Given the recent new drug application for carfilzomib and the upcoming annual meeting of the American Society of Hematology — which undoubtedly will host discussions of many potential new myeloma treatments — it seems an appropriate time to go back to the experts’ review from earlier this year and highlight some of its key points.

The experts begin their review by noting that, despite significant advances in the treatment of multiple myeloma during the last decade, it continues to be challenging to find effective therapies for patients at high risk for early relapse and for patients resistant to multiple drugs or drug combinations.  This makes the search for new treatments particularly important.

The Next Generation of Novel Agents

Regimens containing the novel agents Velcade (bortezomib), thalidomide (Thalomid), and Revlimid (lenalidomide) have played a key role in improving progression-free and overall survival in multiple myeloma patients.  According to the authors of the review article, new drugs that work similarly as these novel agents, but have improved efficacy or safety, have been showing particular promise in clinical trials over the past several years.

Carfilzomib: The Next Generation Velcade

Velcade works by inhibiting proteasome, which is responsible for the break down of proteins in both healthy and cancerous cells. Treatment with Velcade results in the accumulation of proteins within the cell, and it is believed that this excess protein leads to cell death, suppressing tumor growth.

Carfilzomib, which belongs to the same class of drugs as Velcade, has shown high efficacy in clinical trials and may have fewer side effects than Velcade (see related Beacon news). Particularly notable are its lower rates of peripheral neuropathy (nerve damage in the extremities).

There also are other proteasome inhibitors under development for the treatment of myeloma, including salinosporamide A (NPI-0052), and MLN9708/2238, a chemical cousin of Velcade that can be taken orally.

Pomalidomide: The Next Generation Revlimid

Pomalidomide is closely related to thalidomide and Revlimid.  Although the exact ways in which this class of drugs works remain unclear, all three are immunomodulatory agents (drugs that affect the immune system), and they apparently encourage a patient’s immune system to attack and destroy myeloma cells. Clinical trials have shown that pomalidomide is effective in patients who are resistant to treatment with thalidomide, Velcade, and Revlimid (see related Beacon news).

Dr. Vincent Rajkumar, a professor of medicine at the Mayo Clinic, noted in a recent column for The Myeloma Beacon that, of the many drugs currently in development for multiple myeloma, only pomalidomide and carfilzomib have shown significant single-agent activity in multiple clinical trials (see related Beacon news).

In addition to the improvements being made in the currently available multiple myeloma drug classes, ongoing research is being done to identify new classes of drugs.

The authors of the review article believe that several drugs, while not showing potential as single agents themselves, may prove to be effective if given in combination with other currently approved drugs, such as Velcade (see related Beacon news).   These include the histone deacetylase inhibitors, Zolinza (vorinostat), panobinostat and Istodax (romidepsin), which have shown activity when combined with Velcade.

The anti CS-1 antibody, elotuzumab has also been included in this list. This drug targets proteins that are displayed on the surface of myeloma cells but not on healthy cells.  Clinical trials are currently underway to examine the activity of elotuzumab in patients with refractory or relapsed myeloma. It is anticipated that the drug will work best when combined with Revlimid and dexamethasone (Decadron), rather than as a single agent.

Other potential drugs that may work best in combination with existing therapies include heat shock protein inhibitors (see related Beacon news), phosphoinositide 3-kinase pathway inhibitors (for example perifosine), and mTOR inhibitors, such as Torisel (temsirolimus).  At this time, however, none of the drugs in these classes have been approved by the U.S. Food and Drug Administration (FDA) specifically to treat multiple myeloma.

The authors conclude their review of current research on new myeloma treatments by touching on an alphabet soup of drugs in early-stage clinical trials – drugs such as ACE-011, BHQ880, BI-505, defibrotide, GDC-0449, imetelstat (GRN163L), MLN4924, MLN8237, NVP-BEZ235, and siltuximab (CNT 328).  In addition, the authors describe several potential early stage treatments that may stimulate the body’s immune system to attack myeloma cells.

Improving Clinical Trial Results

According to the authors of the review, a large number of drugs that are being developed for multiple myeloma have shown promise in preclinical trials.  These preclinical trials are not carried out in humans, but instead in other models of the disease, such as cells grown in the laboratory setting or small animals (for example mice).  The review authors point out, however, that despite initial promise, fewer than 10 percent of cancer drugs that begin testing in humans ever receive approval from the FDA for patient use.

The authors therefore stress that more preclinical testing is needed and that the models used during this testing should more closely mimic the disease as it is observed in humans. They emphasize, for example, that the environment surrounding the tumor is of equal importance to the tumor itself, and suggest that more models take this so-called “microenvirnoment” into more careful consideration.

They also recommend that patients be carefully selected when clinical trials of a drug begin.  Because some drugs may perform better in specific patient populations, these populations should be established before the start of clinical trials, and patients should be screened to ensure they are in this population before they are enrolled.

Personalized Treatment For Multiple Myeloma

The experts conclude their review by noting that, through work carried out over several decades, cancer biologists have discovered that cancer treatment cannot be a “one-size-fits-all” solution.  At the same time, determining the best method for treating an individual patient for their cancer at the correct time during their disease has proven to be the most challenging aspect of research.  Many researchers believe, however, that this kind of “personalized therapy” offers the most hope for cancer patients.

In this regard, the authors note that the International Staging System, the availability of genetic testing, and the development of risk classification systems by institutions such as the Mayo Clinic and the University of Arkansa have all contributed to greater individualization of multiple myeloma treatment.

The ultimate goal, according to the review authors, will be to identify subsets of patients that will respond most effectively to certain drugs or drug combinations and, thereby, improve the progression-free and overall survival of myeloma patients.  Further investigation is therefore needed into the classification of patients and the development of clinically relevant tests to identify patient classes.

While such studies may not be easy to implement, the authors believe that such issues are likely the next major frontier of myeloma research in the coming years.

For more information, please see the review in the Journal of Clinical Oncology (abstract).

Description:
BI-505 is a fully human antibody that causes cell death. It binds to the protein ICAM-1 (CD54), which is more common in tumors than in normal tissue. BI-505 may therefore be used to kill cancerous cells that have ICAM-1, including multiple myeloma cells. The FDA approved Phase 1 clinical trials for BI-505 in 2009, and the studies began in January 2010.

Clinical Trials:
For a list of clinical trials studying BI-505 for the treatment of multiple myeloma, see ClinicalTrials.gov.

Official website for BI-505: http://www.bioinvent.com/products/pipeline/bi-505

Phase 1 Study Of BioInvent’s Drug Candidate BI-505 Treats First Myeloma Patient – BioInvent announced treatment of the first patient with BI-505 in a Phase 1 study evaluating the drug for the treatment of advanced multiple myeloma. The study is recruiting 30 to 40 patients to receive BI-505 intravenously every second week for four weeks or longer. Researchers will evaluate the drug’s safety, activity, and dosage limits. For more information, please see the BioInvent press release and the clinical trial description.

LLS Seminar: Understanding Lab & Radiology Tests – On January 25, the Leukemia & Lymphoma Society (LLS) is holding an informational seminar on how to read and understand medical results, including CT scans, PETs, MRIs, and blood tests. The event will take place at the Katz Cancer Resource Center in Santa Cruz, CA from 11:30 a.m. to 12:30 p.m. For more information or to register, please visit the LLS Web site.

LLS Event: Living With Myeloma – On January 25, the Leukemia & Lymphoma Society (LLS) will host a free program on multiple myeloma from 5 p.m. to 6:30 p.m. at the Moffit Cancer Center in Tampa, FL. Dr. Melissa Alsina will give an overview of myeloma and cover the following topics: the latest in drug therapies, disease and treatment side effects, emotional repercussions and support resources, and clinical trial options. A question and answer session and complimentary dinner will be included. Pre-registration is required. For more information or to register, please visit the LLS Web site.

For a more detailed listing of myeloma related events, please check the Myeloma Beacon Events Calendar.