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:
Defibrotide is an anticoagulant (a drug that prevents blood clotting) that may make myeloma cells more susceptible to chemotherapy. It is not an anti-tumor drug and only has a significant effect on myeloma when combined with cancer-fighting drugs.  Defibrotide may decrease blood clotting and nerve damage caused by certain myeloma treatments. In combination with granulocyte colony-stimulating factor (G-CSF), defibrotide has been shown to significantly increase stem cell production. Defibrotide has also demonstrated an ability to treat hepatic veno-occulusive disease (VOD), a life-threatening complication of stem cell transplantation that is marked by blocked veins in the liver.

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

Web site for defibrotide: http://www.gentium.it/Defibrotide.aspx

With the development of multiple myeloma therapies, the traditional melphalan-prednisone (MP) treatment regimen has been combined with substances such as Velcade (bortezomib) and thalidomide for more effective results. In particular, clinical trials have shown that these new combination treatments produce greater responses in patients than the traditional MP treatment regimen.

However, the presence of side effects, in particular clotting in the veins, also known as deep-vein thrombosis, and nerve damage in the limbs, also known as peripheral neuropathy, leaves room for improvement in these treatment options.

Defibrotide, an anti-clotting compound, has been shown to sensitize myeloma cells to chemotherapy in in vitro studies when combined with cancer-fighting drugs. In vitro studies are studies performed in controlled environments like test tubes or Petri dishes.

In this Phase 1 trial, researchers attempted to determine the dosage limit of defibrotide in combination with melphalan, prednisone and thalidomide while also evaluating the regimen’s effectiveness and toxicity.

The researchers recruited 24 patients with relapsed or refractory myeloma for their study. As initial treatment, patients received six 35-day cycles of melphalan (0.25 mg/kg on days 1 to 4), prednisone (1.5 mg/kg on days 1 to 4), thalidomide (50 to 100 mg on days 1 to 35), and any of three doses of defibrotide given either orally or intravenously (IV). Patients were then given 1.2 g/day of defibrotide orally and 50 mg/day of thalidomide as maintenance therapy until disease progression or excessive toxicity.

Forty-three percent of patients achieved partial response and nine percent experienced very good partial response or complete response, adding up to an overall response rate of 52 percent. The median progression free survival was 10 months, and at one year, 34 percent of patients remained progression-free. The overall survival rate after one year was 90 percent.

The most common side effects observed in patients included reduced white blood cell count (61 percent), reduced platelet count (39 percent), and fatigue (8 percent). Numerous participants required blood transfusions and the added support of granulocyte-colony stimulating factor (G-CSF), which stimulates stem cell production. One patient (4 percent) experienced clotting in the veins.

The researchers noted that there were no severe cases of peripheral neuropathy, a side effect that, like deep vein thrombosis, is commonly observed with thalidomide.

They did not observe any dose-limiting side effects. The highest dose of defibrotide administered during the trial (7.2 g/day orally on days 1 to 4 followed by 4.8 mg/day on days 5 to 35) was therefore defined as the maximum tolerated dose.

The study authors expressed enthusiasm about the significantly low rate of deep vein thrombosis and peripheral neuropathy attributable to defibrotide. They recommend further investigation of the drug, particularly in combination with thalidomide, Revlimid (lenalidomide), and pomalidomide.

For more information, please see the journal Haematologica (abstract).