Research

The Incurable Disease

Despite recent advances in treatment, multiple myeloma remains incurable as disease relapse is inevitable. Aashruti Kak writes about the existing treatments and the promise of new ones

Although it has been more than three decades and billions of dollars of research, there is still no cure for cancer. And because of fast evolving unhealthy lifestyles, more and more people find themselves victim to various cancers, regardless of their health. However, there are some cancers that have been beaten by effective treatments; sadly, there are still many that cannot be eliminated, or can stay eliminated for long. Multiple Myeloma (MM) falls in the latter category.

MM is a rare cancer of white blood cells and represents roughly one percent of all cancers. Because relapse in the disease is inevitable and the drugs discovered so far have not been able to achieve the adequate efficiency and patient tolerability, it still remains unbeatable. According to Colin White, Healthcare Analyst, Datamonitor, the incidence of MM in the seven major markets (the US, the UK, Japan, France, Germany, Italy and Spain) will reach over 47,000 by 2019. Table 1 shows the crude incidence rates for MM in each of the markets. An increase in incidence would therefore mean an increase in global market size, which according to GlobalData, was worth $1,818.3 million in 2009, and is likely to increase in value.

Existing Treatments

The choice of treatment depends on largely on patient age and transplant elligibility. White informs, "Stem cell transplantation (SCT) forms the mainstay of stage II/III MM treatment, with chemotherapy planned around this approach. Stage I MM patients are observed at regular intervals and do not receive systemic therapy or SCT until they have progressed to stage II or III MM."

SCT is undertaken to improve response rates and survival of eligible MM patients. It is a procedure that is used in conjunction with high dose chemotherapy in order to destroy malignant plasma cells. SCT helps to restore blood cell production in patients who have received high dose chemotherapy.

"Systemic drug therapy is given prior to high dose therapy and SCT to reduce the tumour burden. The patient's age and general physical health are some of the main factors that are considered when determining eligibility for transplant. Generally, older patients with poor organ-function are less likely to receive a transplant," says White.

In general, MM patients will receive at least three lines of treatment. At first, all newly diagnosed patients receive induction therapy (first-line) with or without SCT to induce disease remission. Patients may then receive maintenance drug therapy, usually after SCT if they have achieved a suboptimal response (Datamonitor, Stakeholder Opinions 2007: Multiple Myeloma, December 2007). Once patients relapse for the first time or show signs of disease progression they become eligible for another round of systemic treatment (second-line). If eligible, patients may receive second-line treatment with SCT at this point, regardless of whether or not they received a transplant previously.

Patients may also receive maintenance drug therapy after second-line treatment. At second-relapse, patients receive a third round of drug therapy (third-line treatment) with or without maintenance treatment. It is uncommon for patients to receive SCT at this stage. Patients may then receive further lines of treatment for subsequent relapses (Datamonitor, Stakeholder Opinions 2007: Multiple Myeloma December 2007, DMHC2361).

While autologous (meaning the stem cells came from the patient) stem cell transplantation with high-dose chemotherapy is a standard treatment for myeloma, researchers are studying the benefits of tandem (double) autologous transplantations, allogeneic (when stem cells came from donor) transplantations, and tandem auto mini-allogeneic transplantations.

Traditionally, stage II/III patients were managed primarily using chemotherapy agents such as melphalan, and steroids such as dexamethasone. However, the demand for more effective and better tolerated drugs for MM patients was high, and since 2003, three targeted therapies have gained approval for use in MM, which have revolutionised the treatment regimes.

In targeted therapy there are three drugs, namely, thalidomide (brand name Thalomid-Celgene), a tumour necrosis factor (TNF)-alpha inhibitor and an immunomodulatory agent, approved in the US (May 2006), EU (April 2008) and Japan (September 2008); lenalidomide (brand name Revlimid-Celgene), with same properties as thalidomide, approved in US (June 2006), EU (June 2007), and its preregistration filed in Japan in July 2009; and bortezomib (brand name Velcade-Millenium/Johnson & Johnson), a reversible ubiquitin proteasome and nuclear factor kappa B inhibitor, approved in US (May 2003), EU (April 2004), and in Japan (December 2006).

In cytotoxic therapy there is liposomal doxorubisin (brand name Doxil-US and Caelyx-EU from J&J/Schering Plough), a pegylated liposome-encapsulated form of doxorubicin (DNA intercalator, topoisomerase II inhibitor), approved in the US (May 2007), EU (November 2007) and has not yet been filed in Japan.

Efficacy and Pricing

Dr Vinod Raina, Head-Department of Medical Oncology, and Head-Delhi Cancer Registry, Institute Rotary Cancer Hospital (IRCH), All India Institute of Medical Sciences (AIIMS) informs, "Some of the older drugs like melphalan, cyclophosphamide, steroids, adriamycin, vincristine have a response rate of 10-12 percent, which is very low compared to the new drugs. For instance, thalidomide has a response rate of 30-40 percent, while lenalidomide and bortezomib bring a response rate of 40-50 percent. However, the efficacy of treatments can go up as high as 70 percent with an extended life expectancy of a year and a half if these drugs are used in combination with traditional chemotherapy drugs." As far as autologous transplants are concerned, they too have a response rate of 40-50 percent. (IRCH has carried out 500 transplants in the last 15 years on this condition)."

As per Globaldata, the MM market in 2009 comprised of six therapies--alkeran, Velcade + Doxil, Velcade + melphalan + prednisone, Revlimid + dexamethasone, Thalomid + dexamethasone and mozobil+ G-CSF. The market was majorily dominated by three players, namely Celgene Corporation, Genzyme Pharmaceuticals and Centocor Ortho Biotech, whose main drugs include Revlimid, Mozobil and Doxil.

Accessibility is always an issue; as new and more effective drugs are discovered their affordability drops. For those drugs that are already have generic counterparts are well received by the patient population, eg thalidomide comes to around Rs 20-30 per day, with lanilodomide at Rs 100 per day; bortizomib injection from J&J costs Rs 30,000 per day, while its generic version can cost between Rs 10,000-15,000 every 2 mg.

The Unmet Need

"Systemic drug therapy is given prior to high dose therapy and SCT to reduce the tumour burden" - Colin White Healthcare Analyst, Datamonitor

"Some of the older drugs have a response rate of 10-12 percent, which is very low compared to the new drugs" - Dr Vinod Raina Head-Department of Medical Oncology AIIMS, New Delhi

As per Globaldata estimates, the MM disease developmental pipeline is strong with about 218 products in various phases of clinical development, with 17 molecules in phase III. With more companies foraying into the MM space, the sequencing of drugs needs to be optimised, and companies should concentrate in bringing more effective and less toxic drugs to the table to limit disease management.

In the MM disease market, Schering-Plough, GSK, Amgen, Bristol-Myers Squibb, Mayo Clinic, Bayer Healthcare Pharmaceutical, Biovex, Oncolytics Biotech and GlaxoSmithKline are also estimated to be the future key players, according to Globaldata.

Besides the abovementioned, there are other companies as well that are making their way into the MM market. For instance, last year, an Australian medical research company, Immune System Therapeutics (IST) launched a clinical trial to test its breakthrough treatment for terminal blood cancers and commenced its phase I at the Alfred Hospital in Melbourne. IST had genetically engineered an antibody drug that binds specifically to a target protein found on the surface of some blood cancer cells. Laboratory studies, using cells taken from MM patients, showed that the antibody worked with the human immune system to induce death of the cancer cells. It is anticipated that the antibody will potentially reduce the number of cancerous cells in multiple myeloma patients and improve patient health and well-being.

Indian pharmaceutical company, Piramal Life Sciences' Salinosporamide A (NPI-0052), a novel anticancer compound from marine actinomycetes, Salinispora tropica, is a potent proteasome inhibitor used as an anticancer agent and had entered phase I human clinical trials for the treatment of multiple myeloma last year only three years after its discovery. The company's lead chemical compound, a pan Cdk inhibitor also completed two phase I studies and is being tested in two phase II trials in US and India and another phase I/II trials for multiple myeloma in India.

In May this year, Boehringer Ingelheim and Micromet announced a global research, development and commercialisation collaboration for an MM BiTE antibody. Micromet's BiTE antibodies are designed to direct the body's cytotoxic, or cell-destroying, T cells against tumour cells, and represent a new therapeutic approach to cancer therapy. Typically, antibodies cannot engage T cells because T cells lack the appropriate receptors for binding antibodies. BiTE antibodies have been shown to bind T cells to tumour cells, ultimately inducing a self-destruction process in the cells referred to as apoptosis or programmed cell death.

At the same time, Compugen, an Israel based genomics-based drug and diagnostic discovery company, identified and validated CGEN-928 as a drug target for the treatment of MM, a membrane protein which previously had no known function or potential clinical utility. CGEN-928 demonstrated broad expression in human MM tumour cells, including drug resistant and aggressive primary tumour cell lines. In addition, the protein's expression profile indicated its possible use as both a diagnostic and prognostic marker for MM. The potential of CGEN-928 to address these important unmet medical needs was initially predicted through the use of Compugen's monoclonal antibody targets discovery platform. Patent applications covering the use of CGEN-928 for these and additional therapeutic and diagnostic purposes have been filed by the company.

Miles to Go

"As new molecules are much more effective than old molecules it will now be more difficult to find more effective molecules as you have to improve on these results," avers Raina. This could be a great opportunity for companies to discover and introduce novel agents in the MM market as patients often require multiple lines of therapy. Since a major approach to MM drug therapy the use of combined regimens, companies need to look out for drugs that have the potential to synergise with other approved or emerging drugs.

As more effective drugs find their way into the market it becomes even more imperative to make promising treatments available as quickly as possible to the people most in need of them.

aashruti.kak@expressindia.com