Treating multiple myeloma: An interview with Janssen

We caught up with Janssen’s Dr Catherine Taylor to talk monoclonal antibodies, the rise of immuno-oncology and treating multiple myeloma…

Multiple myeloma — what is the cause of this cancer, and how does it work in the body?

It is not known exactly what causes multiple myeloma. However, exposure to certain chemicals, radiation, or viruses; a weakened immune system; and DNA mutations are thought to be potential causes or ‘triggers’.^1-5 Researchers have also identified certain factors that may increase the risk of developing multiple myeloma, including age, gender, race and other plasma cell diseases.^2,5

Multiple myeloma is a B-cell malignancy that affects the plasma cells, a type of blood cell responsible for the production of antibodies or immunoglobulins.^7-9 It is characterised by aberrant expansion of plasma cells and the overproduction of an abnormal immunoglobulin, the M protein.^7-9

Unlike other cancers, multiple myeloma does not usually take the form of a lump or tumour.^8,10 Instead, the myeloma cells rapidly divide and expand within the bone marrow to form plasma cell clones, which can damage bones and affect the production of healthy blood cells.^8,11 Additionally, plasma cell clones can migrate to other bones, affecting many places in the body, which is why the disease is called multiple myeloma.^7,8,11

Anaemia and neurologic complications are common in multiple myeloma patients.¹¹ The invasion of cell clones can destroy skeletal structures, causing bone pain and fractures.¹¹ Malignant cells may also circulate in the blood and populate multiple organs throughout the body, where accumulation of abnormal M protein can be associated with issues such as kidney failure or blood hyper-viscosity.¹¹

People living with multiple myeloma may experience and report a variety of disease-related symptoms, including a persistent dull ache in their bones, tiredness, repeated infections and shortness of breath.^7,12 These symptoms can affect the individual both physically and emotionally and can have a significant impact on their overall quality of life and their ability to carry out everyday tasks.^13,14

Rare disease

Multiple myeloma is classified as a rare disease,^15,16,17 which generally affects older people with a median age at diagnosis of 70 years.¹⁸ It is the second most common form of blood cancer,⁶ with the most recent data showing that around 39,000 new cases are diagnosed around the world each year.¹⁹ Until a cure is found, these patients live in fear of relapse following their treatment, with multiple myeloma typically becoming more aggressive with each relapse.²⁰ While some treatments have contributed to improved patient outcomes, there remains an unmet medical need.²¹

Altogether over the last decade, the advent of novel agents has resulted in a 50% improvement in median survival.⁷ Survival statistics differ across Europe: 47% of people diagnosed with multiple myeloma in the UK don’t survive more than five years after diagnosis.²² At Janssen, we are focusing our efforts on preventing and curing multiple myeloma. Our immediate aim is to provide treatment options that prolong the survival and improve quality of life for people living with multiple myeloma.

What is a monoclonal antibody and how does it differ from chemotherapy?

A monoclonal antibody, or mAb, is a type of biological therapy that mimics the action of antibodies that our bodies naturally produce as part of the immune response to pathogens, vaccines and other invaders.²³ Immunotherapeutic approaches, such as antimyeloma therapies aimed at targeting the malignant plasma cell, have been explored for some time with limited success.

Though identifying the ideal target was a major challenge, the current clinical activity using the monoclonal antibodies targeting SLAMF7 and CD38 demonstrate much promise.²⁴ MAb therapies are unique in that they operate through multiple modes of action including engaging or augmenting the immune system to target cancer cells, blocking cancer cell signalling necessary for cell division, or by carrying cancer drugs or radiation directly into cancer cells (these types of mAbs are called conjugated monoclonal antibodies).^25,26,27

Targeting proteins

Monoclonal means ‘all one type’, with mAb medications consisting of multiple copies of the same type of antibody that has been carefully engineered to attach to specific defects in cancer cells. These defects on the cancer cells are typically made up of proteins and are often specific to a type of cancer.

MAb therapies offer several advantages as potential treatments for multiple myeloma patients. Firstly, they can harness the patient’s immune system to fight the cancer by directing the immune response to targeted cells.^25,26 They can also allow for precise treatment targeting by binding only to specific proteins expressed on a target cancer cell, which is different from chemotherapies which usually affect all cells they interact with.^25,26

Sustainable response

For patients, mAbs offer an established and manageable treatment option for cancers, and are generally well tolerated.²⁸ These therapies can also be used in combination with other classes of drugs, including chemotherapy (which unlike mAbs do not discriminate between cancerous and healthy cells) providing a well-established strategy, and which can lead to better treatment outcomes.^29-31 Modern combination therapies have been found to induce rapid, deep and sustainable responses in multiple myeloma.²⁴

How does DARZALEX work in the body?

DARZALEX (daratumumab) works by binding to CD38, a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage.^32-34

DARZALEX induces rapid tumour and immune medicated cell death, helping to destroy targeted multiple myeloma cancer cells. DARZALEX induces rapid tumour cell death and immune mediated tumour cell death through complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). DARZALEX has also been found to increase the levels of CD4+ and CD8+ T-cell absolute counts and percentages of lymphocytes in peripheral whole blood and bone marrow, adding to the body’s own immune system. These signals, along with evidence that T-cell clonality is increased with DARZALEX treatment, indicate immune modulatory effects that may contribute to clinical response.^34-38

Targeting CD38 therefore has the potential to alter the biological course of multiple myeloma, significantly delaying future relapses.^21,38-40

Does it have to be combined with another drug?

DARZALEX doesn’t have to be combined with another drug. It is approved in Europe for use as a single-agent therapy (for the treatment of adult patients with relapsed and refractory multiple myeloma whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy) and has recently received approval in Europe for use in combination with standard of care (SOC) therapies (lenalidomide and dexamethasone, or VELCADE^® [bortezomib] and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy).^34,41

It has demonstrated significant single-agent efficacy in highly refractory patients.^42,43 When combined with SOC in relapsing patients, it has also demonstrated significant benefit, with improvements in progression-free survival and meaningful depth of response. The percentage of patients who experienced disease progression or death was reduced by more than 60% and rates of complete response or better doubled.^38-40,42-45

At Janssen, we remain committed to exploring DARZALEX with other standard of care regimens in all disease stages in order to maximise its potential benefits for patients. Recent advances in the treatment of multiple myeloma have resulted in demonstrable improvements in outcomes for patients²⁴ and we are excited to continue in DARZALEX’s journey.

Why is the indication for use following one prior treatment?

Despite recent advances in multiple myeloma therapy, relapse is inevitable in almost all patients. Recurrence of myeloma is typically more aggressive with each relapse, leading to the development of treatment-refractory disease and shorter survival.²⁰ Knowing that DARZALEX has demonstrated remarkable single-agent efficacy in highly refractory patients,⁴⁰ Janssen are keen to ensure that DARZALEX reaches as many patients as possible. The clinical trial programme was therefore designed to also investigate DARZALEX in patients who had received one or more prior lines of therapy.

Phase III studies

The Phase 3 POLLUX (MMY3003) and Phase 3 CASTOR (MMY3004) studies have been pivotal in the clinical development journey of DARZALEX. Data from these studies show a significantly higher proportion of patients achieving very good partial response or better, or a complete response or better, with DARZALEX in combination with standard of care treatments lenalidomide and dexamethasone (POLLUX),⁴⁴ or bortezomib and dexamethasone (CASTOR),⁴⁵ compared with standard of care alone (p<0.0001 in both studies). The addition of DARZALEX significantly reduced the risk of disease progression or death by 63% in POLLUX and 61% in CASTOR when combined with standard of care (p<0.001 in both studies).^44,45

Data from the POLLUX study was presented in the Presidential session at EHA 2016⁴⁶ and published in the New England Journal of Medicine;⁴⁴ the Phase 3 CASTOR study was presented in the plenary session at ASCO 2016⁴⁷ and also published in the New England Journal of Medicine.⁴⁵

Why do you think immuno-oncology has been so successful?

Immuno-oncology (I-O), in which the body’s own immune system is used to treat cancer, is a relatively new area of medicine that harnesses the body’s intrinsic potential for generating an effective immune response against different types of cancer.^25,48,49 Increased understanding of the fundamentals of cellular and molecular tumour immunology has helped identify many ways in which the immune system can be augmented to treat cancer.

An additional benefit is that because these agents often target the immune system and not the cancer, immunotherapies have the potential to offer adaptable and durable cancer control across a variety of tumour types, including those that were not previously considered likely to respond to immune system manipulation. Although the principles have been known for some time, early I-O agents were beset with unpredictable efficacy and considerable toxicity; it has not been until this decade that significant scientific advances have been made, changing the landscape of cancer therapeutics with the introduction of advanced I-O agents.⁴⁸

Do you think immuno-oncology will take a more prominent role in cancer treatment in the future? Is it the future of cancer medicine? 

There has been an explosion in the number of clinical studies to pursue development of next generation I-O targets, and indeed other cancer treatments, particularly where unmet need exists and therapeutic options remain limited.^48,50 Combinations with other I-O or targeted treatments where monotherapy has only shown limited efficacy have also shown promising early results.⁵⁰

However, despite the encouraging progress of I-O therapy, it must continue to be treated with respect and caution. Future developments are moving towards cells being engineered and trained to attack tumour cells, but the ability to recognise the difference between one’s healthy cells and cancerous cells can become blurred, resulting in serious and even life-threatening side effects.⁵²

With additional research and more patients treated will come deeper knowledge and better ability to mitigate risk. The huge potential of being able to provide treatment for currently untreatable diseases cannot be underestimated, bringing hope to many where previously there was none. DARZALEX is a good example of Janssen’s commitment to developing effective and innovative therapy options, which both harness the body’s own immune system to fight cancer and which target cancer cells directly.

About the author

Dr Catherine Taylor is the Medical Affairs Therapeutic Area Lead in Haematology for Janssen Oncology across the EMEA (Europe, Middle East and Africa) region. 

Dr Taylor holds a MD from King’s College London and is a member of the UK Royal College of Physicians. Prior to joining the pharmaceutical industry, she trained and practiced in Clinical Oncology in London for 7 years. She also holds the Diploma in Pharmaceutical Medicine and has completed her UK specialty training in Pharmaceutical Medicine. 

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