The MMRF Immunotherapy Initiative: Immune Dysfunction in Multiple Myeloma

The MMRF launched its Immunotherapy Initiative in an effort to advance the potential of precision immunotherapy to help patients with multiple myeloma live longer. The goal of precision immunotherapy is to ensure that patients receive the best treatment based on their individual genetic and immune characteristics. The MMRF brought together leading cancer immunology experts to help find ways of using this innovative therapeutic approach in multiple myeloma. As part of the Initiative, the MMRF is investing $15 million over three years, with the aim of funding areas of research most likely to yield clinical benefits to myeloma patients as quickly as possible. The program is set to progress in phases. The first phase focuses on generating data and testing hypotheses. The second phase will focus on applying the knowledge from the first phase to novel clinical trials utilizing immunotherapy approaches.

Immunotherapy has helped change the prospects for patients with other cancers (such as metastatic melanoma, a type of skin cancer) who were previously considered difficult to treat or had few options. To understand the reasons for considering this game-changing treatment in multiple myeloma, we need to take a closer look at how immunotherapy works.

Immunotherapy Basics

Immunotherapy is designed to help the patient’s own immune system identify, attack, and kill cancer cells. Immunotherapy stimulates the immune system by directly targeting immune cells or increasing the immune response of the patient. Currently, several types of agents are used to help the immune system find and attack cancer cells. These include:

  • Antibodies that are designed to attach to specific proteins on the surface of cancer cells, thus “marking” them and making them easier for the body’s immune cells to find and destroy.
  • Immune cells from the patient or a transplant donor. Cell-based immunotherapy (also called adoptive cell transfer) uses a specific type of immune cell obtained either from the patient or from a donor. This usually involves T cells, which are white blood cells that recognize, engage, and destroy invaders like disease-causing bacteria. These cells are taken to a laboratory, changed to improve their cancer-targeting capabilities, and reintroduced into the patient. To date, two cell-based immunotherapies (Yescarta and Kymriah), called chimeric antigen receptor (CAR) T-cell therapies, have been approved by the US Food and Drug Administration (FDA) for treating patients with certain types of blood cancers.
  • Immune checkpoint inhibitors that prevent cancer cells from avoiding immune cell-mediated killing. Immune checkpoint inhibitors are antibodies that help the immune system mount a stronger response against cancer cells by binding to special proteins, called checkpoint proteins, on the surface of T cells. When checkpoint proteins attach to other proteins, it creates a signal for the T cells to stop killing. Cancer cells escape T-cell–mediated killing by making large amounts of checkpoint proteins that reduce the killing action of immune cells.
  • Vaccines that boost the anti-cancer immune response. Cancer vaccines boost the immune response against cancer cells; however, unlike other vaccines, they do not prevent disease but are used in treatment instead.

How Multiple Myeloma Inhibits and Evades the Immune System

To use immunotherapy for patients with multiple myeloma, it helps to understand how myeloma avoids detection and killing by the immune system. Myeloma cells release small proteins that inhibit the ability of the body’s immune cells to recognize and kill myeloma cells. These small proteins are called cytokines and growth factors and include interleukin 6 and transforming growth factor-beta.

Patients with myeloma also have larger numbers of myeloid-derived suppressor cells (MDSCs)— a type of blood cell—in their blood. MDSCs absorb essential amino acids, which the immune cells need to work properly, and also damage the immune cells in a process known as oxidative stress. Tumor-killing T cells are more sensitive than myeloma cells to these changes. Moreover, myeloma cells allow MDSCs to flourish. In this way, the myeloma cells ensure that their neighborhood is depleted of the “good guys”—the T cells that patrol the body and kill cancer cells to stop tumor growth—and enrich the “bad guys”—the MDSC cells that stop tumor-killing T cells from thriving.

Immunotherapies Being Used and Studied in Multiple Myeloma

Currently, there are two FDA-approved immunotherapy options for multiple myeloma, Darzalex and Empliciti. These are both antibody-based treatments. Darzalex is an antibody that targets CD38, a protein present in large amounts on the surface of myeloma cells. Empliciti is an antibody that attaches to SLAMF7, a protein found at the surface of myeloma cells and on natural killer cells (a type of immune cell—like T cells—that helps destroy tumors). Revlimid and Pomalyst—drugs from a class called immunomodulatory drugs—are also approved by the FDA to treat patients with multiple myeloma. Other promising immunotherapies are also being studied in myeloma clinical trials; these include bispecific antibodies, antibody-drug conjugates (an antibody that has a toxic drug attached to it), and CAR T-cell therapy.

The MMRF Immunotherapy Initiative includes these three major research projects:

  1. The Combined Chimeric Antigen Receptor Therapy (CAR-T) and Active Immunization project, led by Dr. David Avigan at Beth Israel Deaconess Medical Center in Boston, Massachusetts, focuses on developing CAR T-cell therapies combined with personalized vaccines.
  2. The Dissecting Immune Regulation and Dysfunction Within the Bone Marrow Microenvironment project, led by Dr. Ivan Borrello at Johns Hopkins University in Baltimore, Maryland, focuses on understanding the role of the patient’s immune system and bone marrow in myeloma progression. The goal of this project is to find a way to test the bone marrow microenvironment and predict the patient’s response to immunotherapy.
  3. The Defining Optimal Tumor and Host Signatures for Immunotherapy of Myeloma project, led by Dr. Ola Landgren at Memorial Sloan Kettering Cancer Center in New York City, focuses on analyzing changes in genes, proteins, and serologic markers (chemicals or proteins in blood serum). The goal of this project is to predict a patient’s response to immunotherapy and identify changes that can be targeted by specific treatments.

If you’d like to know more about any of these initiatives or have any remaining questions please contact our Nurse Patient Navigators in the MMRF Patient Support Center.


Additional Resources

MMRF Immunotherapy Initiative: Chimeric Antigen Receptor (CAR) T-Cell Therapy.

ASH 2018 – Darzalex/Empliciti update.

MMRF Strategic Plan 2019. Immunotherapy.

Emerging Immunotherapy Treatments in Myeloma: CAR T-Cell Therapy and BiTEs.

Monoclonal Antibodies and Vaccines: Emerging Myeloma Treatments.