Understanding Clinical Trials

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The International Myeloma Foundation (IMF) is here to help you. We are committed to providing information and support for people with multiple myeloma (which we refer to simply as “myeloma”) and their care partners, friends, and family members. The IMF supports the myeloma community with a broad range of resources available on our website myeloma.org, and through numerous programs and services such as publications, seminars, webinars, workshops, and the IMF InfoLine.

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IMF publications

Myeloma is a cancer that most people have not heard of at the time of their diagnosis. If you have been diagnosed with myeloma or if you suspect that you might have myeloma, the IMF can help you understand this disease so that you can take an active role in your own medical care and make good decisions about your care in partnership with your doctor.

The IMF’s Patient Handbook provides an explanation of myeloma, its diagnosis and risk stratification, its effects on the body, as well as treatment options and supportive care methods. The Patient Handbook will also point you to other helpful resources.

The IMF’s Understanding-series is intended to offer more information about a large range of myeloma-specific topics, including symptoms, treatments, and side effects that may be caused by myeloma or by its treatments.

All IMF publications are free and can be read, downloaded, or requested in printed format at publications.myeloma.org. If you prefer to read IMF publications digitally, just click on the light blue links.

Understanding myeloma vocabulary

Words in bold+blue in IMF publications are explained in a companion booklet, Understanding Myeloma Vocabulary, which you can read or download at glossary.myeloma.org. Myeloma is a complicated disease, but the language that describes it doesn’t have to be hard to understand.

Being comfortable with myeloma-related terms is helpful to understanding the content of these publications and to making your conversations with your doctor more effective.

What you will learn from this booklet

This booklet discusses clinical trials in myeloma. A clinical trial is a medical research study with people who volunteer to test scientific approaches to a new treatment or a new combination therapy. Each clinical trial is designed to find better ways to prevent, detect, diagnose, or treat a medical condition, or to answer scientific questions.

A clinical trial is launched only after laboratory studies have shown the potential of a treatment or procedure to be more effective and/or less harmful than previous methods. For patients with myeloma, clinical trials can be part of normal care that may provide earlier access to new drugs and therapies that are not yet available outside of a study.

Myeloma clinical research is very exciting, with many studies enrolling patients. To help you with personalized support for identifying clinical trial options across the U.S., the IMF has partnered with SparkCures. Visit myeloma.org/sparkcures or contact the IMF InfoLine for more information.

If you would like to explore possible participation in a clinical trial, ask your myeloma doctor if a study may be right for you, and about the potential risks and benefits that may apply to you.

Diversity in clinical trials

Historically, there has been a lack of diverse representation in clinical trials in general and in myeloma clinical trials in particular. In the U.S., approximately 20% of all myeloma patients are of African descent, but only 5%–8% of patients in myeloma clinical trials are of African descent. This is significant for the following reasons:

¡ All patients of all races and ethnicities should be able to benefit from clinical trials.

¡ Diverse patient representation in clinical trials is required to ensure that the outcomes are applicable to all patients.

Reasons for underrepresentation in clinical trials are complex and include systemic racism, accessibility of clinical trials, sensitivity to diversity by medical professionals, misconduct in medicine in the past, the lack of trust in the system, and more.

Increasing diverse representation

Multisystem challenges of improving healthcare equity require multisystem solutions. The myeloma community must unite to work together to overcome

this disparity. This is part of the objective of the IMF’s M-Power nationwide initiative to improve the short-term and long-term outcomes of patients with myeloma in Black communities.

To ensure that clinical trials reflect the diversity of the myeloma patient population, M-Power is bringing together regulators, pharmaceutical companies, healthcare systems and providers, as well as patient advocates and their care partners.

Best practices are being developed for designing clinical trials, appointing diversity officers, setting appropriate patient accrual, engaging the community at large, and including non-traditional clinical trial sites to improve access to all. Visit mpower.myeloma.org for more information.

The partnership of doctors, patients, and care partners

The critical “frontlines” of clinical trials are found in the discussions between doctors and patients and their care partners. The following tips can help myeloma patients communicate with their doctors as they consider participating in a clinical trial:

¡ Talk openly and honestly with your doctor. Discuss the purpose of the proposed clinical trial, as well as its potential benefits and the possible risks.

¡ Include in your discussion the family members or other trusted individuals who can help you with decision-making.

¡ Be aware how the history of mistrust of the medical establishment may influence your thinking about clinical trials.

¡ Do not rush the discussion. Ask all your questions and raise all your concerns, and make sure that they are addressed.

¡ Engage with local and national advocacy groups, such as the IMF, and take part in support groups that encourage dialogue and foster your understanding of clinical trials.

¡ Be sure that you understand the discussions. Ask that explanations are repeated or presented to you in ways that you are comfortable with. If your native language is not English, you can ask that a translator is provided to you.

¡ Secure as much support as possible for the logistics of participating in a clinical trial, including travel assistance, home care, meals, accommodations, etc.

¡ Have a clear understanding about the financial implications of the clinical trial, if any.

When to participate in a clinical trial

Clinical trials have the opportunity to offer new therapies for myeloma that are not approved by the U.S. Food and Drug Administration (FDA). In clinical trials, researchers don’t know if the new method will be better than standard of care (SOC) therapy for patients who are being treated now. What researchers do know is that some clinical trials will result in better treatments for patients in the future.

Taking part in a clinical trial is voluntary. Not all clinical trials are right for every patient. Potential participation in a clinical trial should be discussed in depth with your physician and healthcare team. Before agreeing to participate, patients must learn about possible risks of the therapy being studied and what other options for treatment are available.

Eligibility criteria

There are certain conditions and requirements that patients must meet in order to be enrolled in a clinical trial. When all study subjects meet the same eligibility criteria, it provides researchers with consistent data needed to answer the main question of the study.

Eligibility requirements are based on the type of clinical trial. Examples of eligibility may include age, performance status, type and stage of cancer, certain medical tests, laboratory results, other illnesses, and past treatments received.

The eligibility criteria for each clinical trial have two sections: inclusion criteria and exclusion criteria. Inclusion criteria determine who may participate in the clinical trial. Exclusion criteria are conditions that determine if a patient may not be able to participate in a study. Both the inclusion and exclusion criteria are a vital part of the research plan to get credible and consistent results.

Informed consent

Informed consent is the process that requires a doctor to give a patient enough information about a procedure, strategy, or clinical trial – including the issues of risks, benefits, alternatives, and potential costs – for the patient to make an informed decision about whether or not to consent to the proposed treatment.

Medical progress and patient safety

Clinical trials are used to further test new medications and therapies on human subjects. Clinical trials are performed using protocols that adhere to accepted standards of patient safety, informed consent, and data interpretation. Strict regulation of clinical trials helps to ensure that the balance between medical progress and patient safety is carefully maintained.

Vocabulary of clinical trials

¡ Accrual – The process of enrolling patients in a clinical trial, or the number of patients already enrolled or anticipated to be enrolled in a clinical trial.

¡ Arm – A treatment group in a randomized study, in which there are two or more arms.

¡ Cohort – A group of patients in the same study receiving the same treatment or placebo.

¡ Control group – The arm of a randomized clinical trial that receives the standard of care treatment or placebo.

¡ Dose-limiting toxicity (DLT) – When the side effects of the treatment are severe enough to prevent giving more of the same treatment.

¡ Double-blind – When neither the patient nor the investigator knows the arm of the trial to which the patient is randomized. The purpose is to eliminate any bias in the reporting of results.

¡ Endpoint – The goal of the study. A clinical trial endpoint may aim to measure toxicity, response rate, or survival.

¡ Experimental group – The arm of a randomized trial that gets the new treatment.

¡ Maximum-tolerated dose (MTD) – The highest dose of a treatment that most people can safely withstand.

¡ Placebo – An inert (inactive) substance often used in clinical trials for comparison with an experimental drug. No clinical trial for cancer patients in the U.S. can ethically or legally randomize patients to receive a placebo alone when they require treatment. In the placebo arm of a cancer treatment trial, patients receive treatment with approved therapy plus a placebo.

¡ Progression-free survival (PFS) – The length of time during and after the treatment of myeloma that a patient lives with the disease but the myeloma does not get worse. In a clinical trial, PFS is one way to measure how well the treatment is working.

¡ Progressive disease – Myeloma that is becoming worse or relapsing, as documented by tests. Defined as an increase of ≥ 25% from the lowest confirmed response value in the myeloma protein level and/or new evidence of disease.

¡ Randomized clinical trial – A study in which patients are randomly assigned to receive a particular treatment.

¡ Refractory – Disease that is no longer responsive to standard of care treatments. Myeloma is refractory in patients who have had progressive disease either during treatment or within 60 days following treatment. Most clinical trials for advanced disease are for patients with relapsed and/or refractory myeloma.

Phases of a clinical trial

Phase I clinical trial

The main goal of a phase I clinical trial is to determine the maximumtolerated dose (MTD) and safety profile of a new drug or a new combination of drugs. A phase I study may be the first testing of a new treatment in humans. Please note that in combination therapies, the individual elements may have been already well-tested in humans.

Generally, patients enrolled in phase I clinical trials have advanced myeloma that is refractory to standard of care treatment. A cohort may have 3–6 patients who are given the same treatment at the same dose. The first cohort typically gets a low dose, which is then increased in each subsequent cohort until a set number of patients experience dose-limiting toxicity (DLT). The dose level used for the previous cohort is then taken to be the MTD, which is then used as the dose in a phase II trial.

Phase II clinical trial

A study designed to determine the efficacy and safety of a new therapy that has been tested in a phase I trial. Patients are usually required to have measurable disease that is refractory to any standard of care (SOC) treatment. If the results of a phase II study are clearly much better than the SOC treatment, then the treatment may be approved without being tested in a phase III study. If results from a phase II study are promising, the treatment may then be tested in a phase III study.

Phase III clinical trial

A study that compares two or more treatments. The endpoint of a phase III study may be survival or PFS. Phase III studies are usually randomized, so patients don’t choose which treatment they receive. Some phase III trials compare a new treatment that had good results in a phase II study with a standard of care treatment; other phase III studies compare treatments that are already in common use.

Phase IV clinical trial

Even after a drug has been approved by the FDA for use in a particular indication, there may be need for additional studies. For example, safety surveillance is designed to detect any rare or long-term side effects over a larger patient population and longer time period than was possible during the phase I–III clinical trials.

Measure of efficacy

Clinical trials vary greatly in size, from a single researcher in one hospital or clinic to an international multicenter study with hundreds of participating researchers at hospitals across several continents. The number of patients in a clinical trial can range from a few individuals to several thousand patients.

Overall survival (OS) is the median number of individuals in a group who are alive after a particular duration of time. OS is often used as a measure of treatment efficacy in clinical trials. The lengthening duration of OS in myeloma clinical trials makes OS a difficult endpoint to use, and this led to the effort to validate minimal residual disease (MRD) status as a new endpoint.

In April 2024, the FDA held an Oncologic Drugs Advisory Committee (ODAC) meeting to discuss the use of MRD as an endpoint in myeloma clinical trials, including considerations regarding timing of assessment, patient populations, and trial design for future studies that intend to use MRD to support accelerated approval of a new product or a new indication.

ODAC provides independent expert advice to the FDA on broad scientific topics or on certain products to help the agency make sound decisions based on the available science. If ODAC makes a non-binding recommendation, the FDA generally follows the recommendations but is not legally bound to do so.

The IMF and collaborative research group i2TEAMM (International Independent Team for Endpoint Approval of Myeloma MRD) were key applicants to the ODAC proceedings, along with Sylvester Comprehensive Cancer Center of the University of Miami, Florida.

For this meeting, the FDA convened the advisory committee to discuss the adequacy of available data to support the use of MRD as an endpoint to support accelerated approval of new therapies for patients with myeloma.

The IMF’s International Myeloma Working Group (IMWG) has established uniform response criteria for MRD for use in myeloma. MRD has been included as an exploratory endpoint and secondary endpoint to assess response to therapies in myeloma clinical trials. When the data is robust, MRD data has been included in the prescribing information.

MRD testing has been shown to be prognostic in both frontline and relapse settings. MRD test results have affirmed PFS results that are used as basis for several FDA approvals in phase III clinical trials.

Medical insurance coverage

Tests and procedures that are considered standard-of-care (e.g., routine blood tests, imaging studies, myeloma-specific measurements) are usually covered by health insurance policies.

Study-related tests and procedures are paid for by the study sponsor. These may include additional bone marrow biopsies, more frequent skeletal surveys (metastatic surveys), magnetic resonance imaging (MRI), positron emission tomography (PET), computed axial tomography (CAT or CT), pharmacogenomics -, pharmacodynamics -, and pharmacokinetics -related tests.

In closing

This booklet is not meant to replace the advice of your doctors and nurses who are best able to answer questions about your specific healthcare management plan. The IMF provides educational information that will guide you in your conversations with your healthcare team.

To help ensure a good quality of life through effective treatment, you must have an active role in your own medical care. Please visit myeloma.org and join the IMF Myeloma Knowledge Platform at myprofile.myeloma.org.

Click on the links included in this booklet for quick access to a variety of resources. Sign up at subscribe.myeloma.org for our quarterly journal Myeloma Today and weekly e-newsletter Myeloma Minute, as well as alerts about IMF news, events, and actions.

Founded in 1990, the International Myeloma Foundation (IMF) is the world’s leading organization dedicated to multiple myeloma. The IMF is steadfast in its mission: Accelerating the prevention and cure of myeloma and improving the quality of life for patients and families.

The IMF serves people impacted by myeloma at every stage of the disease by combining world-class research, trusted education, global advocacy, and direct support. A cornerstone of this work is the International Myeloma Working Group® (IMWG) – a network of more than 300 internationally renowned researchers and clinicians who establish the guidelines that shape how myeloma is diagnosed, treated, and managed across the globe.

Through its global network of support groups, educational programs, its 24/7 generative-AI myeloma assistant Myelo® , its InfoLine staff, and its advocacy for greater healthcare access, the IMF helps people living with myeloma and their care partners navigate diagnosis, treatment, and survivorship. At the same time, the IMF ensures scientific advances translate into better care and outcomes.