treated with Velcade plus pegylated liposomal doxorubicin compared to 65% among patients treated with Velcade alone.
Revlimid® (lenalidomide): Revlimid is a derivative of thalidomide which has similar activity but less toxicity.
In a study conducted in the United States and Canada, the addition of Revlimid to dexamethasone has been shown to improve treatment outcomes among patients with relapsed multiple myeloma.4 Compared to patients treated with dexamethasone alone, patients treated with Revlimid plus dexamethasone experienced a longer time to cancer progression (11.1 months vs. 4.7 months) and better overall survival (29.2 months vs. 20.2 months). The addition of Revlimid to dexamethasone did increase the occurrence of side effects, however, such as neutropenia (low white blood cell counts) and blood clots.
Thalomid® (thalidomide): Thalidomid is a drug that was originally developed as a sleeping pill, but researchers began investigating it as an anticancer drug when they discovered that it slows or stops the growth of new blood vessels. Cancer cells require food and oxygen in order to grow and spread. These essential nutrients are transported to the cancer cells by blood vessels. By inhibiting the growth of new blood vessels, Thalidomid “starves” the cancer of the food and oxygen that it needs to survive and grow.
Thalidomid appears to be an active treatment for relapsed multiple myeloma. Results of a clinical trial indicate that one-third of patients treated with Thalidomid experience an anticancer response, including patients who relapse after stem cell transplantation. The researchers estimated that more than half of the patients survived one year or more after treatment.5
Response to treatment may be even greater when Thalomid is combined with other drugs.6 Thalomid and dexamethasone – a combination that has been shown to be effective in the initial treatment of multiple myeloma – has also shown promise in the treatment of relapsed multiple myeloma, and the addition of other drugs may further increase response rates.
High-doses of chemotherapy are more effective at killing cancer cells than lower doses. However, high-dose therapy destroys many other cells in the body. A dangerous side effect of administering high-dose therapy is damage to the cells in the bone marrow that develop into mature blood cells, called stem cells.
Without functioning stem cells in the bone marrow, the body cannot produce red blood cells, white blood cells or platelets, which leaves patients vulnerable to infection and bleeding, and unable to supply adequate oxygen to their tissues.
However, bone marrow function can be restored after high-dose therapy by replacing the damaged stem cells with healthy ones. This is a procedure known as a stem cell transplant.
There are two possible sources of stem cells for transplantation; they may be collected from the patient prior to undergoing high-dose therapy or they may be collected from a donor. A stem cell transplant that utilizes the patient’s own cells is called an autologous stem cell transplant. When the stem cells are from a donor the procedure is called an allogeneic stem cell transplant.
In general, autologous transplants are performed much more frequently than allogeneic transplants. This is due to the fact that there are relatively few patients with suitable donors and because allogeneic transplants are associated with more treatment-related complications.
ASCT is a treatment that is often reserved until multiple myeloma recurs after initial treatment or progresses with treatment. Results of clinical trials indicate that patients did not live longer if they opted for this treatment early in their disease course as opposed to waiting until their myeloma recurred. 78
Following a first ASCT, some patients may undergo a second one. This is known as a tandem, or double, transplant. Studies have suggested that patients who do not achieve a complete or very good anti-cancer response to the first ASCT are the most likely to benefit from a second ASCT.9
It is important to note that undergoing transplantation later in the treatment strategy is more likely to be successful if it is planned for. Stem cells must be collected prior to any other initial treatment because the bone marrow becomes damaged even with conventional-dose chemotherapy.
An allogeneic stem cell transplant involves stem cells collected from a donor. Compared to autologous transplant, a transplant of donor cells is associated with more side effects and a greater risk of death. The benefit of allogeneic transplant, however, is the chance for long-term survival; patients who undergo a donor transplant following cancer recurrence after conventional-dose treatment appear to have a better chance of surviving 10 years or more compared to patients who undergo an autologous SCT. 10 Thus, patients accept more upfront risks with an allogeneic transplant in exchange for the chance of long-term survival.
In an attempt to reduce treatment-related side effects, which can be significant, some researchers have explored the role of reduced-intensity allogeneic stem cell transplantation. A small study conducted in patients with poor-risk, relapsed, or refractory multiple myeloma suggested that an ASCT followed by a reduced-intensity allogeneic transplant may be an effective treatment approach for selected patients.11
The treatment of multiple myeloma is focused on treating the underlying disease (the increased number of abnormal plasma cells). Managing the symptoms and other medical problems resulting from the increased numbers of plasma cells and abnormal (monoclonal) proteins is equally important. The following complications of multiple myeloma have specific treatments available:
Bone complications: In 70% of multiple myeloma cases, the bones develop multiple holes, which explains why the disease is referred to as “multiple” myeloma. The holes are referred to as osteolytic lesions, which cause the bones to be fragile and subject to fractures. Osteolytic lesions are caused by the rapid growth of myeloma cells, which push aside normal bone-forming cells, preventing them from repairing general wear and tear of the bones. Under normal circumstances, cells called osteoclasts destroy dead and dying bone. Multiple myeloma causes the secretion of osteoclast-activating factor, a substance that stimulates osteoclasts.
Multiple myeloma involving the bone can cause pain, fracture and other significant problems for patients. Management of bone involvement is an integral part of the overall treatment strategy for multiple myeloma. The first objective of treatment of bone complications is to prevent new bone disease from developing or progression from existing bone lesions to occur.
Bisphosphonate drugs can effectively prevent loss of bone that occurs from metastatic lesions, reduce the risk of fractures, and decrease pain. Bisphosphonate drugs work by inhibiting bone resorption, or breakdown. Bone is constantly being “remodeled” by two types of cells: osteoclasts, which break down bone; and osteoblasts, which rebuild bone. Although the exact process by which bisphosphonates work is not completely understood, it is thought that bisphosphonates inhibit osteoclasts and induce apoptosis (cell death) in these cells, thereby reducing bone loss. There is also evidence that these drugs bind to bone, thereby blocking osteoclasts from breaking down bone.
Bisphosphonate drugs that are FDA-approved for the treatment of cancer-related skeletal complications include Zometa® (zoledronic acid) and Aredia® (pamidronate). Of these two drugs, Zometa® appears to demonstrate the strongest activity. An added benefit of Zometa® is that it is administered in a dose ten times lower than Aredia®, which considerably reduces the administration time from several hours to 15 minutes, resulting in a more convenient regimen for patients.
A comparison of treatment with chemotherapy plus the bisphosphonate drug Aredia® to chemotherapy alone showed that patients who received the bisphosphonate had fewer bone fractures and decreased pain. In addition, some patients lived longer.12 Research indicates that Zometa® is as effective as Aredia®. Among 1,648 patients with multiple myeloma or advanced breast cancer who had at least one bone lesion, pain and the use of pain medication was decreased with both treatments. However, patients who received Zometa® experienced significantly less need for radiation therapy to treat bone complications.13
Patients with progressive bone involvement from multiple myeloma may experience worsening pain and/or fracture of the bone from the progressive cancer. Low-dose radiation therapy, as well as analgesics, can help control the pain from bone progression of multiple myeloma.
To learn more about bone complications and bone health, go to the Bone Complications and Cancer
Hypercalcemia: Many multiple myeloma patients develop hypercalcemia, which is an increased level of calcium in the bloodstream. Hypercalcemia results from the destruction of bone from osteolytic lesions or sometimes from the development of generalized osteoporosis, in which all the bones are soft and porous and have lost calcium. Hypercalcemia in patients with multiple myeloma causes fatigue, lethargy and other symptoms. Severe hypercalcemia is a medical emergency requiring immediate treatment. Typically, hypercalcemia is treated with bisphosphonates and hydration.
Decreased blood cell production: The multiplication of the plasma cells in the bone marrow eventually crowds out and suppresses the normal production of blood cells. This may cause a significant decrease in red blood cells, causing anemia; in platelets, causing abnormal bleeding and in white blood cells, causing neutropenia.
Anemia: Anemia, or a decrease in the red blood cell hemoglobin concentration necessary for the transport of oxygen to the body’s organs, is a common complication of multiple myeloma. Anemia may cause patients to experience tiredness, fatigue, shortness of breath and/or a reduced tolerance to activity. Anemia resulting from multiple myeloma can often be treated with erythropoietin (Procrit® (epoetin alfa) and Aranesp® (darbepoetin alfa). To learn more, go to Anemia.
Infections: The depletion of normal white blood cells compromises the patient’s immunity in several ways. First, the number of monocytes and granulocytes are greatly reduced so that the patient is at risk from infections. Second, the delicate and complex balance between the different types of lymphocytes is distorted. Patients with multiple myeloma often have reduced levels of normal immunoglobulin necessary to fight certain types of infections. Patients experiencing recurrent infections may need to have immunoglobulin levels replenished. Patients who experience recurrent infections may want to ask their physician about immunoglobulin replacement therapy.
Kidney dysfunction: In 75% of patients, the plasma cells also produce monoclonal incomplete immunoglobulins, called light chains. These are excreted in the urine and are the so-called Bence Jones proteins. Bence Jones proteins are named after a British physician, Henry Bence Jones (1813-1873), who first discovered them. Bence Jones proteins may deposit in the kidney, clogging the tubules. Ultimately, this damages the kidney and can cause renal failure. Hypercalcemia may exacerbate kidney problems because excess calcium in the bloodstream causes excessive fluid loss and dehydration. Because the abnormal proteins produced by the plasma cells are eliminated from the body through the urine, they may accumulate in the kidneys and cause kidney dysfunction. In addition to treating the underlying cancer, it is important for patients to maintain adequate oral intake of fluids to help avoid kidney failure and avoid using over-the-counter medications such as non-steroidal anti-inflammatory drugs that can worsen kidney function.
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of recurrent multiple myeloma will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving the treatment of recurrent multiple myeloma include the following:
New combinations of drugs: the introduction of Thalomid, Revlimid, and Velcade has improved outcomes among patients with multiple myeloma. Nevertheless, the optimal approach to using these drugs is still being explored. Researchers are evaluating several different ways of combining these drugs with each other and with other myeloma therapies in order to further improve outcomes.
Maintenance therapy: The administration of relatively low doses of anticancer drugs after an ASCT could extend the time before cancer progression or prevent relapses. Dexamethasone and interferon are two drugs that have been investigated as maintenance therapy, but benefits remain uncertain.14 New drugs that are being evaluated as maintenance therapy include Thalomid, and Revlimid, and Velcade.
Determining the role of ASCT in the era of new drugs:Autologous stem cell transplantation (ASCT) is a standard treatment for many patients with multiple myeloma. Nevertheless, the role of ASCT in the era of newer drugs such as Thalomid, Velcade and Revlimid is unclear. New combinations of drugs may further improve the results of ASCT, or may eventually replace ASCT in the initial treatment of multiple myeloma.15
Reduced intensity allogeneic stem cell transplant: High-dose therapy followed by allogeneic stem cell transplant is currently the only potentially curative treatment for multiple myeloma. The high risk of serious complications, however, has prompted researchers to explore an alternative procedure known as a reduced-intensity allogeneic stem cell transplant. In a study of 24 patients with poor-risk, relapsed, or refractory multiple myeloma, the approach of starting with an autologous stem cell transplant and then performing a reduced-intensity allogeneic stem cell transplant (with stem cells from an unrelated donor) produced promising response rates with a lower risk of death from treatment.16
Donor lymphocyte infusions: Recent studies have indicated that patients with multiple myeloma who experience a recurrence after an allogeneic transplant achieved high response rates to donor lymphocyte infusions. Researchers from several transplant centers in Europe evaluated 27 patients with multiple myeloma who had a recurrence following treatment with HDC and an allogeneic SCT.17 All of these patients received infusions of donor lymphocytes after recurrence of the cancer. Over half of the patients experienced a partial or complete disappearance of myeloma following the infusion. Unfortunately, graft-versus-host disease, a side effect caused by donor cells attacking healthy tissue of the patient, affected over 75% of these patients. The results of this study suggest that donor lymphocyte infusions may be beneficial to patients with multiple myeloma who have a recurrence after HDC and allogeneic stem cell transplant.
Phase I clinical trials: New anti-cancer drugs are first tested in humans in phase I clinical trials. These trials usually involve a small number of patients for whom other standard therapies have failed or no known alternative therapy is available. Phase I therapy may produce anti-cancer effects and a small number of patients may be helped. However, the primary goals of this phase are to determine the evidence of anti-cancer activity in humans, the maximum tolerated dose of the treatment, the manner in which the drug works in the body, the toxic side effects related to different doses as well as the reversibility of toxic side effects. Upon completion of phase I trials, the information that has been gathered is used to begin phase II trials.
1 Richardson PG, Sonneveld P, Schuster M et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. New England Journal of Medicine. 2005. 352:2487-98.
2 Richarson PG, Hideshima T, Mitsiades C, Anderson KC. The emerging role of novel therapies for the treatment of relapsed myeloma. Journal of the National Comprehensive Cancer Network. 2007;5:149-162.
3 Orlowski RZ, Nagler A, Sonneveld P et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma. Journal of Clinical Oncology. 2007;25:3892-3901.
4 Weber DM, Chen C, Niesvizky R et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. New England Journal of Medicine. 2007;357:2133-42.
5 Singhal S, Mehta J, Desikan R et al. Antitumor activity of thalidomide in refractory multiple myeloma. New England Journal of Medicine. 1999;341:1565-1571.
6 Richardson P, Mitsiades C, Schlossman R et al. The treatment of relapsed and refractory multiple myeloma. Hematology 2007. American Society of Hematology Education Program Book; 317 – 323.
7 Fermand J-P, Ravaud P, Chevret S, et al. High-Dose Therapy and Autologous Peripheral Blood Stem Cell Transplantation: UP-Front or Rescue Treatments? Results of a Multicenter Sequential Randomized Trial. Blood. 1998;92:3131-3136.
8 Barlogie B, Kyle RA, Anderson KC et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. Journal of Clinical Oncology. 2006;24:929-936.
9 Kyle RA, Rajkumar SV. Multiple Myeloma. Blood. 2008;111:2962-2972.
10 Bjorkstrand B. European Group for Blood and Marrow Transplantation Registry studies in multiple myeloma. Semin Hematol. 2001;38:219-225.
11 Georges GE, Maris MB, Maloney GD et al. Nonmyeloablative unrelated donor hematopoietic cell transplantation for the treatment of patients with poor-risk, relapsed, or refractory multiple myeloma. Biol Blood Marrow Transplant. 2007;13:423-432.
12 Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. Journal of Clinical Oncology. 1998;16(2):593-602.
13 Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J. 2001; 7(5):377-387.
14 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. V.1.2008. © National Comprehensive Cancer Network, Inc. 2005/2006. NCCN and NATIONAL COMPREHENSIVE CANCER NETWORK are registered trademarks of National Comprehensive Cancer Network, Inc.
15 Attal M, Harousseau J-L. Role of autologous stem-cell transplantation in multiple myeloma. Best Practice & Research Clinical Haematology. 2007;20:747-759.
16Georges GE, Maris MB, Maloney GD et al. Nonmyeloablative unrelated donor hematopoietic cell transplantation for the treatment of patients with poor-risk, relapsed, or refractory multiple myeloma. Biol Blood Marrow Transplant. 2007;13:423-432.
17 Lokhorst HM, Schattenberg A, Cornelissen JJ et al. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. Journal of Clinical Oncology. 2000;18:3031-3037.
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