Immunotherapy in myeloma Horizons Infosheet Clinical trials and novel drugs

This Horizons Infosheet provides information on immunotherapy, a type of treatment being investigated in myeloma. The Horizons Infosheet series What is immunotherapy? provides information relating Immunotherapy is a type of cancer to novel drugs and treatment treatment which helps the immune strategies that are currently being system to recognise and kill cancer investigated for the treatment of cells. Many myeloma treatments are myeloma. The series also aims to immunotherapies. highlight the considerable amount of research currently taking place in What is the immune system? the field of myeloma. The immune system is made up of The drugs and novel strategies specialised cells, tissues and organs described in the Horizons Infosheets which work together in a process may not be licensed and/or known as an immune response. An approved for use in myeloma. You immune response protects the body may, however, be able to access from foreign organisms (such as them as part of a clinical trial. bacteria or viruses) that enter the body.

Infoline: 0800 980 3332 1 The immune system also identifies of mechanisms, allowing them and kills faulty or abnormal cells in to multiply and grow in the body. the body. Immunotherapy stimulates the immune system to work harder or White blood cells, produced in the smarter to kill myeloma cells. bone marrow, are an important part of the immune system. Different The complexity of the immune types of white blood cell, such as system means that there are plasma cells and T cells, perform many ways in which it can be specific immune functions. harnessed, and many of the different substances produced as part of the Plasma cells immune response can now be made Plasma cells make antibodies (also in the laboratory. known as immunoglobulins) and release them into the bloodstream. Immunotherapy currently in use Antibodies flag foreign or potentially There are a number of myeloma harmful organisms for removal by treatments already in use that work other cells of the immune system. partly through immunotherapy. Myeloma cells are abnormal plasma Allogeneic (donor) stem cell cells which produce a large amount transplantation works by harnessing of a single type of antibody, known the immune system of a healthy as paraprotein, which has no useful donor to attack a patient’s function. myeloma cells. However, the risk of T cells serious side effects is greater with T cells are immune cells that allogeneic stem cell transplantation circulate around the body scanning than autologous (self) stem cell for abnormal or infected cells. T cells transplantation, meaning that it is can either directly kill and remove only appropriate for a small number abnormal or infected cells, or they of myeloma patients. can stimulate healthy plasma cells to make antibodies and flag the cell For more information see the for removal. Allogeneic stem cell transplantation in myeloma Infosheet from How does immunotherapy Myeloma UK in myeloma work? Myeloma cells are able to evade the immune system through a variety

2 myeloma.org.uk The ‘immunomodulatory drugs’ Cells in the body (including (IMiDs) thalidomide, abnormal ones like myeloma cells) (Revlimid®) and pomalidomide all have antigens on their surface as (Imnovid®), are widely used in well. Antigens on abnormal cells can myeloma. They work in several also be targeted by antibodies. different ways including directly Each antibody recognises only killing myeloma cells. They also one antigen, and so millions of stimulate the immune system, which antibodies are produced by the body increases their effect. to defend against a range of foreign Daratumumab (Darzalex®) is a drug organisms or abnormal cells. licensed in the UK to treat myeloma. Monoclonal antibody drugs It is a type of immunotherapy exploit the ability of antibodies to called a monoclonal antibody (see recognise specific antigens. They following section for more about this are engineered in the laboratory type of drug). to recognise antigens specific to myeloma cells so that the immune Immunotherapies system can be directed to recognise in development and kill them. ‘Monoclonal’ means The main types of immunotherapies all one type. This means that each now being investigated for the monoclonal antibody drug is made treatment of myeloma are: up of identical copies of one type of antibody that recognise one specific • Monoclonal antibody drugs antigen, in this case a protein that • CAR- treatments is expressed by myeloma cells (Figure 1). • Oncolytic viruses monoclonal monoclonal antibody drug antibody drug Monoclonal antibody drugs Foreign organisms such as viruses and bacteria have proteins on their cell surface (known as antigens) that are specific to that organism. myeloma myeloma Healthy plasma cells produce cell cell antibodies which recognise and proteins proteins on the cell on the cell surface surface attach to antigens, flagging the monoclonal monoclonal antibody locked antibody locked organism for destruction by other onto the cell- onto the cell- immune cells, such as T cells. surface protein surface protein Figure 1. Mechanism of action of monoclonal antibody drugs.

Infoline: 0800 980 3332 3 Monoclonal antibodies are an Antibody drug conjugates established treatment in myeloma Drugs are also being developed and in many other cancers, with which combine a monoclonal some showing huge promise antibody with a chemotherapy in the treatment of myeloma. drug (known as an antibody- Daratumumab (Darzalex®), was the first drug in this group to be drug conjugate) to guide the approved for myeloma in the UK. It chemotherapy directly to the is available as a monotherapy (given myeloma cells. One of these, ® on its own) for patients who have belantamab mafodotin (Blenrep ), had three previous drug treatments, was recently licensed for use in and as a combination treatment for Europe. It contains the powerful patients at first relapse. chemotherapy drug mafodotin joined to an antibody. Mafodotin is In late 2020, a second monoclonal too toxic to be given on its own, but antibody, called isatuximab in the conjugate it only becomes (Sarclisa®), was approved for active once the antibody had guided patients in England and Wales. It it to a myeloma cell. is available in combination with pomalidomide and dexamethasone for patients who have had three For more information see the previous treatments. Belantamab mafodotin Horizons Infosheet from Myeloma UK For more information see the Daratumumab (Darzalex®) Treatment T cell engagers Guide and the Isatuximab (Sarclisa®) Antibodies called T-cell engagers Horizons Infosheet from Myeloma UK recognise two antigens, one on the myeloma cells and one on T Another monoclonal antibody drug currently being investigated cells. This brings the T cells and for the treatment of myeloma is myeloma cells into close contact, elotuzumab. and targets the T cell activity to the myeloma cells (see Figure 2). T cell For more information see the engagers are at an earlier stage Elotuzumab (Empliciti®) Horizons of development than some other Infosheet from Myeloma UK types of immunotherapy. One T cell engager currently in early clinical trials is called AMG 701.

4 myeloma.org.uk on the surface of myeloma cells. The MYELOMA T cells can then target and kill the CELL patient’s myeloma cells.

proteins on the cell CAR-T cells are used in a process surface proteins on the cell called adoptive T cell transfer. T surface cells are collected from a patient’s BiTE forming a blood and genetically modified in a link between the myeloma cell laboratory, forming CAR-T cells. The and the T cell by locking onto the cells are then multiplied and infused T CELL cell surface proteins. back into the patient (Figure 3). Following the infusion, the CAR-T Figure 2. Mechanism of action of BiTEs cells continue to multiply within the patient’s body and target and kill CAR-T cell treatments myeloma cells. CAR (chimeric antigen receptor) T Results of trials with CAR-T cell cell treatments are a personalised treatments have so far have been treatment. This means the promising with good remission treatment is tailored to an individual rates in relapsed and/or refractory patient. In this case, a patient’s own patients. However, the CAR-T T cells are taken and modified so cells do become exhausted (stop that they recognise a specific target

1. T cells are removed 1. T cells are removed from patient from patient

T cell T cell

DNA DNA

4. T cells target and 4. T cells target and modified kill myeloma cells modified kill myeloma cells gene gene

2. genetic 2. genetic modification 3. patient receives modification 3. patient receives of T cells modified T cells of T cells modified T cells

Figure 3. Adoptive T cell transfer process

Infoline: 0800 980 3332 5 working) eventually. Because CAR-T Oncolytic viruses cell treatments are tailor-made for Oncolytic viruses infect and kill an individual patient, they are very cancer cells, while having only a costly, and there is a delay of a limited effect on normal cells. number of weeks while the CAR-T When an infects cells are produced. CAR-T cell a myeloma cell, it continues to treatments currently in development multiply within the myeloma cell include idecabtagene vicleucel until the cell bursts. This causes (also called ide-cel or bb2121), and the myeloma cell to die and release JNJ-4528. The European Medicines the virus into the surrounding area Agency and the UK drug approval (Figure 4). The virus then goes on to body (NICE) are currently looking at infect other myeloma cells, causing ide-cel for relapsed and refractory them to also die. myeloma patients. At the same time, the virus causes For more information see the the immune system to mount an CAR-T cell treatments Infosheet from immune response against the the Myeloma UK myeloma cell. As such, the effects against the myeloma cells are doubled.

MYELOMA virus myeloma cell MYELOMA virus myeloma cell cell replicates bursts and dies cell replicates bursts and dies

released virus released virus spreads and spreads and infects other infects other oncolytic myeloma cells oncolytic myeloma cells virus virus

HEALTHY virus does healthy cell HEALTHY virus does healthy cell cell not replicate undamaged cell not replicate undamaged

Figure 4. Mechanism of action of oncolytic viruses

6 myeloma.org.uk An oncolytic virus currently being (such as steroids and antihistamines) investigated for the treatment before and after infusions of drugs of myeloma is pelareorep such as daratumumab, to lower (Reolysin®). the chance of infusion reactions. In severe cases, such as during CAR-T For more infomation see the treatment, a specific drug may be Reolysin® Infosheet from Myeloma UK given to damp down the CRS. Some immunotherapies such as What are the potential CAR-T treatments can also cause side effects of effects on the nervous system such immunotherapy? as confusion and stupor (becoming less alert). These can range from mild The term “immunotherapies” covers to very severe, and may need expert a wide range of treatments that work care. in different ways. Their side effects vary depending on the particular Many immunotherapies can cause treatment and how it works, and also reduced numbers in blood cells, depending on the individual patient’s which can lead to infections, bruising/ reaction to the treatment. bleeding, or anaemia. Other possible side effects include diarrhoea and Some side effects of newer fatigue. Belantamab mafodotin can immunotherapies can be serious and cause effects on the eyes. Allogeneic may need expert care. stem cell transplantation can cause One reason side effects can happen adverse effects when the donated is if the immunotherapy makes the (allogeneic) stem cells attack the person’s immune system over-react. patient’s own body (called graft- An example is release versus-host-disease). syndrome (CRS), also called infusion As immunotherapies are still in reaction. CRS can happen if the white development, new side effects may blood cells are triggered to release be discovered that are not yet known excessive amounts of chemicals about. called into the blood. This causes side effects including fever, nausea, fast heart rate and low blood pressure. Often these side effects will be short-lived and mild, but they can be serious. You will be given drugs

Infoline: 0800 980 3332 7 For an up-to-date list of UK clinical For more information about side trials involving immunotherapies, effects of immunotherapies, see the visit the Myeloma Trial Finder at Treatment Guides and the Allogeneic myeloma.org.uk stem cell transplantation in myeloma Infosheet, and for newer treatments To be enrolled on a clinical trial see the Horizons Infosheets, from patients have to meet certain Myeloma UK. conditions known as eligibility criteria. You should speak to your doctor in the first instance if you are interested in UK availability of taking part in a trial. immunotherapy treatments If you are considering taking part in a Allogeneic stem cell transplantation, clinical trial your doctor will discuss in IMiDs such as lenalidomide, and detail the risks and benefits for you. the monoclonal antibody drugs They will give you detailed information daratumumab and isatuximab to enable you to make an informed are currently available to selected decision about whether to take part. groups of patients. Elotuzumab and belantamab mafodotin are Future directions licensed for use in Europe, but are not As understanding of myeloma and approved for use on the NHS in the the immune system has grown, UK. Some patients may be treated research into immunotherapy has with belantamab mafodotin as part of advanced and some promising an expanded access scheme for the clinical trial results have been drug. generated.

For more information about drug The complexity of the immune licensing and approval, see the Health system means there are many Technology Assessment (HTA) different ways in which it can be Infosheet from Myeloma UK triggered to kill myeloma cells. Different immunotherapies are being The other immunotherapy studied which recognise different treatments for myeloma discussed in proteins on myeloma cells. this Infosheet are at an earlier stage of development, but patients may be Researchers are also looking at how given them as part of a clinical trial. in future immunotherapies could be combined with existing treatments

8 myeloma.org.uk or other immunotherapies to • A number of types of maximise their effect on the immunotherapy are now being myeloma. developed to treat myeloma. These include monoclonal Another important research area is antibodies, CAR-T cell treatments, the reasons why myeloma becomes and antibody combinations resistant to different treatments, and how this can be overcome or • The newer immunotherapies delayed. now being developed are proving effective in treating myeloma. In future, immunotherapies may They can trigger side effects that be given at earlier stages in the can be serious and need expert myeloma treatment pathway. care Researchers are looking at how best to use them. This includes • Clinical trials and other how to use them in older and non- research are helping scientists transplant eligible patients. The aim to understand better how the is always to maximise effectiveness immune system works and ways and length of response, while to harness it to treat myeloma minimising side effects. Immunotherapy is a fast-moving About this Infosheet and exciting research area, with The information in this Infosheet the potential to provide new and is not meant to replace the advice powerful treatment options for of your medical team. They are the myeloma patients. people to ask if you have questions about your individual situation. Key points For a list of references used to • Myeloma cells are able to escape develop our resources, visit the body’s immune system in myeloma.org.uk/references a variety of ways. The aim of We value your feedback about our immunotherapies is to stimulate patient information. the immune system to work harder For a short online survey go to or smarter to kill myeloma cells myeloma.org.uk/pifeedback • Some myeloma drugs already or email comments to in use are immunotherapies, [email protected] for example thalidomide and daratumumab

Infoline: 0800 980 3332 9 Other information available from Myeloma UK Myeloma UK has a range of publications available covering all aspects of myeloma, its treatment and management. Download or order them from myeloma.org.uk/publications To talk to one of our Myeloma Information Specialists about any aspect of myeloma, call our Myeloma Infoline on 0800 980 3332 or 1800 937 773 from Ireland. The Infoline is open from Monday to Friday, 9am to 5pm and is free to phone from anywhere in the UK and Ireland. Information and support about myeloma is also available around the clock at myeloma.org.uk

10 myeloma.org.uk Notes

Infoline: 0800 980 3332 11 Horizons Infosheet – Clinical trials and novel drugs: Immunotherapy in myeloma

We’re here for everything a diagnosis of myeloma brings Get in touch to find out more about how we can support you Call the Myeloma Infoline on 0800 980 3332 Email Ask the Nurse at [email protected] Visit our website at myeloma.org.uk

Myeloma UK 22 Logie Mill, Beaverbank Business Park, Edinburgh EH7 4HG Published by: Myeloma UK 0131 557 3332 Publication date: November 2016 Last updated: November 2020 [email protected] Review date: May 2021 Registered Charity No: SC026116

Myeloma Awareness Week • 21–27 June