RxPG News : Multiple Myeloma

Predicting response of treatment in Multiple Myeloma patients

Sun, 10 Dec 2006 12:50:17 PST

( from http://www.rxpgnews.com ) Researchers at Mayo Clinic Cancer Center, in cooperation with industry partners, have, for the first time, identified tumor specific alterations in the cellular pathway by which the multiple myeloma drug bortezomib (Velcade) works, and they have identified nine new genetic mutations in cancer cells that should increase a patient's chance of responding to the agent.

The investigators say these findings, presented Sunday, Dec. 10, at the 2006 American Society of Hematology Annual Meeting in Orlando, may help physicians tailor treatment to patients with multiple myleoma, a difficult-to-treat cancer of plasma cells that is the second most common blood cancer in the United States.

"Bortezomib seems to work in about one-third of patients who use it, but we have not been able to predict which ones," says the study's lead author, Leif Bergsagel, M.D., a hematologist at Mayo Clinic Arizona. "We now have identified a group that will likely respond because these nine mutations seem to be present in at least 25 percent of newly diagnosed patients.

"Now that we know the pathway the drug targets, and genetic mutations within this pathway that make patients respond better, we are working on a simple way to select those patients who are the best candidates for use of bortezomib," says Dr. Bergsagel.

In 2003, after only a four-month review, the Food and Drug Administration (FDA) approved use of bortezomib in patients who have failed other treatments for multiple myeloma. Later studies showed it lengthened survival by as much as six months. The drug was the first approved in a new class of agents known as proteasome inhibitors. Proteasomes are large protein groups inside cells that break down other proteins. Agents that inhibit the proteasome cause a buildup of proteins that affect many signaling cascades (various necessary biological processes). Bortezomib was initially thought to exert its activity by disrupting one of two known NF-êB (Nuclear Factor kappa B) pathways which keep cancer cells from self destructing the first-discovered, or canonical, NF-êB pathway.

But through extensive genetic examination of 42 unique multiple myeloma cell lines and tumor samples taken from 68 patients, the investigators defined multiple genetic mutations in the other NF-êB pathway, the so-called non-canonical pathway. "These mutations make the tumor more dependent on that pathway, and consequently more susceptible to bortezomib treatment," said senior author Rafael Fonseca, M.D., also at Mayo Clinic in Arizona.

"Identifying these mutations in patients will help us decide who should be treated with bortezomib, probably as an initial therapy," he says. The researchers are developing a test to check for activation of the non-canonical NF-êB pathway in patients.

Now that the mutations have been identified, drug designers may be able to fashion new therapies that are more specific to these genetic alterations and, therefore, less toxic,

Dr. Bergsagel says. "These mutations represent good targets for drug development," he says.

Lenalidomide & dexamethasone combination shows promise for multiple myeloma treatment

Sun, 04 Sep 2005 07:15:38 PST

( from http://www.rxpgnews.com ) Mayo Clinic Cancer Center investigators report that combination therapy with lenalidomide (RevlimidTM) and dexamethasone (combination is called Rev/Dex) looks like a breakthrough treatment for multiple myeloma. Results of a Phase II clinical trial were published online Aug. 23 in Blood.

"Previous studies have shown Rev/Dex to be effective for recurrent or highly resistant forms of myeloma," says S. Vincent Rajkumar, M.D., Mayo Clinic hematological oncologist and lead investigator of the study, "In this study, the first one to use the combination as initial therapy in newly diagnosed patients, we find that the Rev/Dex combination reduced the myeloma cancer protein levels by more than half in 91 percent of patients much higher than response rates obtained with current approved therapies."

The goal of this clinical trial was to determine the response rate and toxicity (type and severity of side effects) of Rev/Dex in patients with previously untreated, newly diagnosed multiple myeloma. Over the course of the trial, 34 patients underwent the combination treatment, with 31 (91 percent) showing positive response to the treatment, and all within a rapid period average response time was one month. In addition to the quick and positive responses, side effects were manageable, and common ones associated with thalidomide treatment, such as constipation, blood clots and neuropathy, were uncommon. Rev/Dex is administered orally making it a more attractive option to many patients compared to traditional intravenous treatments.

"We see this as potentially the way of the future for many myeloma patients," says Morie Gertz, M.D., Mayo hematological oncologist and co-investigator, "We are happy that two large Phase III trials are currently ongoing, moving forward the testing of Rev/Dex as initial therapy for myeloma."

Multiple myeloma is a malignant cancer of the blood that causes 11,000 deaths each year. Standard therapy of melphalan and prednisone results in about 50 percent of patients having a positive response i.e. the cancer cells lessen by more than half. Vincristine, doxorubicin and dexamethasone (VAD) is another chemotherapy regimen used to treat myeloma, typically for patients who are candidates for stem cell transplantation because it allows adequate and safe stem cell harvest during treatment for a future transplantation. However, the use of VAD chemotherapy has decreased greatly because of the need for intravenous therapy and the need for a catheter bringing other potential health risks.

Recent studies have looked at the oral combination of thalidomide and dexamethasone (Thal/Dex) as an alternative to VAD. Although response rates are excellent (approximately 70 percent), the combination causes significant side effects. Lenalidomide is a compound similar to thalidomide, but one which previous studies have shown to work better both for recurrent and highly resistant myelomas, both alone and in conjunction with dexamethasone. It has fewer side effects than thalidomide and has even caused improvement in patients who are nonresponsive to thalidomide.

Lenalidomide is not commercially available; approval by the Food and Drug Administration is pending. The study was funded with grants from the National Cancer Institute and Celgene Corporation, which manufactures RevlimidTM.

Novel combination overcomes drug-resistant myeloma

Fri, 03 Jun 2005 16:50:38 PST

( from http://www.rxpgnews.com ) A novel strategy devised by Dana-Farber Cancer Institute scientists has proved highly effective in killing drug-resistant multiple myeloma cells in the laboratory and could open a new form of attack on the deadly blood cancer, they report.

Highly encouraged by the findings, the researchers hope to move rapidly to clinical trials of the therapy, a combination of the drug Velcade and an experimental compound that was designed by researchers at the Broad Institute of Massachusetts Institute of Technology and Harvard University.

The report, which will be posted online this week by the Proceedings of the National Academy of Sciences (http://www.pnas.org/papbyrecent.shtml), demonstrates that the combination was more than twice as effective as either drug alone in killing resistant cells from patients' bone marrow.

The promise is particularly exciting, scientists say, because many patients don't respond to Velcade, a drug approved just two years ago that's been an important new therapy for multiple myeloma, a disease which caused an estimated 11,000 deaths in 2004, according to the Multiple Myeloma Research Foundation.

"This is not just another drug, this is a whole new approach to treating multiple myeloma," said Kenneth Anderson, MD, senior author of the paper, whose lead author is Teru Hideshima, MD, also of Dana-Farber. Others include Stuart L. Schreiber, PhD, of Harvard University and the Broad Institute, and Jay Bradner, MD, of Dana-Farber and the Broad Institute.

Velcade is the first in a class of so-called proteasome inhibitors, which cause lethal stress in cancer cells by blocking the proteasome, a disposal mechanism that rids the cell of abnormal proteins. Cells in which the proteasome is jammed eventually commit suicide, triggered by the accumulation of proteins, explains Anderson, who is also the Kraft Family Professor of Medicine at Harvard Medical School.

However, many cancer cells are resistant to proteasome inhibitors like Velcade. Recent studies have revealed an alternative protein-disposal complex, the aggresome, that may take over enough of the job when the proteasome falters to allow the cells to survive.

Therefore, the Dana-Farber researchers suggested that blocking both protein disposals at once might get around this resistance mechanism. Scientists led by Schreiber at the Broad Institute designed a drug, tubacin, that blocks histone deacetylase 6, an enzyme that is critical to the aggresome's ability to function.

These highly promising results, wrote the researchers, "provide the framework for clinical trials designed to enhance sensitivity and overcome resistance to bortezomib [Velcade], thereby improving patient outcome in multiple myeloma."

Bortezomib Based Therapies may Become the New Standard of Care in Multiple Myeloma

Thu, 14 Apr 2005 20:56:38 PST

( from http://www.rxpgnews.com ) Millennium Pharmaceuticals, Inc. (Nasdaq: MLNM - News) today announced the presentation of positive clinical results for VELCADE in treating patients across the multiple myeloma (MM) treatment paradigm at the 10th Annual International Myeloma Workshop (IMW) in Sydney, Australia. Data regarding the use of VELCADE as a single agent and in combination with standard and emerging MM therapies were reported at the meeting.

Data presented provided evidence for the potential of VELCADE to induce higher response rates in earlier lines of therapy. Front- line studies of VELCADE were the highlight of several scientific sessions and showed very high response rates in previously untreated MM patients with manageable toxicities.

These studies were the basis for three large, multicenter, independent phase III studies. VELCADE is approved in the U.S. for the treatment of patients who have received at least one prior therapy.

"These front-line data suggest VELCADE may offer a new option for patients with multiple myeloma who have not yet been treated," said David Schenkein, M.D., senior vice president, clinical research, Millennium. "While VELCADE is the only single agent to demonstrate a statistical survival advantage in relapsed patients, the benefits in combination with other therapies confirm our belief that VELCADE based therapies can become the new standard of care in multiple myeloma."

The following is summary data from clinical studies of VELCADE presented at the IMW:

Front-line treatment in MM patients

In five investigator-initiated studies of VELCADE, two conducted by cancer cooperative groups, outcomes reported in combination with standard and emerging therapies included overall response rates of up to 95 percent and high complete and near complete response rates of up to 32 percent. A complete and near complete response rate of 57 percent was reported following single stem cell transplant preceded by induction with VELCADE/adriamycin/ dexamethasone (PAD). This response rate was similar to the complete response rate reported for tandem transplants. Front-line data showed patients were able to have successful stem cell harvest and transplantation after VELCADE® (bortezomib) for Injection.

In the front-line phase II Cancer and Leukemia Group B (CALGB) study, an initial report of responses in combination with liposomal doxorubicin showed complete and partial responses in 12 of 15 patients and no patients have progressed so far on study. Toxicities in this study were similar to the phase I study in which high response rates in relapsed or refractory patients prompted this front-line investigation. Other front-line combinations presented were VELCADE with high-dose dexamethasone and VELCADE with melphalan/prednisone. In these five studies overall, adverse events were found to be manageable and included gastrointestinal, asthenic conditions, hematologic, neurologic, skin toxicity, musculoskeletal and pyrexia. Positive results from these front-line studies have led to three large, international, randomized, phase III trials; two of which are being conducted by cooperative groups.

Second-line MM

In a phase III, multicenter trial comparing single agent VELCADE to high-dose dexamethasone, VELCADE demonstrated a 45 percent response rate, including an approximate 13 percent complete (6.25 percent) and near complete response rate (6.25 percent). Importantly, a longer duration of response and a statistically significant survival advantage were found in patients who had received only one prior therapy. Results showed that the probability of death with dexamethasone was 2.56 times that of VELCADE therapy. Side effects were as expected from prior experience with VELCADE, were manageable and peripheral neuropathy improved or reversed in nearly half of all patients. The most common adverse events reported in this study as related to VELCADE were gastrointestinal, neurologic, musculoskeletal and hematologic. These data were the basis of the recent FDA approval for VELCADE use in MM patients who have received at least one prior therapy.

Relapsed or refractory MM

Investigator-initiated studies demonstrated VELCADE was well tolerated and provided a high overall response rate as both a single agent and in combination with standard and emerging therapies, such as liposomal doxorubicin/thalidomide, melphalan and lenalidomide. In combination studies, the response rates of more than 60 percent in heavily pre-treated patients without additive toxicities showed the compatibility of VELCADE with these agents. Other combinations presented were VELCADE plus dexamethasone and VELCADE plus intravenous melphalan.

About Multiple Myeloma

MM is the second most common blood cancer and although the disease is predominantly a cancer of the elderly (the average age of onset is 65 to 70 years of age), recent statistics indicate both increasing incidence and younger age of onset. In the United States, more than 40,000 individuals have MM and over 14,000 new cases of the disease are diagnosed each year. Worldwide there are approximately 74,000 new cases and over 45,000 deaths due to multiple myeloma each year.

About VELCADE® (bortezomib) for Injection

VELCADE is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

Risks associated with VELCADE therapy include new or worsening peripheral neuropathy, hypotension, cardiac disorders, gastrointestinal adverse events, thrombocytopenia and tumor lysis syndrome. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE.

In 331 patients who were treated with VELCADE 1.3 mg/m2 dose in the phase III APEX study, the most commonly reported adverse events were asthenic conditions (61%), diarrhea (57%), nausea (57%), constipation (42%), peripheral neuropathy (36%), vomiting (35%), pyrexia (35%), thrombocytopenia (35%), psychiatric disorders (35%) and anorexia and appetite decreased (34%). Fourteen percent of patients reported at least one episode of grade 4 toxicity; the most common grade 4 toxicities were thrombocytopenia (4%), neutropenia (2%) and hypercalcemia (2%). A total of 144 patients on VELCADE (44%) reported serious adverse events (SAEs) during the study. The most commonly reported SAEs were pyrexia (6%), diarrhea (5%), dyspnea and pneumonia (4%) and vomiting (3%).

VELCADE is being co-developed by Millennium and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Millennium is responsible for commercialization of VELCADE in the U.S.; Ortho Biotech and Janssen-Cilag are responsible for commercialization in Europe and the rest of the world. Janssen Pharmaceutical K.K. is responsible for Japan. VELCADE is approved in more than 40 countries worldwide including the U.S., European Union members, and a number of countries within Latin America and South-East Asia such as Argentina, China, Korea, Singapore and Thailand.

FDA Fully Approves Bortezomib for Treatment of Relapsed and Refractory Multiple Myeloma

Sat, 26 Mar 2005 10:01:38 PST

( from http://www.rxpgnews.com ) Millennium Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) approved the Company's supplemental New Drug Application (sNDA) for VELCADE(Bortezomib). This approval expands the label to include the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy.

Bortezomib is the only drug therapy that has demonstrated a significant survival advantage as compared to a standard therapy in relapsed MM. Initial accelerated approval for relapsed and refractory MM was granted in May 2003.

Bortezomib is now fully approved in relapsed MM.The approval was based on data from the randomized phase III APEX study that compared single-agent Bortezomib to a traditional MM therapy, high-dose dexamethasone. The study demonstrated a significant survival advantage with
Bortezomib (p less than 0.05) in patients who had received one to three prior therapies.

Importantly, this pronounced survival advantage was also observed in the second-line MM patients. The safety profile of Bortezomib remained consistent with previous phase II findings. This indication doubles the number of U.S.
patients who could potentially benefit from Bortezomib to approximately 22,000.

"We are thrilled that more patients will have access to Bortezomib earlier in their treatment where Bortezomib has shown a significant improvement over a standard therapy in improving survival and delaying disease progression," said
David Schenkein, M.D., senior vice president, clinical research at Millennium.

"Millennium is committed to making a difference in patients' lives and will continue, in partnership with Johnson & Johnson Pharmaceutical Research and
Development L.L.C., to explore extensively the benefits of Bortezomib across the multiple myeloma treatment paradigm as well as in other hematologic and solid tumors."

The approval of this supplementary filing comes approximately 22 months after the initial FDA approval of VELCADE(R) (bortezomib) for Injection.

Bortezomib, the first of a new class of medicines called proteasome inhibitors,is the first treatment in more than a decade to be approved for patients with multiple myeloma, a cancer of the blood.

The sNDA submission was based primarily upon the results of the phase III APEX study, which compared Bortezomib to high-dose dexamethasone. The APEX trial enrolled 669 patients with relapsed multiple myeloma (patients had received one to three prior therapies) at 93 centers in North America, Europe and Israel.

This study was conducted under the direction of Paul Richardson, M.D.,clinical director, Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute. The APEX trial was halted one year early after an independent data
monitoring committee concluded the findings of a pre-specified interim analysis showed a statistically significant improvement in time-to-disease progression in favor of Bortezomib.

In the overall study population, Bortezomib was superior to high-dose dexamethasone based on time to progression (p less than 0.0001), overall survival (p less than 0.05) and response rate (p less than 0.0001).

Additional findings include the following:

-- Overall, 40 percent fewer patients died in the Bortezomib arm relative to the dexamethasone arm;
-- Overall response rate of 38 percent with Bortezomib, with a median duration of response of 8.0 months compared with a response rate of 18 percent, with a median duration of response of 5.6 months for dexamethasone;
-- Six percent of Bortezomib patients had a complete response and 7 percent had a near complete response as compared to less than one percent each with dexamethasone;
-- After a median of 8.3 months of follow-up, improvement in median time to progression was 78 percent with Bortezomib relative to dexamethasone.

Among the 251 second-line multiple myeloma patients (those who had only one prior therapy), Bortezomib was superior based on time to progression (p=0.0019), response rate (p=0.0035) and overall survival (p less than0.05).
Additional findings include the following:

-- Overall, 55 percent fewer patients died in the Bortezomib arm relative to the dexamethasone arm;
-- Overall response rate with Bortezomib was 45 percent (median duration of response was 8.1 months) compared with 26 percent for dexamethasone (median duration of response 6.2 months); and
-- Six percent of Bortezomib patients had a complete response and 6 percent had a near complete response as compared to two percent each with dexamethasone.

Adverse events on the Bortezomib arm were predominantly grade one or two,were similar to those previously observed in other trials and were considered manageable by the investigators.

-- The most commonly reported adverse events were asthenic conditions,diarrhea, nausea, constipation, peripheral neuropathy, vomiting,pyrexia, thrombocytopenia, psychiatric disorders and anorexia and appetite decreased;
-- The most commonly reported serious adverse events were pyrexia,diarrhea, dyspnea, pneumonia and vomiting.

Bortezomib is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Bortezomib is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

Bortezomib is being co-developed by Millennium and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Millennium is responsible for commercialization of Bortezomib in the U.S.; Ortho Biotech and Janssen-Cilag are
responsible for commercialization in Europe and the rest of the world. Janssen Pharmaceutical K.K. is responsible for Japan.

Risks associated with Bortezomib therapy include new or worsening peripheral neuropathy, hypotension, cardiac disorders, gastrointestinal adverse events,thrombocytopenia and tumor lysis syndrome.

Women of childbearing potential should avoid becoming pregnant while being treated with Bortezomib.

In 331 patients who were treated with Bortezomib 1.3 mg/m2 dose in the phase III APEX study, the most commonly reported adverse events were :

-asthenic conditions (61%),
-diarrhea (57%),
-nausea (57%),
-constipation (42%),
-peripheral neuropathy (36%),
-vomiting (35%),
-pyrexia (35%),
-thrombocytopenia (35%),
-psychiatric disorders (35%) and
-anorexia and appetite decreased (34%)

Fourteen percent of patients reported at least one episode of grade 4 toxicity;the most common grade 4 toxicities were:
-thrombocytopenia(4%),
-neutropenia(2%)
-hypercalcemia(2%).

A total of 144 patients on Bortezomib(44%) reported serious adverse events (SAEs) during the study.The most commonly reported SAEs were pyrexia(6%),diarrhea(5%), dyspnea and pneumonia(4%) and vomiting(3%).