Stages II-III Multiple Myeloma
Stage II or III multiple myeloma is characterized by an intermediate or high amount of cancer in the body. Patients with these stages of multiple myeloma typically have bone complications as a result of their disease and usually experience symptoms that require treatment.
With current therapy, curing patients with multiple myeloma is uncommon; recent advances in treatment, however, have prolonged survival by several years. The only potentially curative treatment for multiple myeloma remains high-dose therapy followed by a stem cell transplant using donor cells (allogeneic stem cell transplant). This treatment, however, is associated with significant side effects and is only appropriate for younger patients or those who have failed other therapies.
There are a large number of effective chemotherapy drugs now available for initial, standard-dose treatment of patients with multiple myeloma. The main goal of initial therapy of multiple myeloma is to produce a complete or near complete disappearance of myeloma cells in the body. Approximately 30-50% of patients can expect to achieve this goal.
About this Treatment Information
The following is a general overview of conventional and investigative treatments for stage II-III multiple myeloma. Cancer treatment may consist of chemotherapy, targeted therapy, high-dose therapy and stem cell transplant, 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.
Planning Treatment for Multiple Myeloma
Before beginning treatment for multiple myeloma your physician may discuss with you the option of undergoing high-dose chemotherapy with an autologous stem cell transplant, which utilizes the patient’s own stem cells. Most of the clinical trials conducted over the past two decades have shown that patients who undergo autologous stem cell transplantation after they have achieved a remission with conventional chemotherapy are more likely to experience a prolonged time to disease progression compared to patients who undergo only conventional therapy.
It is important discuss the possibility of a future autologous stem cell transplant at the time of diagnosis because stem cells have to be collected and frozen early in the disease course even if the treatment plan involves reserving the transplant for treatment after the disease recurs.
The other reason it is important to have this discussion is that opting to plan for an autologous stem cell transplant determines which chemotherapy drugs will make up the initial treatment. Alkeran® (melphalan) damages stem cells making collection difficult or impossible. Thus, patients who elect to have stem cells collected and stored are frequently treated with a Thalomid® (thalidomide)-based regimen that does not include Alkeran. Patients who elect not to receive a stem cell transplant, or who are not candidates for stem cell transplantation because of advanced age or poor health, are often treated with an Alkeran-based regimen.
Standard-Dose Systemic Therapy for Multiple Myeloma
Most patients with stage II or III multiple myeloma will initially receive standard-dose chemotherapy. The main goal of initial treatment is to induce a complete or near complete disappearance of myeloma cells, and this treatment is sometimes referred to as induction therapy. The selection of initial therapy depends largely on patient age and general medical condition. Patients in good health irrespective of age are often treated aggressively to produce a complete remission while more debilitated patients receive less aggressive therapy at the beginning of treatment.
There are a large number of chemotherapy drugs approved by the US Food and Drug Administration for initial treatment of multiple myeloma, including the following:
- Alkeran® (melphalan)
- Adriamycin® (doxorubicin)
- Oncovin® (vincristine)
- Thalomid® (thalidomide)
- Cytoxan® (cyclophosphamide)
- Velcade® (bortezomib)
These agents are usually administered in combination with other drugs. Some of the common combinations include:
- Thalomid and dexamethasone
- MP (Alkeran and prednisone)
- MP plus Velcade
- MP plus Thalomid
- VAD (Oncovin, Adriamycin and dexamethasone)
- Cytoxan, Thalomid and dexamethasone
Thalomid-based therapy: Currently more than 70% of newly diagnosed patients receive a combination that includes Thalomid. Results of clinical trials indicate that combination treatment with Thalomid and dexamethasone produces anticancer responses in approximately two-thirds of patients, which is significantly improved over dexamethasone treatment alone.1,2
Alkeran-based therapy: Prior to the widespread use of Thalomid the most frequently used regimens were Alkeran and prednisone and Oncovin, Adriamycin and dexamethasone (VAD).3 Alkeran-based therapy is still the most common treatment for patients who do not plan to undergo autologous stem cell transplant at some point in their disease course.
Alkeran and prednisone has been shown to produce anticancer responses in more than half of patients (60%), and that response lasts for a year and a half, on average. Patients typically survive two to three years after treatment with Alkeran and prednisone.4 While patients may respond more quickly to combination chemotherapy such as VAD, overall, anticancer responses are the same with Alkeran and prednisone.5
Alkeran, prednisone, and Velcade: A benefit of Velcade among patients with previously untreated multiple myeloma was demonstrated by the phase III VISTA trial. Study participants received treatment with either MP (Alkeran and prednisone) alone or MP plus Velcade. A complete response (complete disappearance of detectable myeloma) occurred in 30% of patients treated with MP plus Velcade, but only 4% of patients treated with MP alone. Patients treated with Velcade also had better progression-free survival.6
Alkeran, prednisone, and Thalomid (MPT): The addition of Thalomid to Alkeran/prednisone appears to produce quick and lasting anticancer responses in the treatment of patients with newly diagnosed multiple myeloma. Clinical trial results indicate that patients responded to MPT treatment within four months and nearly three-quarters of patients experienced a partial or near-complete disappearance of their myeloma. Approximately nine out of 10 patients (91%) survived two years or more after treatment.7
The addition of Thalomid to Alkeran/prednisone also appears to improve outcomes in the treatment of elderly patients compared to Alkeran/prednisone alone. More than three-quarters (76%) of patients treated with the three-drug combination experienced complete or partial remissions compared to less than half (47.6%) of patients treated with Alkeran/prednisone.8
MPT also appears to produce longer survival compared to intermediate-dose Alkeran followed by autologous stem cell transplantation in the treatment of elderly patients with multiple myeloma.
High-dose Therapy and Stem Cell Transplant for Multiple Myeloma
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 stem cells in the bone marrow that develop into mature blood 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.
High-dose therapy followed by autologous stem cell transplant (ASCT) is a standard approach to treating patients with stage II or III multiple myeloma. Following an initial ASCT, some patients may benefit from a second ASCT. 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
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. In an attempt to reduce treatment-related side effects which can be significant, some researchers have explored the role of reduced-intensity (RIC) allogeneic stem cell transplantation. This approach carries a lower risk than conventional allogeneic stem cell transplant, but has also been linked with a higher risk of relapse.10 Nevertheless, one small study has reported that ASCT followed by RIC allogeneic stem cell transplantation resulted in better overall survival than tandem ASCT.11
Initial High-Dose Therapy and Stem Cell Transplant or Wait Until After Relapse?
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. 1213 Based on these findings, a recent review of multiple myeloma concluded that the timing of ASCT “is based on patient and physician preference and the ability to cryopreserve stem cells.”9 A potential advantage of early ASCT is that it involves a shorter duration of chemotherapy.
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.
Supportive Care: Managing the Side Effects of Myeloma
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 proteins is equally important.
The following complications of multiple myeloma have specific treatments available:
- Bone complications
- Decreased blood cell production
- Kidney dysfunction
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.
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) or 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. To learn more, go to Neutropenia.
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 multiple myeloma will result from the continued evaluation of new treatments in clinical trials.
Patients may gain access to better treatments by participating in a clinical trial. Participation in a clinical trial also contributes to the cancer community’s understanding of optimal cancer care and may lead to better standard treatments. 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 stage II-III multiple myeloma include the following:
New Targeted Therapy
Revlimid® (lenalidomide): Revlimid is a derivative of thalidomide which has shown significant activity for the treatment of multiple myeloma. The combination of Revlimid and dexamethasone has been shown to be effective in previously-treated myeloma patients, and studies suggest that this combination may have a role in induction therapy as well.14 In this setting, the combination of Revlimid with low-dose dexamethasone appears to result in better survival than the combination of Revlimid with high-dose dexamethasone.
Revlimid is also approved by the US Food and Drug Administration for patients who have failed one line of therapy and will probably be approved in the near future for first-line therapy.
New Combinations of Drugs:
The identification of new drugs with activity against multiple myeloma raises the question of whether new combinations of drugs will increase response rates and survival. For example, Velcade – a drug approved for both first-line and subsequent treatment of multiple myeloma – has demonstrated effectiveness when combined with Alkeran and predisone in patients with previously untreated multiple myeloma. Promising results have also been observed for Velcade in combination with Thalomid and dexamethasone prior to stem cell transplantation.15
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.16
More Individualized Treatment
There is no longer a “one-size-fits-all” approach to cancer treatment. Even among patients with the same type of cancer, the behavior of the cancer and its response to treatment can vary widely. By exploring the reasons for this variation, researchers have begun to pave the way for more personalized cancer treatment. It is becoming increasingly clear that specific characteristics of cancer cells and cancer patients can have a profound impact on prognosis and treatment outcome. Although factoring these characteristics into treatment decisions makes cancer care more complex, it also offers the promise of improved outcomes.
In the case of myeloma, specific chromosomal changes can be used to identify patients with “high-risk” myeloma. These high-risk patients have relatively poor survival even with ASCT, and may be candidates for alternative approaches to treatment.17
1 Weber D, Rankin K, Gavino M, et al. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. Journal of Clinical Oncology. 2003;21:16-19.
2 Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. Journal of Clinical Oncology. 2006;24(3):431-6.
3Alexanian R, Dimopoulos M. The treatment of multiple myeloma. New England Journal of Medicine. 1994;330:484-489.
4 Gregory WM, Richards MA, Malpas JS, Combination chemotherapy vs. melphalan and prednisolone in the treatment of multiple myeloma: An overview of published trials. Journal of Clinical Oncology. 1992;10:334-342.
5 Gregory WM, Richards MA, Mlpas JS. Combination chemotherapy vs. melphalan and prednisolone in the treatment of multiple myeloma: An overview of published trials. Journal of Clinical Oncology. 1992;10:334-342.
6Millennium Pharmaceuticals. FDA approves Velcade® (bortezomib) for injection for patients with previously untreated multiple myeloma. Available at: https://investor.millennium.com/phoenix.zhtml?c=80159&p=irol-newsmediaArticle&ID=1168334&highlight=. Accessed June 2008.
7 Palumbo A, Bertola A, Musto P et al. Oral Melphalan, Prednisone, and Thalidomide for Newly Diagnosed Patients with Myeloma. Cancer. 2005;104:1428-33.
8 Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomized controlled trial. The Lancet. 2006;367:825-831.
9 Kyle RA, Rajkumar SV. Multiple Myeloma. Blood. 2008;111:2962-2972.
10 Harousseau J-L. Role of stem cell transplantation. Hematology/Oncology Clinics of North America. 2007;21:1157-1174.
11 Bruno B, Rotta M, Patriarca F et al. A comparison of allografting with autografting for newly diagnosed myeloma. New England Journal of Medicine. 2007;356:1110-1120.
12 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.
13 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.
14 Rajkumar SV, Jacobus S, Callander N et al. A randomized trial of lenalidomide plus high-dose dexamethasone (RD) versus lenalidomide plus low-dose dexamethasone(Rd) in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. Presented at the 49th Annual Meeting of the American Society of Hematology, Atlanta, Georgia, December 8-11, 2007. Abstract 74.
15Cavo M, Patriarca F, Tacchetti P et al. Bortezomib (Velcade®)-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD) in preparation for autologous stem-cell (SC) transplantation (ASCT) in newly diagnosed multiple myeloma (MM). Presented at the 49th Annual Meeting of the American Society of Hematology, Atlanta, Georgia, December 8-11, 2007. Abstract 73.
16 Attal M, Harousseau J-L. Role of autologous stem-cell transplantation in multiple myeloma. Best Practice & Research Clinical Haematology. 2007;20:747-759.
17 Dispenzieri A, Rajkumar SV, Gertz MA et al. Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clinic Proceedings. 2007;82:323-341.
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