In order to better follow Crash's treatment for multiple myeloma cancer, it is helpful to understand some of the intrusive symptoms that he may be experiencing, as well as some fundamental explanations about the different treatment aspects themselves. All information has been taken directly from literature published and distributed by the International Myeloma Foundation.
Multiple Myeloma and Monoclonal Protein
Myeloma is a cancer of the plasma cells in the bone marrow. Myeloma is synonymous with multiple myeloma and plasma cell neoplasm. Plasma cells produce antibodies, also know as immunoglobulins, which are proteins that help fight infection. Each type of plasma cell produces only one type of immunoglobulin. There are many different types of plasma cells in the body, resulting in the production of a variety of different immunoglobulins. In multiple myeloma, one particular type of plasma cell is duplicated a very large number of times, causing excess production of one type of immunoglobulin, which is referred to as a monoclonal protein, or M-protein. M-protein is also called myeloma protein, para-protein, or the protein spike. M-protein is important for diagnosis and for monitoring treatment in multiple myeloma. The free light chains are derived from the monoclonal protein. See Figure 1 below.
What are Free Light Chains?
Immunoglobulins or monoclonal proteins are composed of two types of smaller molecules, one called a heavy chain and the other called a light chain. There are five types of heavy chains, referred to by letter, with the abbreviation for immunoglobulin (lg) before the letter: lgG, lgA, lgM, lgD, and lgE. There are two types of light chains, referred to as kappa (ĸ) and lambda (λ). Each plasma cell produces only one type of heavy chain and only one type of light chain.
The heavy and light chains are produced separately within the plasma cell and are then assembled to form a whole immunoglobulin. When the light chains are attached to the heavy chains, the light chains are referred to as bound light chains. However, when the light chains are not attached to the heavy chains, they are called free light chains. For unknown reasons, the plasma cells typically produce more light chains than are required to create the whole immunoglobulin or monoclonal protein. The excess light chains enter the blood stream as free light chains (i.e. unattached to the heavy chains). Thus both in the normal situation and in patients with myeloma and monoclonal gammopathies (e.g. MGUS, or monoclonal gammopathy of undetermined significance), excess light chains enter the blood stream as free light chains. The normal levels of free light chains in serum have recently been reported, along with the normal ratio of kappa free light chains to lambda free light chains. Normal levels of kappa free light chains are between 3.3 and 19.4 mg/L, while normal levels of lambda free light chains are between 5.71 and 26.3 mg/L. The kappa/lambda ratio, which is normally between o.26 and 1.65, is as important for diagnosis and monitoring of myeloma as are the levels of kappa and lambda light chains. As one might suspect in patients with active myeloma, the free light chain levels are higher than normal. In patients with myeloma in which only light chains are produced (Bence Jones myeloma), the type of light chain corresponding to the type of myeloma, either kappa or lambda, is present in increased amounts. But excess light chains in the serum can also occur to a greater or lesser extent with all types of myeloma, not just light chain or Bence Jones myeloma.
Background Rationale for Use of High-Dose Chemotherapy and Blood Stem Cell Transplant or Rescue
• Myeloma cells and normal blood stem cells are in the same bone marrow micro-environment. As myeloma cells build up in the bone marrow, they become intermixed with normal blood stem cells responsible for the production of normal red and white cells as well as platelets. Any drugs reaching the bone marrow microenvironment can therefore damage both the myeloma cells and the normal blood stem cells.
• High-dose melphalan seriously damages normal stem cells. High-dose melphalan is a very effective treatment against myeloma, but can also permanently damage normal blood stem cells. High dosages of melphalan can be especially helpful in eradicating myeloma cells from the bone marrow. To circumvent the problem of simultaneous severe damage to and potential destruction of normal blood stem cells in the bone marrow, techniques for collecting and saving normal blood stem cells before administering the melphalan have been developed.
• Stem cells can be collected (harvested) and infused after treatment to replace those damaged by treatment. Normal blood stem cells are collected or "harvested" from the patient or donor before administration of the melphalan. The harvested normal blood stem cells are returned to the blood circulation by a process similar to blood transfusion By a seeding process, the stem cells pass from the circulation back into the bone marrow where they divide and grow to repopulate the bone marrow space. Approximately 36-48 hours after administering the melphalan are very low and do not harm the new stem cell growth. This whole process of harvest and re-infusion at the best time is called "stem cell transplant."
Types of Stem Cell Transplant
• Autologous stem cell transplant. Stem cells are harvested from a myeloma patient following initial therapy and re-infused after high-dose melphalan therapy has been administered. This is the most common type of stem cell transplant. The procedure can be performed once (single autotransplant) or twice (double or tandem transplant).
• Syngeneic stem cell transplant. Stem cells are harvested from an identical twin. In this case, the stem cells from the identical twin are infused after high-dose therapy, which can be melphalan or other agents.
• Allogeneic stem cell transplant. Stem cells are harvested from a family member who is not an identical twin, but is well matched by tissue (HLA) typing. Again, the stem cells are infused after the high-dose therapy.
• "Mini" or non-myeloablative allogeneic transplant is a newer and safer procedure than full allogenic transplant. It involves the use of reduced intensity chemotherapy in combination with an allogeneic stem cell transplant.
• Matched Unrelated Donor (M.U.D.) stem cell transplant. Stem cells are harvested from a non-family member. In this case, the stem cells are rarely a 100% tissue (HLA) match. Hence the term, "mismatch" is frequently used in this situation.
How Stem Cell Transplant is Used as a Part of Myeloma Therapy
• Following diagnosis, several options are available for initial or front-line therapy.
Typical frontline regimens currently utilized are:
• Thalidomide plus dexamethasone
• Dexamethasone alone
• Various dexamethasone combinations incorporation an anthracycline (e.g., Adriamycin® or Doxil® as part of VAD or VDD), Velcade®, or more recently Revlimid® combinations. Cytoxan® can also be used as part of the initial approach.
Full details of these treatments are discussed in other publications of the International Myeloma Foundation.
• In general, stem cell transplant is a potential option for all myeloma patients upon completion of frontline therapy. However, since transplant is an intensive approach, patients over the age of 65 years and/or those with other medical conditions may not be able to tolerate the procedure and/or may run the risk of more serious complications. If stem cell transplant is considered to be a potential option, the most important caution is to avoid use of melphalan by mouth prior to stem cell harvesting, since this can lead to damage of normal bone marrow stem cells. Thus, avoiding melphalan initially and keeping all options open is the most commonly recommended strategy. Conversely, if stem cell transplant can never be an option or is not preferred, for whatever reason, melphalan pills as a part of initial therapy can be a simple and very effective treatment.
• Stem cells are harvested and transplant is performed after initial or frontline therapy. This means that treatment is used to achieve response and at least some degree of remission before proceeding to therapy with high-dose melphalan and blood stem cell rescue.
Major details include:
•Initial therapy for 3-6 months with drugs that do not damage normal blood stem cells.
•Ideally, response is achieved with >50% reduction in myeloma protein levels and/or other indicators of active myeloma prior to the collection of normal blood stem cells. However, even less degrees of response may be sufficient to allow safe and effective stem cell collection to be performed.
What are the Benefits of High-Dose Chemotherapy with Blood Stem Cell Rescue?
• Further improvement in the level of response achieved with frontline therapy is a major advantage of high-dose therapy with stem cell transplant. Over half the time, partial responses will be improved to either VGPR (very good partial response, with >90% myeloma protein reduction) or CR (complete response, with a disappearance of measurable myeloma protein level.
• Enhanced benefits in patients who have already achieved VGPR or CR. With the advent of more frequent VGPR or CR with novel front-line therapies, the added benefit of high-dose therapy in this setting is coming under closer scrutiny. High-dose chemotherapy has conferred statistically significant benefit following traditional chemotherapy induction using, for example, VAD chemotherapy. However, novel therapy combinations can produce high levels of VGPR and CR. The additional benefit of high-dose therapy for a patient who has already achieved VGPR or CR is under investigation.
• Enhanced Response with the necessity of maintenance. A particular benefit of high-dose therapy is that added response can occur within a few weeks of the procedure. If CR or VGPR occur, then such patients can be followed and monitored without the absolute need for ongoing maintenance anti-myeloma therapy. Patients undergoing high-dose therapy also tend to be in remission longer and thus to have a longer period before treatment is required. Thus, the potential ongoing toxicity, inconvenience, and expense of maintenance can be avoided. However, depending upon the individual details, including chromosome testing, maintenance therapy and/or other (consolidation) therapy may be recommended after transplant.
• Potential benefit with double or tandem transplantation. If CR or >VGPR are not achieved with a single autologous transplant, then a second autologous (or an alternate transplant such as "mini allogeneic" (see above)) can be offered. Continuing in the attempt to achieve >VGPR with the second transplant does appear to confer benefit.
• Significance of achieving CR or VGPR. It has been generally accepted that patients achieving better response such as CR or VGPR have better outcomes (versus, for example, partial response (PR)). However, further studies are required. Having a durable response at a particular lever, whether that is a simple PR (> 50% improvement), VGPR (>90%) or CR (100%), is more important than the level of the response in itself. Response lasting > 2 years is particularly beneficial. The relative benefit of stable disease at the PR, VGPR, or CR level is under further study.
Thalidomide is a drug that was first used in the late 1950's in Europe for the treatment of morning sickness. It was later withdrawn from use when it was reported that the drug produced severe, life-threatening birth defects.
Today, the medical community has a better understanding of this drug and how it works. Thalidomide is classified as an immunomodulatory agent, which means it affects the levels of certain chemicals in the body that control the activity of cells. We know that thalidomide can produce many other effects that are helpful, such as slowing or stopping the growth of new blood vessels, called angiogenesis. Today, a program call the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.®) helps to ensure that every effort is made to use the drug safely.
Is Thalidomide The Same As Chemotherapy?
Chemotherapy works by killing cells that are dividing. These cells include cancer cells as well as some normal cells in the body. Hair loss, nausea and vomiting, and gastric upset are common side effects that occur, because some healthy cells are affected by chemotherapy. Thalidomide is not considered a form of chemotherapy. It is instead considered a new kind of treatment, because it can affect the levels of certain proteins that the body normally uses to control the activity of cells.
Today, thalidomide is approved for the treatment of erythema nodosum leprosum. However, thalidomide has also been studied in a number of other diseases, including cancer.
Clinical trials have shown that thalidomide is active against myeloma and can produce lasting complete or partial responses, as well as disease stabilization. In these trials, thalidomide has been found to be effective in patients with different stages of myeloma, including:
• Patients with newly diagnosed myeloma
• Patients who have not responded to other treatments
• Patients in whom myeloma has returned after initial successful treatment.
Additionally, thalidomide has been successful in treating myeloma either when give alone or when given in combination with the drug dexamethasone, a type of steroid. Selection of an appropriate treatment is made on a case-by-case basis. The ideal daily dose of thalidomide is under investigation. In some cases, low doses have been found to be effective alone and in combination.
Response to thalidomide therapy takes time. Generally, improvement in the disease is seen after about 3 months of treatment; however, improvements have been noted as early as 2 weeks and as late as 8 months. Once a response is achieved, the physician will determine if ongoing, or maintenance, therapy is needed. It is important to note, however, that not everyone who takes thalidomide will have a response, and other therapies may be considered.
HOW DOES THALIDOMIDE WORK?
Although scientists are still trying to understand exactly how thalidomide fights cancer, thalidomide fights cancer, thalidomide is known to work on 2 important levels. First, thalidomide is believed to boost the body's immune response to cancer. Second, it helps to block the blood supply of cancerous tumors. Cancer cells, like normal cells, need to get nutrients and oxygen from the blood to survive and multiply. Some tumors send chemicals into the body that can trigger the formation of new blood vessels. As more blood vessels grow into the tumor, it can become larger. It is thought that one way thalidomide may help to limit tumor growth is by hindering new blood vessel growth within tumors.
Thalidomide is also believed to act in several other ways against myeloma, including targeting the myeloma cells and the molecules that allow them to grow. However, these exact effects are not clear and scientists are actively studying them.
