Patients Starting Treatment:

Thanks to the efforts of the MMRF, there is tremendous progress in the field of myeloma research and scientific advances now offer and unprecedented opportunity to treat myeloma patients. This section will help you better understand the treatment options for myeloma. It provides information about how treatments are chosen, and the goals and outcomes of treatment, as well as an overview of currently available therapies and how they are used in myeloma.

Information regarding treatments for the disease is constantly changing, and the MMRF will update this section as new discoveries take place. The MMRF advises patients and caregivers to work with their physicians regarding specific questions relating to treatment and urges health care professionals to share this information with their patients.

Information about specific treatments can be found using the links below.

Revlimid^® (lenalidomide)
Velcade^® (bortezomib) for Injection
Thalomid^® (thalidomide)
High Dose Chemotherapy and Stem Cell Transplantation

Treatment Overview

• What factors help determine treatment?
  
• What are the goals of treatment?
• What are the potential outcomes of treatment?
• What therapies are used in myeloma?
• How is myeloma treated?
• What are some questions to ask my doctor?

What factors help determine treatment?

Deciding on a particular treatment for myeloma is a complex process. Treatment is tailored to each patient according to several factors, including:

• results of the physical exam
• results of laboratory tests
• the specific stage or classification of their disease
• their age and general health
• their symptoms
• whether complications of the disease are present
• whether they have previously received treatment for their disease
• their lifestyle and their view and philosophy on quality of life

Disease Classification

Patients with myeloma can be classified as having either inactive disease or active disease.

Inactive disease is asymptomatic disease that does not require immediate treatment. Patients with inactive disease do not have evidence of any myeloma-related organ or tissue impairment (also known as end-organ damage). Inactive disease includes the following classifications subtypes of myeloma:

• Monoclonal gammopathy of undetermined significance (MGUS)
• Smoldering myeloma (SMM)
  • Stage I disease

Active disease is symptomatic disease that requires treatment. Patients with Stage II and Stage III disease fall into this category.

Disease Status

The treatment options available to a patient also take into account their disease status, that is, whether they have already received therapy and if so, what was the outcome.

Patients with newly diagnosed disease are individuals who have myeloma that has not yet been treated.

Patients who have received therapy may fall into several categories:

• Responsive disease refers to myeloma that is responding to therapy. There has been a decrease in M protein of at least 50%. Some myeloma groups consider a decrease in M protein between 25% and 50% to be a minimal response whereas others consider this to be stable disease.
• Stable disease refers to myeloma that has not responded to treatment (ie, the decrease in M protein has not reached 50%), but has not progressed (gotten worse). Some myeloma groups consider a decrease in M protein between 25% and 50% to be a minimal response.
• A plateau is reached when the outcome of therapy, be it a response or stable disease, has leveled off and disease parameters remain at a stable level.
• Progressive disease refers to active myeloma that is worsening (ie, increasing M protein and worsening organ or tissue impairment [end organ damage]). In most cases, relapsed and/or refractory disease can be considered to be progressive disease.
• Relapsed disease refers to myeloma disease that initially responded to therapy but has then begun to progress again. Patients may be further classified as having relapsed after initial therapy or after subsequent therapy.

What are the goals of treatment?

Treatment regimens may be designed to meet one or more different therapeutic goals, which can include:

• Destroying all evidence of disease, which may require accepting higher levels of toxicity
• Controlling disease activity to prevent damage to other organs of the body, using a regimen with an acceptable toxicity level
• Preserving normal performance and quality of life for as long as possible with minimal intervention
• Providing lasting relief of pain and other disease symptoms, as well as managing side effects of treatment
• When applicable, managing myeloma that is in remission over the long-term

What are the potential outcomes of treatment?

There are several potential outcomes of treatment in myeloma, which can be categorized based on levels of M protein and other disease parameters. Stringent response criteria, such as those listed in the table below, are used to define response to therapy in myeloma clinical trials. Recently revised response criteria known as the International Myeloma Working Group (IMWG) Uniform Response Criteria are now being incorporated in some new myeloma trials. Note that response may also be referred to as remission; these terms are interchangeable.

We have made much progress in our understanding of myeloma and the development of many new effective therapies. However, we have yet to achieve the maximal benefit possible with regard to patient survival and improvement in quality of life. For these reasons, patients with myeloma should strongly consider participating in a clinical trial if it is an appropriate option for them.

What therapies are used in myeloma?

Myeloma therapy is tailored to each patient. It is important to note that there is no one "standard therapy" for active myeloma. The treatment regimens that are often referred to as standard therapies are those that have been traditionally used for the treatment of the disease and proven effective in clinical trials.

The various treatments used in myeloma are summarized in the table below.

How is myeloma treated?

Treatment of myeloma can be a complex process because many factors must be taken into account, such as the patient's overall state of health, other medical issues/diseases, and how well the disease is currently controlled, as well as the type, number, and response to previous therapy. Moreover, there is no single test result that can lead to a diagnosis of myeloma and determine its prognosis; many factors must be considered.

Many centers have developed their own guidelines for treating myeloma and these may vary from center to center. The National Comprehensive Cancer Network (NCCN) has also developed a set of general practice guidelines to aid physicians in treating myeloma. These guidelines indicate particular therapies that have been deemed appropriate based on a review of the literature and on the expertise and clinical experience of a panel of experts. (NCCN Practice Guidelines in Oncology. Multiple Myeloma. Available at www.nccn.org.)

To further advance therapy for multiple myeloma, it is highly suggested that all eligible patients be included on clinical trials. Clinical trials, especially Phase II and Phase III trials, are designed to be at least as effective as what is considered standard therapy.

Treatment approaches to myeloma depend on whether a patient has inactive or active disease. This section provides an overview of the various treatment approaches and therapeutic options for myeloma.

Inactive Disease

Patients with inactive (asymptomatic) disease are typically observed and not treated unless their disease begins to progress. No therapy is recommended outside of a clinical trial unless there is evidence of active disease with end organ damage. However, in some cases, bisphosphonates and other forms of supportive may be appropriate for patients with smoldering myeloma or Stage 1 disease. Participation in a clinical trial is also an option. For example, agents such as thalidomide are being tested in patients with inactive disease. You can access the MMRF Patient Navigator Program to see what clinical trial options might be appropriate for you.

Active Disease

Patients with newly-diagnosed, active (symptomatic) myeloma typically receive some form of initial therapy, as well as bisphosphonates and supportive care as required to treat bone disease and other complications of the disease. Subsequent treatment options are often decided based on previous treatments received and the outcome.

The pathway below and the text that follows outline the typical options available to a newly-diagnosed patient with symptomatic myeloma requiring treatment. Participation in a clinical trial is an option at virtually every step in the pathway.

The choice of initial therapy is dependent on whether a patient is a candidate for high-dose chemotherapy and stem cell transplant. Patients under the age of 65 in good physical condition with adequate kidney, lung, and heart function are potential transplant candidates. However, older patients may be eligible if they are in very good health.

Individuals Who Are Not Candidates for a Transplant

Advances in myeloma research have expanded the treatment options for individuals who are not candidates for stem cell transplantation. For these individuals, drugs are given at standard doses to avoid damage to normal cells. At one time, the most common initial treatment was the combination of melphalan and the corticosteroid prednisone (a combination referred to as MP). Now however, Velcade (bortezomib) and Thalomid (thalidomide) are being combined with MP and other agents for use as front-line therapy. These drug combinations have been shown to offer improved response rates compared with standard MP. The combination of MP and newer agents approved for use as second-line therapy, such as Revlimid (lenalidomide), also have been shown to be more effective than MP alone. However, the increased efficacy must be balanced against a potential increase in side effects.

In addition, regimens that are options for individuals who are candidates for stem cell transplantation may also be appropriate for individuals who are not transplant candidates. These include regimens such as low-dose dexamethasone alone or in combination with Revlimid, Thalomid, or Velcade, and other Velcade-based regimens, as described below.

Initial therapy for myeloma is continued for about a year or until the response of the disease to the treatment reaches a plateau. At that time, the individual may be followed-up closely with no therapy (often referred to as "observation") or the doctor may ask the individual to consider maintenance therapy, which may be also done with the patient participating in a clinical trial.

Individuals Who Are Candidates for a Transplant

Stem cell transplantation involves the use of higher than conventional doses of chemotherapy, and the stem cells provided by the transplant replace normal cells damaged by the chemotherapy. This approach offers a chance for a good response and survival, but the individual must be able to tolerate the side effects of the higher doses of chemotherapy. Therefore, potential candidates must be in good physical condition, with adequate kidney, lung, and heart function.

Induction Therapy

Before the transplant is done, initial treatment, referred to as induction therapy, is given to reduce the amount of myeloma cells. Because prolonged use of melphalan may impair the ability to collect stem cells for use in a transplant, MP and MP-based regimens are not options for transplant candidates.

One of the most commonly used induction therapies had been the combination of Thalomid and dexamethasone (Thal-dex). However, Revlimid and Velcade, in combination with dexamethasone and other agents, are now being used more frequently as induction therapy. For example:

• Revlimid and low-dose dexamethasone (known as Revlimid-low-dose dex) has been found to be a highly effective induction regimen and is associated with better outcomes than Revlimid and high-dose dexamethasone; it may also be better tolerated.
• Velcade-based regimens, such as Velcade and dexamethasone (Velcade-dex); Revlimid, Velcade, and dexamethasone (Rev-Vel-dex); Velcade, Thalomid, and dexamethasone (Velcade-Thal-dex); and Velcade and Doxil, may also be options for individuals who are candidates for a transplant.

Participation in a clinical trial, such as one evaluating an investigational induction regimen that includes Velcade, Revlimid, Thalomid, or Doxil, is also an appropriate option for patients considering a transplant.

High Dose Chemotherapy and Stem Cell Transplantation

Stem cells are normally found in the bone marrow and in the peripheral blood (blood found in the arteries or veins). Virtually all transplants in myeloma are now obtained from the peripheral blood and are referred to as peripheral blood stem cell (PBSC) transplants.

Stem cell transplantation is done after completion of induction therapy. With an autologous transplant, the individual's stem cells are collected (also called "harvested") and are reintroduced following high-dose chemotherapy.

An allogeneic transplant involves collecting stem cells from a donor (usually a relative of the individual with myeloma) and infusing them into the individual after high-dose therapy. This type of transplant is infrequently performed today because of the high risk of complications. A mini (nonmyeloablative) allogeneic transplant is a modified form of allogeneic transplant in which a lower dose of chemotherapy is used.

What are some questions to ask my doctor?

1. Should I be treated now or should therapy be delayed?
2. What is the expected outcome of the treatment? What are the goals of this therapy (is it given primarily to treat the disease or to relieve symptoms)?
3. What is the recommended treatment? Is it a single drug or a combination of drugs? How is the drug administered: orally or intravenously (by IV)? How long is treatment given? How will I be monitored?
4. Am I a candidate for stem cell transplantation? If so, what kind — autologous or allogeneic?
5. How likely is a complete or partial remission? What factors contribute to better or worse odds?
6. How will I feel during and after treatment? What kinds of side effects might I expect? What should I do if I experience side effects? What kind of impact will treatment have on my daily life?
7. How long is the typical recovery time? Is there any follow-up or maintenance therapy?
8. What is the cost of therapy? What costs will my insurance cover and what costs will I have to pay?
9. What are the alternatives to this treatment? How do the different therapies (standard and alternative) compare with respect to effectiveness and side effects?
10. Are there any clinical trials that are appropriate for me? If so, what is involved? What are the potential risks and benefits? What are the costs?
11. If one or more types of treatment fails, what are my options?