Multiple myeloma: a transformation in treatment

Multiple myeloma: Danielle Barron reports

Danielle Barron speaks to Harvard Professor Kenneth Anderson about the impact of new treatments on outcomes in multiple myeloma.

Dr Kenneth Anderson is the Kraft Family Professor of Medicine at Harvard Medical School as well as Director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Centre at the Dana-Farber Cancer Institute.

As one of the top researchers in the field, he has witnessed first-hand the positive progress in multiple myeloma treatment in recent years and its tangible impact on patient outcomes. This transformation is even more dramatic when one considers the ineffectiveness of previous treatments.

“When I began treating patients with multiple myeloma, which is well over three decades ago, the therapies were very ineffective. The responses were very transient, and the side effects profiles were very high,” explains Professor Anderson.

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“Therapy did not meaningfully impact survival, and complications in bone led to pain and fractures, limiting the quality of life as well.”

With the advent of high dose therapy and stem cell transplant in the 1980s and 1990s, and more recently with novel targeted therapies and immune therapies, the outlook for patients with multiple myeloma has been completely transformed, Professor Anderson says.

“Novel agents such as proteasome inhibitor bortezomib and immunomodulatory drug lenalidomide used in combination, with or without stem cell transplant, can achieve high response rates and extent of response, and markedly prolong survival. At the same time, advances in the management of complications have improved the quality of life. For example, since the early 1990s the ability to reduce complications in bone using bisphosphonates has markedly improved the quality of life for patients with myeloma.”

There have been a staggering 22 FDA-approvals for treatments for multiple myeloma in the past decade and a half, he adds. “The ability to use these agents at all stages of disease – to treat newly- diagnosed patients, relapsed patients, and as maintenance therapies_ has transformed the outlook for patients with myeloma and their families.”

Because of this, the way multiple myeloma patients are treated has not only changed dramatically, but also their expected outcomes, Professor Anderson continues.

“We have the immunomodulatory drugs, proteasome inhibitors, an HDAC [histone deacetylase] inhibitor, and monoclonal antibodies. As a result of using these classes of drugs, usually in combination, patients are living three to four times longer, and many patients now have multiple myeloma as a chronic disease,” he explains.

According to the professor, the excitement going forward in multiple myeloma is concentrated in two major areas. The first is understanding the genomics, or abnormalities within myeloma, that allow it to grow, survive, and resist drugs. “Targeted therapies are directed to interrupt these abnormally-circuited cells very selectively and potently, and because these targeted therapies are acting selectively on the cancer cells, they are also likely to be very well-tolerated,” he says.

The second area is that of immune treatments for myeloma. “These are very exciting and include monoclonal antibodies which bind to myeloma cells, allowing for their immune depletion. A second modality is immunotoxins, which are monoclonal antibodies bound to toxins that selectively deliver these toxins to the tumour cells,” says Professor Anderson.

He adds that the third class of immunotherapies are bispecific T-cell engagers (BiTEs). “These off the shelf novel agents bind to the tumour cell by virtue of BCMA antigen expressions and at the same time bind and attract immune T cells to the tumour. These BiTEs have the opportunity to deliver high immune activity exactly at the site of the tumour, and are therefore likely to be very effective and well-tolerated, with few side effects,” he explains.

CAR-T cells (chimeric antigen receptor) are perhaps the most newsworthy of the new wave of treatments. Professor Anderson explains that immune T cells are harvested from patients and then transfected so that they are activated against particular targets, commonly BCMA (B cell maturation antigens) in myeloma.

“These activated cells against BCMA are grown up in large numbers in the laboratory, and then transfused to the patient as their own immune army. The CAR T cells have achieved remarkable responses, even in patients who have had multiple prior treatments. There is much ongoing research to improve the efficacy, the sustainability, and tolerability of CAR-T cells.” According to Professor Anderson, the outlook in myeloma has “never been brighter”.

“On one hand we have targeted therapies that can be utilised in combinations to achieve unprecedented levels of response such as minimal residual disease (MRD), fewer than one myeloma cell in one million normal cells. Then we have the immune therapies, which have the ability to restore in patients immune activity towards myeloma. The combination of achieving minimal MRD, coupled with the ability to restore in patients an immune activity against their own myeloma cells, is highly likely to further improve patient outcome in myeloma.”

So, what does the not-too-distant future hold for multiple myeloma treatment? Professor Anderson is unequivocal when he says a chronic disease and potential cure for the condition is on the horizon. “We will be approaching newly-diagnosed patients with myeloma with combinations of targeted and immune therapies which will achieve an unprecedented extent of response, MRD negativity The ability with immune treatments not only to deplete tumour, but also to restore immune activity in patients against their own tumour, will markedly prolong those responses. Achieving minimal residual disease and maintaining those impressive responses is certain to transform myeloma into a
chronic disease and some day a cure.”

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