Clinical Insights Education Program – The Multiple Myeloma Research Foundation (MMRF) is sponsoring an education program about multiple myeloma clinical insights. The event will be held on September 8 in St. Louis. Myeloma experts Drs. Ravi Vij, Todd Zimmerman, Keith Stockerl-Goldstein, Shaji Kumar, and David Vesole will speak about the latest advances in frontline therapy, stem cell transplants, relapsed and refractory myeloma, supportive care, and clinical trials. There will also be a question and answer session. Registration will begin at 10 a.m., and the program will conclude at 3 p.m. A similar program will be held in Houston on October 15. For more information about the St. Louis program or to register, please see the MMRF website.

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

Stem cell mobilization is the process of increasing the number hematopoietic (blood forming) stem cells in the circulating blood to ensure that enough are available to be collected for the transplant. Hematopoietic stem cells are primarily found in the bone marrow and circulate in very low concentrations in the blood. During mobilization, the administration of growth factors, such as granulocyte colony-stimulating factor (G-CSF), causes hematopoietic cells in the bone marrow to be released into the circulating blood stream.

Although G-CSF is the most commonly used mobilization agent, one recent study reported that only 34 percent of patients treated with G-CSF alone mobilized a sufficient number of stem cells for transplant over a two day collection period.

Other studies have shown that initial treatment with Revlimid (lenalidomide) has a negative impact on stem cell mobilization when G-CSF was used as a single mobilization agent.

Supplementing G-CSF with chemotherapy such as cyclophosphamide can increase the number of stem cells harvested during collection and reduce collection failure rates compared to the administration of G-CSF alone.

While cyclophosphamide is effective in improving stem cell yields, it increases the risk of low blood cell counts and high fevers associated with low white blood cell counts. In order to avoid these side effects, researchers in this study investigated the efficacy of an etoposide (VP-16) and G-CSF combination as a stem cell mobilization regimen in multiple myeloma patients.

Etoposide is a form of chemotherapy used for the treatment of lung cancer, testicular cancer, and lymphoma.  Previous studies have shown that etoposide is highly effective in mobilizing stem cells.

The 152 multiple myeloma patients enrolled in the study received 375 mg/m² of etoposide once daily on days 1 and 2 of the stem cell mobilization process. G-CSF was administered twice daily starting on day 3 until the last day of stem cell collection. Stem cells were collected from all patients between day 7 and day 13 of treatment.

Stem cells were successfully collected from all patients after one mobilization regimen.

Stem cells were harvested from 94 percent of these patients in one day of collection.  The majority of patients (61 percent) were able to undergo stem cell collection 11 days after the start of their etoposide and G-CSF regimen.

Furthermore, twice the number of stem cells were collected with G-CSF and etoposide than with G-CSF alone. These numbers were comparable to those obtained with a cyclophosphamide and G-CSF regimen.

Side effects experienced by patients in the study were manageable and were mostly the result of complications caused by low blood cell counts, which required 20 percent of patients to receive blood transfusions.  Severe fevers that required hospitalization or the administration of intravenous antibiotics occurred in 17 percent of patients.

The researchers suggested further studies be conducted to determine which compound yields the best results in combination with G-CSF in patients who are predicted to be poor stem cell mobilizers and which patients may not need a second agent for successful stem cell mobilization.

For more information, please see the study in Biology of Blood and Marrow Transplantation (abstract).

Astex And MMRC Begin Phase 2 Study Of AT7519 For Myeloma – Astex Therapeutics has launched a Phase 2 clinical trial, funded by the Multiple Myeloma Research Consortium (MMRC), of AT7519 for relapsed or refractory multiple myeloma patients. AT7519 is a cyclin-dependent kinase inhibitor that prevents the growth and spread of myeloma cells by interfering with cell division. Previous trials have shown it has significant anti-tumor effect. AT7519 will be tested alone and in combination with Velcade (bortezomib). For more information, see the MMRC press release.

IMF Will Hold Myeloma Patient And Family Seminar – The International Myeloma Foundation (IMF) will hold an educational program for multiple myeloma patients and their families on August 27 and August 28 in Universal City, CA. Doctors in the myeloma field will answer questions and cover topics such as managing side effects, current standard treatments, and on-going clinical trials. The cost for the seminar is $60 per person. For more information or to register, please see the IMF website.

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

These results suggest that adding cyclophosphamide as the fourth drug in the treatment therapy may be just as or more effective than traditional two- and three-drug combinations. The study also determined that 500 mg/m² cyclophosphamide, the highest dose tested, could safely be used in the RVCD drug combination.

Previous studies have shown that three-drug combinations can be very effective, including the Revlimid (lenalidomide)-Velcade (bortezomib)-dexamethasone (Decadron) (RVD) combination as well as cyclophosphamide and dexamethasone in combination with Revlimid or Velcade. In this study, researchers combined all four of the above mentioned drugs in hopes of further advancing combination therapies and responses to them.

Dr. Shaji Kumar of the Mayo Clinic explained, “The concept of four drug regimens was to examine if the natural history of the disease [could be altered] by producing deeper responses.”

The 25 myeloma participants in the study, all of whom were newly diagnosed and previously untreated, received 100, 200, 300, 400 or 500 mg/m² cyclophosphamide once a week along with maximum RVD doses for eight 21-day cycles. Starting with the lowest dose of cyclophosphamide, a couple of patients were enrolled at each dosage level until participants experienced severe side effects.

Of the 25 patients, 96 percent responded to treatment. Twenty percent achieved a stringent complete response, another 20 percent achieved a complete or near complete response, and 28 percent achieved a very good partial response. These responses are just as strong, or in some cases, stronger, than leading three-drug combination treatments.

The median time to the first response was 49 days, and the median time to best response was 95 days.

The time to disease progression, progression free survival, and overall survival rates have not yet been reached.

There was no significant difference in response that could be determined between groups that received different dosages of cyclophosphamide. “It is difficult to make any conclusions regarding differences between the different doses of cyclophosphamide, since only three to six patients were enrolled at each dose level. However, no obvious differences stood out,” explained Dr. Kumar.

In addition to investigating the efficacy of the RVCD regimen, the safety of the therapy was also determined.
Based on tolerability of the highest dose of cyclophosphamide tested, the researchers recommended that 500 mg/m² cyclophosphamide be used when administered with the RVD combination.

Dr. Kumar explained that raising the dose above 500 mg/m² would have made little-to-no difference in response rates at the expense of a higher rate of side events. “Increasing the dose of cyclophosphamide would not have made much impact on the response rate, but certainly could have compromised the doses of other drugs in terms of common toxicities,” Dr. Kumar stated.

Forty percent of study participants experienced at least one serious side effect. The most common severe side effects were low white blood cell counts (24 percent), peripheral neuropathy (pain or tingling in the extremities, 16 percent), low red blood cell counts (12 percent), low platelet counts (12 percent), and back pain (12 percent).

Two patients required dose reductions: One patient experienced fever and low white blood cell counts, requiring a dose reduction while on 400 mg/m² cyclophosphamide. Another patient developed severe herpes zoster and required a dose reduction while on 500 mg/m² cyclophosphamide.

Eight patients left the study due to side effects and personal decisions to decline further treatment. One patient died during the study due to disease progression.

Dr. Kumar concluded, “The response rates did not seem substantially different between the three and four drug regimens. So, at this point, it is hard to say that a four drug regimen is required. However, novel combinations of multiple drugs with different mechanisms of action should continue to be studied in trials.”

The Phase 2 portion of this study will compare RVCD with RVD and Velcade-cyclophosphamide-dexamethasone.

Further research also needs to address whether high response rates from multi-agent drug regimens lead to improved survival rates.

For more information, please see the study in Nature (abstract).

The analysis also showed that patients’ response to Revlimid and dexamethasone improved over time with continuous treatment.

The authors of the analysis therefore suggested continuing treatment in patients who achieved partial response as long as possible to achieve best outcome.

They added that treatment of multiple myeloma should not only focus on achieving an initial response, but on achieving best outcome by treating patients beyond initial response.

Recent studies have shown that more relapsed and refractory patients achieve a complete or very good partial response with the Revlimid (lenalidomide)-dexamethasone (Decadron) combination treatment However, it is not clear if the quality of response is associated with better prognosis.

Researchers therefore analyzed the data from two previous Phase 3 trials to determine whether achievement of a complete remission or a very good partial response confers a clinical benefit over the achievement of a partial response.

Of the 353 relapsed and refractory myeloma patients who received Revlimid and dexamethasone, 32 percent achieved a complete remission or a very good partial response, while 28 percent achieved a partial response.

The median duration of response to the Revlimid-dexamethasone combination was longer for patients who achieved complete remission or a very good partial response (24 months) than those who had only achieved a partial response (8.3 months).

The median time to disease progression for patients who achieved a complete remission or a very good partial response was also longer (27.7 months) than those who had achieved a partial response (12 months).

After four years, 60 percent of patients who had achieved a complete remission and a very good partial response were alive, compared to 42 percent of those who had achieved a partial response.

Median overall survival had not been reached for the complete or very good partial response group, while for the partial response group median overall survival was 44.2 months.

Researchers also found that after four years, 33 percent of patients who achieved a complete remission or very good partial response experienced disease progression. Of those who had achieved a partial response, 56 percent experienced disease progression.

The analysis also showed that the disease status of the participants generally improved as the trial progressed. Of the patients who achieved a partial response as initial response, 50 percent achieved complete remission or very good partial response with continued treatment.

Of the patients who achieved a complete remission or a very good partial response as best response, 82 percent had initially achieved a partial response at first evaluation.

It was also confirmed that the sooner a patient achieved a partial response, the greater the probability of achieving a very good partial response or complete remission with further treatment.

Patients who achieved a partial response by the fourth cycle had a 43 percent chance of achieving a complete response or very good partial response later, while those who achieved a partial response by the sixth cycle had a lesser chance of 38 percent.

Side effects were similar for patients who achieved complete remission or a very good partial response and those who achieved a partial response. The most common severe side effects included low white blood cell counts, low platelet counts, and blood clots.

For more information, please see the full analysis in Haematologica (pdf).

Immunomedics Doses First Multiple Myeloma Patient With Milatuzumab-Doxorubicin Combination – Immunomedics has dosed the first patient in a Phase 1/2 study of its milatuzumab-based treatment for multiple myeloma. This treatment has doxorubicin (Adriamycin), a chemotherapy drug, bound to milatuzumab, an antibody. It will be evaluated for its efficacy as a treatment for relapsed and refractory multiple myeloma patients. For more information, please see the Immunomedics press release and the clinical trial description.

ImmunoGen And Sanofi-Aventis Announce Beginning Of Phase 1 Trial Of Potential New Myeloma Treatment – ImmunoGen Inc. and Sanofi-Aventis announced the initiation of a Phase 1 clinical trial of SAR650984, an antibody that targets cancer cells. In preclinical testing, SAR650984 was found to have anti-cancer effects, and is now being investigated as a treatment for relapsed and refractory multiple myeloma as well as other blood cancers. For more information, please refer to the ImmunoGen press release.

Everolimus is marketed by Novartis under the brand name Afinitor for the treatment of advanced kidney cancer and under the name Zortress to prevent kidney transplant rejection.  Everolimus is currently being investigated as a potential treatment for multiple myeloma, and often goes by the codename RAD001 in clinical trial descriptions. The drug has not shown any anti-myeloma effects as a single agent. However, previous studies have shown that drugs similar to everolimus in combination with Revlimid may be effective against myeloma.

In their study, researchers sought to determine whether the combination of everolimus with Revlimid would have anti-myeloma effects.

The trial enrolled 28 patients who received varying doses of the oral combination treatment for 21 days with a 7-day rest period. All patients had previously experienced either relapse, meaning they became more ill after a partial recovery from multiple myeloma, or were refractory, meaning they did not respond to the most recent treatment they were given.

Patients received treatment until disease progression or unacceptable levels of side effects were observed.

Data from 26 patients were analyzed. Nineteen of the patients had completed two treatment cycles at the time of analysis.

Researchers observed at least a minor response in 63 percent of the patients who had completed two treatment cycles. One patient reached stable disease.

Eleven percent of patients experienced severe low white blood cell counts (neutropenia), and 22 percent of patients experienced severe low platelet counts (thrombocytopenia). These side effects were severe enough that they limited the dosing of the drug. Researchers reported 5 mg of everolimus and 15 mg of Revlimid as the maximum tolerated dose.

The most common mild to moderate side effects included nausea, fatigue, shortness of breath, diarrhea, constipation, tingling or numbness in fingers and toes (peripheral neuropathy), and muscle cramps.

Researchers concluded that the treatment was well-tolerated and may provide a non-steroid based treatment alternative for relapsed/refractory multiple myeloma patients.  However, Dr. Robert Z. Orlowski of the MD Anderson Cancer Center described the results as “mixed,” given the neutropenia and peripheral neuropathy observed in the trial participants.

Researchers suggested further testing of the combination treatment in Phase 2 trials.

For more information, please see abstract 8032 at the ASCO Meeting website.

The study compared CyBorD with Revlimid (lenalidomide)-dexamethasone treatment (abbreviated RD) and cyclophosphamide-Revlimid-dexamethasone treatment (abbreviated CRD). The results of the Phase 2 trials indicate that RD and CyBorD treatment were similar in efficacy and safety. CRD, however, was not as effective and had more severe side effects than RD and CyBorD.

All drugs included in the trials have been approved for use in multiple myeloma by the United States Food and Drug Administration. RD as well as Velcade-dexamethasone are commonly used to treat newly diagnosed myeloma patients. This study shows that the addition of cyclophosphamide may increase the efficacy of the Velcade regimen, but not the Revlimid regimen.

A total of 150 patients were enrolled in the trials, including 40 who were considered high risk due to chromosomal abnormalities.

The average number of cycles completed during the trial varied by regimen, with RD patients staying on therapy the longest (patients completed a median of four cycles CyBorD, eight cycles RD, or five cycles CRD). Following completion of treatment, patients in the CyBorD and RD groups responded much better than those in the CRD group, with near complete response rates of 41 percent, 35 percent, and 11 percent, respectively.

Survival was similar among the treatment groups, with overall median progression-free survival of 2.6 years and 2-year overall survival of 87 percent to 95 percent. However, 3-year survival was significantly longer in patients who subsequently received a stem cell transplant (95 percent survival) as compared to those who did not (75 percent).

Regardless of treatment regimen, high-risk patients experienced earlier relapse than standard-risk patients. Fifty percent of high-risk patients experienced two years without disease progression as opposed to 70 percent of standard-risk patients.

Fewer patients receiving CyBorD (8 percent) and RD (9 percent) experienced severe complications as compared to patients receiving CRD (25 percent). However, 58 percent of CyBorD patients experienced peripheral neuropathy (tingling and pain in the extremities often associated with Velcade therapy), a rate much higher than in the RD (20 percent) and CRD (13 percent) groups.

The researchers concluded that CyBorD treatment resulted in superior response rates and similar or fewer side effects than treatment with RD and CRD. However, they noted, “At this time, improved early depth of response does not translate into different survival outcomes.” They are encouraged, though, by the fact that 82 percent of patients enrolled in the trial have survived four years since treatment.

For more information, see abstract 8131 on the ASCO meeting website.

In August 2008, Phil Brabbs was diagnosed with smoldering myeloma, which most physicians do not treat until symptoms begin and the disease progresses to multiple myeloma. After more than a year of physicians carefully reviewing his blood work, Phil’s smoldering myeloma progressed to multiple myeloma, and his physicians wanted to begin treatment.

Phil’s doctor suggested that he participate in a clinical trial that would test a new combination of myeloma treatments.

“My biggest concern was that I would be part of an unproven treatment that could have negative or dire effects on my health,” said Phil. “I was more concerned about taking the best known treatment for multiple myeloma, rather than signing up for something that was unproven.”

However, Phil’s doctor said that based on early results from the ongoing clinical trial, he recommended that Phil use the clinical trial treatment protocol, regardless of whether Phil qualified for the Phase 1/2 clinical trial at the University of Michigan Cancer Center.

The trial called for treatment with a combination of Revlimid (lenalidomide), Velcade (bortezomib), dexamethasone (Decadron), and Doxil (doxorubicin liposomal).

“Being young, I wanted to take on a treatment that was aggressive and could provide the most positive lasting effects,” said Phil, who is 29 years of age.

Once Phil realized that we would be using this new combination regardless of whether he participated in the clinical trial, the decision to participate was quite easy. Since the chemotherapy drugs were paid for in full as part of the trial, it was as Phil described, “A no brainer.”

In addition, Phil liked that participating in a clinical trial would benefit others as well as himself. “With treatment options for multiple myeloma still very limited, there is an opportunity to be part of the next big advancement of treatment options that could not only positively affect the patient’s outcome but also help all future patients and doctors,” he said.

Despite his initial reservations about participating in a trial, Phil decided that the pros of trying a new treatment outweighed the cons.

Signing up for the trial was quite easy. “It was a very simple process of looking over some documents, meeting with my physician’s assistant and oncologist, and signing the forms.” Additionally, several tests were required for the screening process.

“Most of my treatment is at home, but I do go in twice a week for two weeks, then one week off,” said Phil, conveying the convenience of the treatment. He saw his physician about as often as he did before joining the trial. Phil also explained that his lifestyle was not interrupted by the trial and that it allowed him to receive a new combination treatment that had a positive response.

Overall, Phil is happy with his choice to participate in a clinical trial, “The trial is proving to have a better response rate than previous therapies.”

Since completing the clinical trial protocol, Phil has undergone two autologous stem cell transplants. For each transplant, Phil received high-dose melphalan (Alkeran) chemotherapy to kill off the myeloma cells, and then his own stem cells were transplanted back into his blood steam. The Beacon wishes Phil a smooth recovery from his second transplant, which took place on Wednesday.

For more information about Phil and his clinical trial participation, please read a previous Beacon interview with Phil and visit his blog “Multiple Myeloma for Dummies.” To learn more about clinical trials, please read the previous articles in the series.

“There are novel therapies that have improved the outcome, literally doubled the survival, of patients with myeloma. Despite these incredible advances, inevitably most patients relapse, and so we need [new] novel therapies,” said Dr. Anderson of the Dana-Farber Cancer Institute.

For this reason, panobinostat is being developed by Novartis for the treatment of relapsed and refractory myeloma patients. Panobinostat works by preventing the breakdown of proteins in tumor cells. It is the resulting accumulation of these proteins that causes the cancerous cell to die.

Initial studies to determine the efficacy of panobinostat as a single drug therapy showed only two patients out of 38 responded. “This degree of activity did not warrant going forward as a single agent,” said Dr. Anderson.

The goal of each Phase 1b combination trial was to determine the maximum tolerated dose of panobinostat. Efficacies of the therapy regimens were also monitored.

Panobinostat In Combination With Velcade

The Phase 1b clinical trial investigating panobinostat in combination with Velcade was presented at ASCO by Dr. Anderson.

Forty-seven patients were enrolled in the panobinostat-Velcade combination trial. All patients had received prior treatment for multiple myeloma, including some patients who had been previously treated with Velcade.

To determine the maximum tolerated doses of panobinostat and Velcade in combination together, patients were divided into five groups. Each group of patients received a different combination of doses.

Researchers found that there were responses even at the lowest doses, and complete and very good partial responses were observed at the highest tolerated dose of panobinostat. The overall response rate was 70 percent, with 10 percent complete response.

“Importantly, and I think this is key, if you look at the patients who are Velcade refractory, we actually have 60 percent responses,” said Dr. Anderson.

Dr. Anderson commented, “I think this is among the most active, if not the most active, combination in Velcade-refractory disease.”

Dose-limiting side effects occurred in patients receiving more rigorous regimens. As a result of these side effects, Dr. Anderson concluded, “Panobinostat can safely be combined with Velcade with a recommended dose of 20 mg of panobinostat three times per week and Velcade at 1.3 mg/m² given twice a week for two weeks.”

Though significantly low platelet counts (81 percent of patients), white blood cell counts (57 percent), and red blood cell counts (21 percent) were side effects of treatment, these levels could be managed with dose modification and platelet transfusion. Other common side effects included diarrhea, nausea, fever, fatigue, and weakness.

An international Phase 3 trial of panobinostat-Velcade compared to Velcade alone in relapsed myeloma is ongoing. Additionally, a Phase 2 trial of panobinostat-Velcade treatment for refractory multiple myeloma is underway in the United States, “hopefully to achieve accelerated approval for this unmet medical need,” said Dr. Anderson.

Panobinostat In Combination With Revlimid And Dexamethasone

Results of the ongoing Phase 1b clinical trial of panobinostat-Revlimid-dexamethasone were presented at ASCO during a poster session. The trial enrolled 46 multiple myeloma patients, 25 of whom had refractory disease.

Patients received 5, 10, 20, or 25 mg panobinostat plus 25 mg Revlimid and 40 mg dexamethasone.

Among the participants who have been evaluated, 57 percent responded to the combination therapy. Additionally, 26 percent of all participants remain on the study.

Dose-limiting side effects occurred in 25 percent of evaluated patients, with nearly half of the patients in the 25 mg panobinostat group experiencing such side effects. The most common serious side effects were low platelet levels (44 percent of patients) and low white blood cell levels (37 percent). Two deaths occurred during the study and were suspected to be treatment related.

Researchers concluded that “no new safety concerns were identified and preliminary efficacy [of panobinostat-Revlimid-dexamethasone therapy] was very encouraging.”

However, during a discussion about the results, Dr. Robert Z. Orlowski of the MD Anderson Cancer Center expressed concern about the side effects, which he said were most likely due to high-dose dexamethasone.

Further studies are ongoing to determine the maximum tolerated dose of panobinostat as well as effects of lower dexamethasone and non-continuous panobinostat dosing.

Although panobinostat alone had minimal benefit as a therapy for myeloma, Phase 1b trials suggest that panobinostat may be highly effective against advanced multiple myeloma when given in combination with other currently used therapies.

For more information, please see abstract 8001 (combination with Velcade) and abstract 8030^ (combination with Revlimid and dexamethasone) on the ASCO Meeting website.