Treatment of Stage II-III Multiple Myeloma
Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 9/2018
Stage II or III multiple myeloma is characterized by an intermediate or high amount of cancer in the body. Patients with either of these stages of multiple myeloma often have bone complications as a result of their disease and usually experience symptoms that require treatment.
Recent advances incorporating new precision medicines, immunotherapy, stem cell transplantation, CAR T cells, and maintenance therapy have significantly improved the survival of individuals diagnosed with multiple myeloma 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 side effects, and requires a donor. CAR T cells are another recent advance playing in a role in treatment of multiple myeloma.
There are several effective chemotherapy, immunotherapy, and precision medicines used in combination as standard induction 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. A majority of patients can expect to achieve this goal with current therapies. Once this therapy is completed additional therapy with an autologous stem cell transplant (ASCT), CAR T, or maintenance therapies can further improve survival and should be discussed with your treating 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 ASCT which utilizes a patient’s own stem cells. Most clinical trials conducted over the past two decades have shown that patients who undergo ASCT after they have achieved a remission with conventional induction therapy experience improved outcomes.
It is important to consider the possibility of a future ASCT at the time of diagnosis because stem cells have to be collected and frozen early in the disease course even if the initial treatment plan involves ASCT for treatment after a myeloma recurrence.
The other reason it is important to have this discussion is that opting to plan for an ASCT determines which drugs will make up the initial treatment. Some drugs such as Alkeran® (melphalan) damage stem cells making collection difficult or impossible. Thus, patients who elect to have stem cells collected and stored are frequently treated with induction regimens that do not include Alkeran or other alkylating agents.
Standard Therapies for Multiple Myeloma
Thalomid® 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. Thalomid® is an active treatment for relapsed multiple myeloma. Results of clinical trials indicate that one-third of patients treated with Thalomid® experience an anticancer response, including patients who relapse after stem cell transplantation.1 Response to treatment may be even greater when Thalomid® is combined with other drugs.,
Revlimid® is a derivative of Thalomid® and is active in the treatment of recurrent myeloma. The addition of Revlimid® to dexamethasone has been shown to improve treatment outcomes among patients with relapsed multiple myeloma., The addition of Revlimid® to dexamethasone can also increase the occurrence of side effects such as neutropenia (low white blood cell counts) and blood clots.
Pomalyst® is an immunomodulatory drug that works by directly inhibiting the growth of blood vessels that supply nutrients to the myeloma cells. Inhibition of this angiogenesis reduces and prevents myeloma cell growth. Pomalyst® alone has shown limited effectiveness in patients with recurrent multiple myeloma, but synergistic effects have been noted when combined with dexamethasone.
Velcade® is a targeted therapy that is classified as a proteosome inhibitor. Velcade® produces its anti-cancer responses by inhibiting proteosome complexes in a cell. Proteosome complexes have many different functions in a cell, including growth and death pathways of many different proteins. Inhibition of proteosome complexes ultimately causes cellular death.) Studies have also evaluated Velcade®in combination with other therapies, and several of these combinations have produced promising results.,
Kyprolis® is a next generation proteasome inhibitor and a very effective treatment of myeloma. Patients with advanced myeloma treated with Kyprolis® in combination with Revlimid® and low-dose dexamethasone lived on average over 10 months longer compared to patients treated with Revlimid® and low-dose dexamethasone alone.
Ninlaro® is an oral proteasome inhibitor that also has promising anti-myeloma effects and low rates of peripheral neuropathy. Velcade® was the first in a new class of anticancer agents known as proteasome inhibitors to be approved for the treatment of multiple myeloma and has become a standard of care as part of initial treatment. Velcade®, Revlimid®, and dexamethasone are highly effective treatments for newly diagnosed multiple myeloma. Substituting Ninlaro® for Velcade® allows for the creation of an oral drug regimen with potential for improved patient convenience.
Darzalex® is a precision medicine-monoclonal antibody that targets the CD38 antigen on the multiple myeloma cells surface. When added to dexamethasone and either Velcade®or Revlimid®, Darzalex® improves outcomes when compared to dexamethasone and Velcade® or Revlimid® alone.,
Farydak® is a drug that belongs to a class of drugs called histone deacetylase (HDAC) inhibitors. They work by increasing the production of proteins that slow cell division and cause cell death. Adding Farydak®to Velcade® and dexamethasone is reported to improve the time to cancer progression from 8 to 12 months with over twice as many patients surviving 2 years. Longer follow up is required to determine any overall survival benefit.
Empliciti® is a precision medicine-monoclonal antibody, which binds to a protein (the CS1 glycoprotein) commonly found on myeloma cells and rarely found on normal cells. This treatment activates natural killer cells of the immune system to selectively kill myeloma cells. Empliciti® in combination with Revlimid® and low-dose dexamethasone, was evaluated in relapsed multiple myeloma. Overall, 82% of patients in the trial responded to treatment.
Standard-Dose Induction Therapy for Multiple Myeloma
Most patients with stage II or III multiple myeloma will initially receive treatment with a combination of approved medications 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 on patient age the availability of appropriate precision medicines and a patients overall 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.
The following medicines are approved by the U.S. Food and Drug Administration for the initial treatment of multiple myeloma: These medicines are typically used in combinations to attain the best results.
- Steroids (e.g., dexamethasone and prednisone).
- IMiDs (immunomodulatory drugs)
- Revlimid®: (Lenalidomide)
- Proteasome inhibitors.
- Alkylating agents
These agents are usually administered in combination with other drugs and continue to be evaluated in clinical trials. Some of the common established combinations include the following but evaluating new drugs in combination regimens is an active, ongoing area of research.
- Revlimid® and dexamethasone.
- Revlimid® Velcade® and dexamethasone.
- Thalomid®and dexamethasone
- MP (Alkeran and prednisone)
- MP plus Velcade®
- MP plus Thalomid®
- VAD (Oncovin, Adriamycin and dexamethasone)
- Cytoxan, Thalomid®and dexamethasone
Revlimid®-based therapy: Revlimid® is an oral derivative of Thalomid® which has shown significant activity for the treatment of multiple myeloma.5,6 Several clinical trials have demonstrated that Revlimid® combined with dexamethasone or Velcade improves survival and delays time to cancer progression., Revlimid® combinations are among the most active but are associated with substantially greater myelosuppression but less neuropathy than seen with Thalomid®; however, both have the same tendency for causing blood clots in the lower extremities.,,
Thalomid® -based therapy: Currently many 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. Importantly, Thalomid® doesn’t damage stem cells.,
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). 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. While patients may respond more quickly to combination chemotherapy such as VAD, overall, anticancer responses are the same with Alkeran® and prednisone.,,,
Velcade®: is classified as a proteosome inhibitor. Velcade® produces its anti-cancer responses by inhibiting the proteosome complexes in a cell. Proteosome complexes have many different functions in a cell, including growth and death pathways of many different proteins. Inhibition of proteosome complexes ultimately causes cellular death.,
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 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.
Alkeran®, prednisone, and Thalomid (MPT): The addition of Thalomid® to MP 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.
The addition of Thalomid® to MP also appears to improve outcomes in the treatment of elderly patients compared to MP 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 MP.
MPT also appears to produce longer survival compared to intermediate-dose Alkeran® followed by ASCT in the treatment of elderly patients with multiple myeloma.
Maintenance therapy is the ongoing use of a medicine or another treatment for months to years to help lower the risk of recurrence after initial therapy has induced a cancer remission. Some studies evaluating maintenance therapy using Velcade® in elderly patients have reported a delay in the time to cancer recurrence, but not all have ultimately increased overall survival.,, The use of Revlimid® maintenance after ASCT has also been shown to delay the time to cancer recurrence and prolong survival. Revlimid® is also associated with an increase in the risk of developing myelodysplasia or acute leukemia from 3% to 7%.,
High-dose Therapy and Stem Cell Transplant
A large, comparative, phase III clinical trial recently confirmed that upfront ASCT remains superior to novel agents for treatment of multiple myeloma and should still be the treatment of choice in younger patients with newly diagnosed multiple myeloma. The clinical trial evaluated a total of 1,266 patients less than 65 years of age with newly diagnosed multiple myeloma between February 2011 and April 2014.
High doses of chemotherapy are more effective at killing myeloma 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.
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 stem cells is called an ASCT. When the stem cells are from a donor the procedure is called an allogeneic stem cell transplant.
High-dose therapy followed by ASCT is a standard treatment for 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.,,
In general, ASCT is 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.
Initial High-Dose Therapy and Stem Cell Transplant or Wait Until After Relapse?
Although ASCT as part of initial therapy appears superior to novel agents for treatment of multiple myeloma some patients and physicians elect to wait until multiple myeloma recurs after initial treatment or progresses with treatment before proceeding to ASCT. Results of clinical trials indicate that patients may have similar survival whether they elect to undergo ASCT as part of initial therapy or at the time of relapse.17,18 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.” One potential advantage of early ASCT is that it involves a shorter duration of chemotherapy.
It is important to note that undergoing ASCT at the time of myeloma progression 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.
Managing Complications & Side Effects of Myeloma
The treatment of multiple myeloma is focused on controlling 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 are complications of multiple myeloma that 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.
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).
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.
Strategies to Improve Treatment
Advances in precision medicine are leading to the development of more effective treatments for multiple myeloma. Advances require that these new and innovative therapies be evaluated with cancer patients in clinical trials. Patients should discuss the role of clinical trials in the management of their condition with their doctor.
Precision Medicine- Cancer used to be diagnosed solely by a visual microscopic examination of tumor tissue and all patients received the same chemotherapy. Now, doctors are personalizing care by finding the genetic alterations within the cancer that drive its growth and use medicines that specifically counteract the cancerous effects of those genes. In addition, these “targeted therapies” are designed to treat only the cancer cells and minimize damage to normal, healthy cells. The ability to test a patients’ cancer for individual differences at the genetic level, and to make treatment decisions based on those differences is the hallmark of precision medicine.
Darzalex® (daratumumab) is a precision medicine-monoclonal antibody that targets the CD38 antigen n the multiple myeloma calls. When added to dexamethasone and either Velcade®or Revlimid®, Darzalex® improves outcomes when compared to dexamethasone and Velcade® or Revlimid® alone.,
Farydak® (panobinostat) is a drug that belongs to a class of drugs called histone deacetylase (HDAC) inhibitors. They work by increasing the production of proteins that slow cell division and cause cell death. Adding panobinostat to Velcade® and dexamethasone is reported to improve the time to cancer progression from 8 to 12 months with over twice as many patients surviving 2 years. Longer follow up is required to determine any overall survival benefit.
Kyprolis® (carfilzomib) belongs to a class of drugs known as proteasome inhibitors. They work by preventing the breakdown of protein in cancer cells, triggering their death. Patients with advanced myeloma treated with Kyprolis® in combination with Revlimid® and low-dose dexamethasone lived on average 26.3 months without their disease worsening compared to 17.6 months for patients treated with Revlimid® and low-dose dexamethasone.
Empliciti® (elotuzumab) is a precision medicine-monoclonal antibody, which binds to a protein (the CS1 glycoprotein) commonly found on myeloma cells and rarely found on normal cells. This treatment allows the immune system to selectively kill myeloma cells. Empliciti® in combination with Revlimid® and low-dose dexamethasone, was evaluated in relapsed multiple myeloma. Overall, 82% of patients in the trial responded to treatment.
Pomalyst® (pomalidomide) is an immunomodulatory drug that works by directly inhibiting angiogenesis and myeloma cell growth. Pomalyst alone has shown limited efficacy in patients with relapsed multiple myeloma, but synergistic effects have been noted when combined with dexamethasone.
Ninlaro® (ixazomib) is an oral proteasome inhibitor that also has promising anti-myeloma effects and low rates of peripheral neuropathy. Velcade® was the first in a new class of anticancer agents known as proteasome inhibitors to be approved for the treatment of multiple myeloma and has become a standard of care as part of initial treatment. Velcade®, Revlimid®, and dexamethasone are highly effective treatments for newly diagnosed multiple myeloma. Substituting Ninlaro® for Velcade® allows for the creation of an oral drug regimen with potential for improved patient convenience. In a clinical trial evaluating the oral regimen the therapy was generally well tolerated and 92% of patients experienced at least a partial disappearance of their cancer.
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.
Researchers conducted a Phase III clinical trial in 614 patients under the age of 65 who had undergone ASCT for initial treatment of multiple myeloma and then treated either Revlimid® or a placebo. Treatment with Revlimid® delayed the progression of myeloma but did not prolong overall survival.
Progression-free survival was 46 months with Revlimid® and 24 months with placebo. Overall survival is ~ 81 months in both groups.
Reduced Intensity Allogeneic Stem Cell Transplant:
Reduced Intensity Transplants: In an attempt to reduce treatment-related side effects, 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., Nevertheless, one small study has reported that ASCT followed by RIC allogeneic stem cell transplantation resulted in better overall survival than tandem ASCT.
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.
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.
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.
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