In a recent review article published in the journal Clinical Cancer Research, two myeloma experts from the Dana-Farber Cancer Institute, Dr. Nikhil Munshi and Dr. Kenneth Anderson, review the latest strategies in the treatment of multiple myeloma.
In their article, the experts discuss newer therapies that appear to be promising in clinical and preclinical studies.
According to the physicians, combination therapies that specifically target a patient’s genetic form of the disease will be required for long-term disease control and ultimately a cure.
Some Historical Perspective
In their review article, Drs. Munshi and Anderson describe that 50 years ago, the use of melphalan (Alkeran) and prednisone improved the survival of myeloma patients to a median of two to three years. Following that, the use of high-dose chemotherapy and stem cell transplantation further improved survival to a median of four to five years.
Furthermore, they state that the novel agents thalidomide (Thalomid), Velcade (bortezomib), and Revlimid (lenalidomide) have transformed how myeloma is treated.
According to Drs. Munshi and Anderson, the median survival for myeloma patients has increased to over seven years as a result of these novel therapies.
Despite these advances and the recent approvals of Kyprolis (carfilzomib) and Pomalyst (pomalidomide), they point out that myeloma remains incurable for most patients.
Therefore, they state that further research is needed to develop additional novel therapies (including immunotherapy), to learn how to best use them in combination, and to better understand how genomics (a patient’s DNA) can be used to personalize therapy.
Proteasome Inhibitors
Proteasome inhibitors are a class of drugs that work by preventing the breakdown of protein in cancer cells, triggering their death.
Drs. Munshi and Anderson emphasize in their article that the proteasome inhibitor Velcade has been extremely beneficial for newly diagnosed as well as relapsed and refractory myeloma patients.
However, they point out that not all patients respond to Velcade and that those who do respond eventually relapse.
As a result, the authors believe that additional proteasome inhibitors and combination therapies are needed to overcome Velcade resistance.
Kyprolis, another proteasome inhibitor, was approved by the U.S. Food and Drug Administration (FDA) in July 2012 for use in relapsed and refractory myeloma patients.
Specifically, Kyprolis was approved for myeloma patients who have already been treated with at least Velcade and either Revlimid or thalidomide and who have also progressed on or within 60 days of completing their last therapy (see related Beacon news).
According to the experts, Kyprolis improves upon Velcade by irreversibly inhibiting the proteasome and by causing less peripheral neuropathy (pain, tingling, or loss of sensation in the extremities).
They state that results from a Phase 1/2 trial show that 20 percent of relapsed and Velcade-resistant myeloma patients responded to Kyprolis for a median of 8 months. They also state that Kyprolis prolonged survival (to 15 months) (see related Beacon news).
They point out that the response rate for Kyprolis is at least 40 percent in patients who have never been treated with Velcade.
Moreover, they state that the combination of Kyprolis plus Revlimid and dexamethasone (Decadron) appears effective in both relapsed and newly diagnosed patients (see related Beacon news about the combination for relapsed and newly diagnosed patients).
Drs. Munshi and Anderson further discuss several additional proteasome inhibitors that are still in clinical and preclinical development.
Results from clinical studies of ixazomib (MLN9708), an oral proteasome inhibitor, show that the drug is effective for relapsed and refractory myeloma patients as well as in combination with Revlimid and dexamethasone for newly diagnosed patients (see related Beacon news).
Preclinical studies of another proteasome inhibitor known as marizomib (NPI-0052) indicate that the drug may be effective in patients who no longer respond to Velcade, and early clinical trial results show signs of efficacy (see related Beacon news).
The authors recommend the development of additional novel drugs that use other methods to block protein degradation.
Histone Deacetylase Inhibitors
Histone deacetylase (HDAC) inhibitors work by increasing the production of proteins that slow cell division and cause cell death.
Zolinza (vorinostat) is an oral HDAC inhibitor that is already approved in the United States, Canada, and Australia for a certain type of lymphoma. It is not yet available, however, in Europe.
Drs. Munshi and Anderson highlighted results from a Phase 3 study with myeloma patients that showed the overall response rate for Zolinza plus Velcade was 54 percent, compared to 41 percent for Velcade alone. However, the addition of Zolinza only had a small impact on progression-free survival: 7.6 months for the combination versus 6.8 months for Velcade alone (see related Beacon news).
Another Zolinza study that the authors did not mention showed that 53 percent of relapsed and refractory myeloma patients responded to treatment with Zolinza plus Revlimid and dexamethasone (see related Beacon news).
Finally, the experts highlighted a study of the HDAC inhibitor rocilinostat (ACY-1215), which has shown initial promise alone and in combination with Velcade (see related Beacon news).
The authors do not, however, discuss the potential of panobinostat, another HDAC inhibitor that is currently in Phase 3 testing for myeloma.
Immunomodulatory Drugs
Immunomodulatory drugs are a class of drugs that include thalidomide, Revlimid, and Pomalyst and work by inducing a patient’s immune system to attack and destroy myeloma cells.
Dr. Munshi and Dr. Anderson explain that thalidomide and Revlimid have become commonly used for newly diagnosed and relapsed myeloma patients as well as part of maintenance therapy.
They describe Pomalyst, which was approved in February by the FDA for use in relapsed multiple myeloma patients, as the most potent of the three, with an overall response rate of 30 percent to 40 percent in patients who are both Revlimid and Velcade resistant.
Specifically, Pomalyst was approved for use in patients with multiple myeloma who have received at least two prior therapies including Revlimid and Velcade and have demonstrated disease progression on or within 60 days of completion of the last therapy (see related Beacon news).
There are many ongoing Pomalyst studies, but the authors highlighted in particular those studying Pomalyst in combination with a proteasome inhibitor, such as Velcade or Kyprolis.
Monoclonal Antibodies
Monclonal antibodies teach a patient’s own immune system to attack and eliminate cancer cells.
The authors state that among the many monoclonal antibodies that have been studied in myeloma, elotuzumab is one of the most promising for the treatment of multiple myeloma.
Although clinical studies have shown elotuzumab has limited efficacy by itself, they have also shown that elotuzumab in combination with Revlimid and dexamethasone is particularly effective in relapsed myeloma patients. In particular, the overall response rate for the combination was 82 percent and the median progression-free survival was not yet reached at a median follow-up time of 16.4 months (see related Beacon news).
The experts also highlighted daratumumab, which has shown initial promise in heavily pretreated myeloma patients (see related Beacon news), and BT-062, which consists of a chemotherapeutic drug combined with an antibody that helps deliver the drug to myeloma and other cancer cells (see related Beacon news).
They also mentioned siltuximab, BHQ880, tabalumab, and denosumab as having promise for myeloma or myeloma-related bone disease.
Therapeutic Vaccines
Drs. Munshi and Anderson state that, based on the success of donor (allogeneic) stem cell transplants in achieving long-term remission, therapeutic vaccination approaches are being studied for the treatment of myeloma.
Therapeutic vaccines stimulate an immune response against an already established disease, such as myeloma or other types of cancer.
When developing therapeutic vaccines for myeloma, researchers must vaccinate against components (antigens) that are present in myeloma cells but not normal cells.
Drs. Munshi and Anderson highlight in their review a number of antigens that are being targeted by different myeloma vaccines and mention that several personalized vaccines have shown benefit following stem cell transplantation.
The authors suggest that vaccination is best used early in the disease course or in the presence of minimal residual disease.
Additional Promising Approaches
Both authors expect the treatment of myeloma to rapidly change in the coming years. They discuss three new targets that have shown promising results in preclinical trials: BET bromodomains, MMSET, and BTK.
BET bromodomains are involved in regulating the cell cycle and cell death. The researchers suggest that drugs that target bromodomains may be able to trigger death of myeloma cells. They mention JQ1 as the first drug to target BET bromodomains and to show activity in preclinical myeloma studies.
MMSET is a cancer-causing gene associated with the t(4;14) chromosomal abnormality that is present in about 15 percent of myeloma patients. The authors suggest that small-molecule drugs could be used to inhibit MMSET and specifically treat myeloma patients with the t(4;14) chromosomal abnormality.
Finally, BTK is a protein that plays a role in the growth of both myeloma and bone cells. Inhibitors of BTK may be able to slow myeloma cell growth as well as myeloma-associated bone degradation.
In addition, the authors stressed the need to develop personalized therapies for myeloma patients based on their specific genetic abnormalities.
They point out that certain chromosomal abnormalities, such as t(4;14), t(14;16), and del(17p13), have been associated with poor prognosis in myeloma patients.
They suggest that the next step is to develop treatments that target these abnormalities as well as ones that cause drug resistance, especially at early stages of the disease.
In addition, they state that combination therapies are key in the longer-term to overcoming drug resistance and improving response in all patients.
“Ultimately,” they conclude, “prolonged disease free survival and cure [are] on the horizon” for multiple myeloma.
For more information, please see the review article in the journal Clinical Cancer Research (abstract).
