Get Curious with Biotechin.Asia: Prof.Chng on Multiple Myeloma, Darzalex and what it means for patients

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As a healthcare hub, we constantly aim to give voice to key opinion leaders in the healthcare ecosystem in Asia. Here, Prof.Chng Wee Joo, Centre Director of the National University Cancer Institute, Singapore (NCIS) gives us more insight into the recent approval for Johnson&Johnson’s Darzalex in Singapore.

A medical doctor by training from the University of Leeds, Prof.Chng moved to Singapore after his fellowship in Hematology. As an A*STAR international fellow, Prof.Chng also worked at the Mayo Clinic where he honed his expertise in Multiple Myeloma genetics. Prof.Chng is one of the founders of the Asian Myeloma Network and is a key leader in the field. Here he gives us an insight into the basics of Multiple Myeloma, the critical gap that Darzalex addresses and what it means to patients.

Please give our readers a brief insight into this disease.

Myeloma is a cancer arising from plasma cells, a type of immune cell that secretes antibodies and lives in the bone marrow. It is the second most common blood cancer in the world. It manifests with symptoms of anaemia, bone pain due to bone lesion, renal impairment and hypercalcaemia.

Did you have a defining moment when you wanted to work with Multiple Myeloma? Was this a pure research interest or sparked by a patient or a specific people?

I developed my interest in myeloma about 17 years ago as a trainee in hematology due to the diagnostic challenge and multi-system manifestation of the disease. At that time, there were few treatment options and little understanding of its underlying biology, so the challenge of developing better treatment and understanding of the disease was a great motivation.

As a clinician scientist, you have the unique experience of fighting Multiple Myeloma at two levels. In the frontline working with patients as well as in the lab, how have treatment regimens evolved over the years?

Yes, in the clinic we have a clear perspective of the problems. We bring this back to the lab to research in depth in order to improve treatment for our patients. In this regard, we have been focused on studying high-risk myeloma characterized by specific mutations. Patients with these mutations still have very poor outcomes, which is the current therapeutic gap and challenge. My hope is that through our research, we will be able to find better treatments to improve outcomes for these patients.

Immunotherapy is the biggest buzzword in Cancer treatment today, with experts predicting “the beginning of the end of the cancer epidemic” that has overwhelmed the world, please give our readers some insight on immunotherapy and its potential to cure patients? How has life changed for these patients after the advent of immunotherapy?

Immunotherapy is a general term that encompasses all treatments utilizing the immune system to eradicate the tumor. The idea is not new. Allogeneic Stem Cell Transplant and monoclonal antibodies which have been used to treat cancers for a couple of decades are examples of immunotherapy. Recently, advances have seen immunotherapies targeting the exhausted T-cells by releasing the brakes on them or modifying their ability to target cancers. These advances have produced very exciting results with cures achieved in very refractory blood cancers. For those where it works, it can be life changing. However, there are still significant challenges as only a few types of tumors respond to this treatment at present. It is also very expensive and some of the protocol are logistically challenging.

What are the immunotherapy options available for multiple myeloma and what are some of the common targets?

For myeloma, Daratumumab and Elotuzumab are new monoclonal antibodies that have been approved for the treatment of myeloma. Another new target in myeloma is BCMA, a molecule that is more specifically expressed in plasma cells. Currently, there are naked antibodies, antibody drug conjugate, bispecific T-cell engager (BiTE) and chimeric antigen receptor T-cells(CAR-T) that are in clinical trials, and have been developed to target BCMA. In addition, some vaccine therapies where an immune response against myeloma cells are stimulated, are also undergoing clinical trials.

What is the function of CD38 in normal cells and why is it widely expressed? What makes it a good target in multiple myeloma?

The role of CD38 in normal cells is still not well understood. It is expressed in plasma cells but also other blood cells including progenitor cells. Its level of expression is high in myeloma and it is also expressed in some pre-plasma cells, which is useful as some myeloma may arise from these early plasma cells.

DARZALEX is indicated for the treatment of patients with relapsed or refractory multiple myelomas? What are the prospects or limitations of using it as the first line of therapy in recently diagnosed patients?

DARZALEX (daratumumab) is currently undergoing clinical trials in the upfront setting. As it is well tolerated, very efficacious and combines well with other anti-myeloma drugs, I foresee no difficulties in it eventually getting approved for frontline treatment of myeloma.

Studies show that CD38 is highly expressed by plasma cell tumors at all stages. Considering this, please help us better understand the rationale for use of different drug classes such as proteasomal inhibitors and IMiDs?

IMiDs and proteasome inhibitors have a broad spectrum of activities including activating and modulating the immune system in myeloma which will augment the activity of Daratumumab.

Are there any strong features of DARZALEX that make it optimal for therapy over Isatuximab or MOR202?

There is no head to head comparison so it is unclear if there are huge advantages. However, DARZALEX has had very impressive results in phase 3 clinical trial studies whereas the other two compounds are still relatively early in their clinical development.

What was life like before the approval of DARZALEX for patients with multiple myeloma?

As myeloma is still an incurable condition, having more effective treatment is critical. DARZALEX is an important addition to the treatment armamentarium. It’s good toxicity profile and potent activity, as well as ease of combining with other therapies, make it a strong backbone for a future anti-myeloma treatment regimen.

How expensive is DARZALEX immunotherapy compared to PIs or IMiDs? Is insurance coverage for this drug available for all patients?

It is several times more costly than IMiDs and Proteasome inhibitors.

As one of the founders of Asian Myeloma Network, how do you intend to work with the industry to make DARZALEX mediated therapy more effective?

Our aim is to develop the Asian Myeloma Network (AMN) as a preferred partner for the industry in clinical trials for myeloma in Asia. We think that the situation in Asia is different. Specifically, we need to understand toxicities in Asians, as well as study combinations that are logical and affordable. We cannot rely on trials in the US and Europe to provide such information.

With CD38 CAR T cells in pre-clinical evaluation for the treatment of multiple myeloma, how do you see the monoclonal antibody field evolving? What will be the trajectory for therapy of this class?

As mentioned, CAR-T cells are still very challenging to deliver. In the short-term, good monoclonal antibodies are still very attractive as they are easier to deliver. Certainly, in the fields of treating hematological malignancies, antibodies such as Rituximab has changed the outlook of patients with lymphoma. We hope Daratumumab will do the same for myeloma.