In their statement, the experts reviewed the main findings from previous clinical trials that investigated the impact of maintenance therapies containing the novel agents thalidomide (Thalomid), Revlimid (lenalidomide), and Velcade (bortezomib).

Maintenance therapy is a prolonged, and often low-dose, form of treatment given to myeloma patients after their initial therapy. The goal of maintenance therapy is to prevent disease progression for as long as possible while maintaining a favorable quality of life. Maintenance therapy is different from consolidation therapy, which usually involves a shorter course of treatment with the goal of deepening patients’ responses to the initial therapy.

Based on these results, the experts came to the following conclusions for myeloma patients considering maintenance therapy:

The experts did not come to a consensus on the use of Revlimid as maintenance therapy. Revlimid maintenance increased progression-free survival in younger patients, which according to some experts speaks in favor of using Revlimid maintenance. However, Revlimid maintenance was also associated with an increased risk of secondary cancers, which according to some experts cannot be neglected when deciding whether to use Revlimid maintenance. The experts, therefore, said that longer-term survival data is needed before they can make a recommendation in favor, or against, Revlimid maintenance.

The experts stated that thalidomide maintenance is a treatment option for younger patients after stem cell transplantation, since thalidomide maintenance is associated with an increase in progression-free survival. For older patients who are not candidates for stem cell transplantation, the use of thalidomide maintenance is less clear because trial results were mixed in this patient population.

According to the experts, there is currently insufficient evidence available to make specific recommendations for, or against, Velcade maintenance therapy.

Additionally, the experts did not recommend maintenance therapy with interferons or corticosteroids alone.

Revlimid

Summary:

The experts found that Revlimid maintenance is associated with a significant increase in progression-free survival in both younger patients undergoing stem cell transplantation as well as older patients receiving conventional chemotherapy. Results of one study also showed a significant survival benefit with Revlimid maintenance therapy. However, the experts acknowledged that myeloma patients with high-risk chromosomal abnormalities do not benefit from Revlimid maintenance.

However, the experts pointed out that Revlimid maintenance therapy may be associated with an increased risk of secondary cancers (see related Beacon news), which they recommended physicians should bear in mind when deciding whether to prescribe Revlimid maintenance.

If the decision is made to use Revlimid maintenance therapy, the experts recommended a starting dose of 10 mg per day for both younger and elderly standard-risk patients. They added that both continuous therapy, as well as a “three weeks on, one week off” approach, may be effective.

Additional Information:

Results of two clinical trials, the United States CALGB 100104 trial and the French IFM 2005-02 trial, suggest that Revlimid maintenance may be effective in younger, standard-risk myeloma patients who received a stem cell transplant (see related Beacon news).

Results of the CALGB 100104 trial showed that after a median follow-up of 28 months, the median time to disease progression was significantly longer for patients who received Revlimid maintenance than for patients who received a placebo (48 months versus 31 months).

Patients who received Revlimid maintenance also had a significantly longer event-free survival than patients who received a placebo (42 months versus 22 months).

However, they also experienced more cases of low white blood cell counts, low red blood cell counts, low platelet counts, and infections.

Results of the IFM 2005-02 trial showed that after a median follow-up of 36 months, the median progression-free survival was significantly longer in patients who received Revlimid maintenance (41 months versus 24 months). However, the progression-free survival and overall survival were shorter in patients who had high-risk chromosomal abnormalities.

According to the authors of the review, a notable result of both the CALGB 100104 and IFM 2005-02 trials was the increased occurrence of secondary cancers among patients who received Revlimid maintenance.

Last year, after months of controversy over the apparent increase of secondary cancers among myeloma patients receiving Revlimid maintenance, both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) began safety reviews of Revlimid. The EMA concluded that the benefits of Revlimid continue to outweigh its risks. However, the agency also recommended that the prescribing information for Revlimid be updated with a warning about the risk of new cancers (see related Beacon news).  The FDA investigation is still ongoing.

The experts commented that further studies are needed to evaluate the true risk of secondary cancers to identify risk factors and to develop strategies for their prevention in myeloma patients. According to the experts, “physicians and patients must weigh the benefits of Revlimid maintenance therapy against the low but relevant risk of secondary cancers.”

In addition to the CALGB 100104 and IFM 2005-02 trials, results of an Italian study indicated that Revlimid maintenance also prolongs the progression-free survival of elderly myeloma patients treated with conventional chemotherapy (31 months versus 13 months).

Thalidomide

Summary:

The experts found that thalidomide maintenance after stem cell transplantation may increase progression-free survival and, to a lesser degree, overall survival. However, they pointed out that patients with high-risk chromosomal abnormalities did not benefit from thalidomide maintenance.

The experts added that the lowest active dose of thalidomide is 50 mg per day and that the duration of thalidomide therapy should be limited to one year in order the limit the risk of severe side effects.

For older patients who are not candidates for stem cell transplantation, the experts pointed out that the use of thalidomide maintenance is less clear because trial results were mixed in this patient population.

Additional Information:

Studies of thalidomide maintenance therapy have been primarily in younger patients receiving a stem cell transplant.

In a small number of clinical trials investigating the impact of thalidomide maintenance in elderly patients, roughly half of the patients had been exposed to thalidomide during initial therapy. Results of these trials showed a significant increase in progression-free survival, but not overall survival, in elderly patients treated with thalidomide maintenance (see related Beacon news).

However, the experts were unable to confirm whether elderly patients who had not received thalidomide during initial therapy would benefit more from thalidomide maintenance than patients who had previously received thalidomide.

They indicated that thalidomide maintenance may be a valuable option in standard-risk elderly patients, although elderly patients may not tolerate thalidomide as well as younger patients.

According to the experts, most clinical trials have shown that thalidomide maintenance increases the quality of response and prolongs the progression-free survival of younger myeloma patients (see related Beacon news 1, 2, and 3). Additionally, these trials indicate that the risk for disease progression is similar in patients who received thalidomide during both their maintenance and initial phases and in patients who received thalidomide during their maintenance phase only.

However, the impact of thalidomide maintenance on overall survival rates is not as clear. While some studies indicate that thalidomide maintenance increases overall survival, other studies have shown that thalidomide maintenance fails to provide an overall survival benefit (see related Beacon news).

Therefore, the experts stated that the improved overall survival associated with thalidomide maintenance, as demonstrated in some studies, must be interpreted with caution.

They speculated that the most common explanation for the difference in overall survival rates across studies is the inclusion of elderly patients in some of the thalidomide maintenance trials that showed no improvement in overall survival. Moreover, they commented that differences in the availability of novel agents at relapse across studies may have also contributed to the different overall survival rates of myeloma patients receiving thalidomide maintenance.

In addition, the results of several clinical trials suggest that patients without high-risk chromosomal abnormalities are more likely to benefit from thalidomide maintenance than patients with high-risk factors.

For instance, in the MRC Myeloma IX trial, myeloma patients receiving thalidomide maintenance who did not have high-risk chromosomal abnormalities had a significantly better overall survival than patients who had chromosomal abnormalities.

Velcade

Summary:

The experts acknowledged that specific recommendations cannot be made for Velcade maintenance therapy at the present time because more information is needed regarding the optimal scheduling, dosing, and duration of Velcade maintenance.

They proposed further studies involving patients not previously exposed to Velcade in order to address these issues.

Additional Information:

According to the experts, single-agent Velcade maintenance therapies have only been investigated in myeloma patients who had already received Velcade during initial therapy.

For instance, the HOVON/GMMG clinical trial compared the effectiveness of a Velcade-doxorubicin (Adriamycin)-dexamethasone (Decadron) initial therapy followed by Velcade maintenance (PAD/Velcade) with a vincristine-doxorubicin-dexamethasone initial therapy followed by thalidomide maintenance (VAD/thalidomide).

After 36 months, patients who received PAD/Velcade had significantly better progression-free survival (78 percent versus 48 percent) and overall survival (71 percent versus 42 percent) rates compared to patients who received VAD/thalidomide.

Although the results of the HOVON/GMMG trial showed that Velcade maintenance therapy can be tolerated for up to two years, the experts claimed that the design of the study does not allow for a clear interpretation of the role of Velcade maintenance therapy because patients received different initial therapies.

Other studies have assessed the impact of Velcade maintenance in combination with thalidomide. Two of these studies indicated that Velcade plus thalidomide increases progression-free survival when administered as maintenance therapy.

Chemotherapy, Interferon, And Corticosteroids

Summary:

The results of previous clinical trials have suggested that conventional chemotherapy – melphalan (Alkeran) or BCNU (carmustine) typically used in combination with prednisone – prolongs the duration of remission in myeloma patients initially treated with melphalan plus prednisone. However, the experts pointed out that the use of chemotherapy in maintenance strategies was not pursued further when it was determined that chemotherapy failed to improve overall survival.

Interferon has also been shown to increase the duration of remission in myeloma patients, although results across studies have been mixed. According to the experts, physicians have abandoned the use of interferon in maintenance therapies because of toxicities and the inability to adequately select patients who are likely to benefit from interferon therapy.

Corticosteroids such as prednisone and dexamethasone have also yielded mixed results across studies. While prednisone has been shown to increase remission duration and survival, dexamethasone has been shown to lack benefit in myeloma patients. Taken together, the experts stated that the current data is insufficient to recommend corticosteroid maintenance therapy in myeloma patients.

For more information, please see the IMW consensus statement in the journal Blood (abstract).

But suffice it to say that lately there has been a lot going on with me, and it has brought to the forefront that inevitable discussion about what to do next should my current treatment regimen of Revlimid (lenalidomide) and dexamethasone (Decadron) start to fail.

I’ve discussed this prospect at various times over the past year with the handful of myeloma doctors who treat me as well as with other myeloma doctors I know.  They are unanimous that the next best thing for me would be a drug in the pipeline called carfilzomib.

The book on this new drug is that it is pretty effective and well tolerated.

The myeloma doctors I know talk about carfilzomib’s efficacy and especially about the fact that side effects seem to be relatively few and less onerous than with many treatment options.

I’d say that carfilzomib is one of the most highly anticipated new treatment drugs for myeloma – right up there with the introduction of Velcade (bortezomib) and Revlimid a few years ago.

Carfilzomib, however, is having a bit of trouble getting to the marketplace.

In December, I was watching NBC’s Nightly News when there was an item stating that the U.S. Food and Drug Administration (FDA) announced that it was not going to use the expedited approval process for carfilzomib – that it “did not see the urgency.”

In one of those talking-to-an-inanimate-object moments, I started shaking my hand at my TV and at either Lester Holt or Brian Williams (I was too distraught at the time to remember now which one) saying things like:

                        “Wait a minute, who says there’s no urgency?”

                        “I’m a myeloma patient – I’ll bet there are a lot more who think there’s an urgency here.”

                        “It’s urgent to me!”

So, instead of being approved – if it even gets approved – by this March, the FDA won’t reach a conclusion on carfilzomib until July 27 through the standard review process.

Not getting expedited approval was a surprise to just about everybody – even Wall Street analysts.  All the myeloma doctors I spoke with in the past year told me that they expected carfilzomib to be approved right after the first of the year.  Not so, now that the FDA has spoken.

It’s been a bumpy ride for this drug.

The first significant problem happened in the fall of 2010 when Onyx Pharmaceuticals, the company developing carfilzomib, moved from clinical to commercial-scale manufacturing, which resulted in “minor variations.”  This required fixing, of course, and an FDA review, forcing delay in the plan to file a New Drug Application by the end of 2010.

Another problem is that research supporting carfilzomib is only an open label, single-arm Phase 2b clinical study.  In a single-arm study, patients are managed with a specific therapy, and a proposed drug is systematically observed to measure outcomes among patients with the specific disease.  Participants are not randomized to receive either the study drug or the standard treatment, so no direct comparison can be made.

Pretty much everything I read in researching this column says that the FDA’s Oncology Drug Advisory Committee really prefers Phase 3 trial results.  Nonetheless, the FDA has given new drugs approval based on Phase 2 research on several occasions.

One of the things that Onyx did last year was gather additional safety data from other carfilzomib studies that are underway, which were included in the New Drug Application that was finally submitted at the end of last September.

The good news is that the FDA accepted the application in late November.  In its filing communication letter two weeks later, one of the review concerns raised by the FDA in accepting the application, however, was whether there was appropriate balance between risk and benefit.

The letter also included the bad news:  The FDA said no to a priority review.

In order to get priority review, it’s important to show significant benefit and a high degree of unmet need, especially when the supporting study is a single-arm Phase 2 trial.

So I guess what the FDA is saying is that while the results of the study show respectable benefit, they aren’t spectacular, and that those of us who are relapsed/refractory have a number of other treatment options that work.

Well, for many people that’s likely true, but for others, maybe not so.

You can get carfilzomib today under two conditions.  One is through a clinical trial, which means you can only get it at treatment centers participating in the study.

For me, if the time comes when switching treatment makes sense, it wouldn’t be too bad to enter a trial – under normal circumstances.  I’d have to be at Memorial Sloan-Kettering Cancer Center two days a week.  Since I work in New York City, that’s pretty much a no-brainer.  Heck, lots of myeloma patients have packed up and moved temporarily to another location for months in order to participate in a clinical study.

Unfortunately, if that “time” to switch is neigh upon me, my circumstances right now aren’t “normal.”  I’m sort of under indefinite house arrest with a broken foot, and home is almost 200 miles away from Memorial Sloan-Kettering.  Everyone there feels that trying to make that trip frequently would likely wreck any healing that’s going on with my broken bone.

You can also access carfilzomib as a last-ditch “salvage therapy.”  The Carfilzomib Myeloma Access Program (C-MAP), a joint undertaking of Onyx and the Multiple Myeloma Research Foundation, makes carfilzomib available to seriously ill myeloma patients in the U.S. lacking any other treatment options.

As for the prospects of carfilzomib winning approval this summer, the jury is still out. One Wall Street analyst pegs approval chances at around 80 percent.  Others aren’t quite so sure, seeing the failure to win priority review as a red flag.  And these Wall Street guys aren’t ignorant about things, especially new drugs, because there’s oodles of money to be made by those who get in early in pharmaceutical developments.  If you want to know what’s going on with a drug that’s under development, check with the Wall Street guys – reporters and analysts.  They pretty much deal with the cold, hard facts.

If carfilzomib doesn’t get approval, Onyx would have to submit a new application supported by a Phase 3 study; the main one underway is called “Aspire.”  It would move up a prospective launch to sometime in 2014, at the earliest.

Okay, just let me say that this all doesn’t seem right to me.

I know that the safety-benefit issue is important, and I have heard a few anecdotal reports of individual problems with carfilzomib.  But a handful of serious problems accompanying most any drug out there seems to be a matter of course today – just listen to the disclaimers on those incessant pharmaceutical ads on television.

I think the key matter here is that, as best I can tell, the benefit of this drug is clear.

It works.  Not for everyone.  Maybe not spectacularly.  But the key thing is: carfilzomib is effective.

The fact is, and we all know it, there’s no cure for myeloma.  And no single treatment works forever.

We need in the arsenal every possible and practical drug intervention to keep us alive.

I think the failure to give priority review to carfilzomib, and an FDA decision that the drug’s Phase 2 study is insufficient for approval, would deny myeloma patients an apparently effective and overall safe treatment option.

Carfilzomib is the wrong drug for the FDA’s Oncology Drug Advisory Committee to use just to make a point about Phase 2 research.

I think that doing so would be unconscionable.

Forcing relapsed myeloma patients to continue to wait for the wide availability of carfilzomib – perhaps another two years or more depending on how this drama plays out – would be just plain wrongheaded.

In addition, the company said that it plans to submit a similar application to the European Medicines Agency (EMA) during the first half of this year.

The updated submission timeline means that pomalidomide could be approved for use in the United States and in Europe by the end of this year.

Celgene’s announcement was made in a company earnings report.

Pomalidomide, which belongs to the same class of drugs as thalidomide (Thalomid) and Revlimid (lena­lidomide), is being developed by Celgene (NASDAQ: CELG) for the treatment of multiple myeloma and myelofibrosis.

Results from the latest clinical trials involving pomalidomide were presented at the American Society of Hematology meeting last month (see related Beacon news).  Physicians and industry analysts have responded positively to the drug’s performance, particularly among patients previously treated with both Revlimid and Velcade (bortezomib).

Under the FDA’s standard review process, the agency must decide whether to approve a drug within 10 months of the time the drug is submitted for review.  However, the FDA can grant priority review to drugs that offer significant advances in treatment, particularly for diseases in which there are inadequate treatment options. If the FDA grants pomalidomide priority review, the agency would need to complete its review of the drug within six months.

Thus, if the FDA approves pomalidomide based on the application Celgene submits this quarter, the drug could be available for use in the U.S. by the last quarter of 2012 or early 2013.

In Europe, the EMA must review drug applications within 210 days of submission.  If, however, a drug is granted an accelerated assessment due to therapeutic innovation or because it is of significant interest to the public health, the EMA must review the application within 150 days.

These timelines mean that, if the EMA approves pomalidomide based on the application Celgene submits during the first half of this year, the drug could be available for use in Europe by the end of 2012 or the first quarter of 2013.

An EMA approval of pomalidomide would allow the drug to be marketed in all 27 countries of the European Union and in Norway, Iceland, and Liechtenstein.

Along with carfilzomib – which works similarly to Velcade – pomalidomide is considered one of the most promising new myeloma treatments that could be approved by the FDA in the next few years.

For the full earnings report, see the Celgene website.

More details are provided in this article to answer multiple myeloma patients’ questions about the FDA decision.

What exactly did the FDA approve?

The FDA approved a supplemental new drug application for Velcade (bortezomib), which is an application to make changes to an already approved product.  Specifically, the FDA approved updated prescribing information that now says Velcade can be administered by intravenous (in the vein) injection or subcutaneous (under the skin) injection.

A drug’s prescribing information is an official document that describes the FDA’s approved uses of the drug, dosage and administration information, efficacy and safety data, and other pertinent information about the drug.

Velcade’s updated prescribing information also includes instructions on how to prepare and inject Velcade subcutaneously, a recommendation that subcutaneous administration should be considered for patients with pre-existing or at high-risk of peripheral neuropathy (pain and tingling in the extremities), as well as safety and efficacy data comparing intravenous and subcutaneous administration of Velcade.

What impact will the FDA decision have on myeloma patients in the U.S.?

Prior to the FDA decision, many treatment centers in the U.S. did not offer subcutaneous Velcade.  With the recent FDA approval, Dr. Ravi Vij, a myeloma specialist from Washington University in St. Louis, said, “I anticipate that the subcutaneous route will become the preferred route for administration of [Velcade].”

Some myeloma patients were receiving Velcade by subcutaneous injection prior to the FDA’s recent decision, so how will the FDA approval change anything?

Once a drug is approved by the FDA, physicians may prescribe the drug in ways that differ from the FDA approval, such as for other diseases or via a different route of administration.  However, FDA approval is an important sign to the medical profession of what is strongly supported by available clinical data.  Therefore, it has a definite impact on medical practice.

FDA approval also influences reimbursement decisions by health insurers.  The approval of subcutaneous Velcade should eliminate resistance by insurance companies to the reimbursement of Velcade when it is administered subcutaneously.

What impact will the FDA decision have on myeloma patients outside the U.S.?

Janssen, the Johnson & Johnson subsidiary that markets Velcade outside of the U.S., submitted an application in March 2011 to the European Medicines Agency for the approval of subcutaneous Velcade.  Although the European agency has not yet issued a decision, myeloma specialists from several European countries have indicated that subcutaneous Velcade is already being used in their countries (see related Beacon news).

A spokesperson from Janssen said that the company also has plans to seek approval in additional countries.

Dr. Vij indicated that he anticipates that the subcutaneous route will also become the preferred route for patients outside of the U.S.

What are the benefits of subcutaneous Velcade compared to intravenous Velcade?

According to Dr. Vij, “The major advantage is lower rates of neuropathy.”  Results from a Phase 3 trial showed that subcutaneous injection of Velcade significantly reduced the rate of severe peripheral neuropathy (6 percent of patients) compared to intravenous injection (16 percent).

“Subcutaneous administration is also more convenient for patients as it is quicker, so they do not have to spend as much time in the doctors’ offices,” added Dr. Vij.

When will subcutaneous Velcade be available?

Subcutaneous Velcade is available immediately.  It is the same formulation as intravenous Velcade; no new form of Velcade needs to be ordered by health care professionals.  Velcade comes packaged as a single-use vial of powder.  The same dose is used regardless of the route of administration.  However, the powder should be dissolved in a different amount of saline solution based on the route of administration.  The updated prescribing information provides instructions for how much solution to use for each type of administration.

Does the approval mean that Velcade will have to be given subcutaneously?

No.  Velcade can be given intravenously or subcutaneously.  However, the prescribing information specifically states that Velcade should not be administered by any other route.

Will all treatment centers in the U.S. offer subcutaneous Velcade?

Dr. Vij believes that all treatment centers will offer subcutaneous Velcade.

Now that subcutaneous Velcade is FDA approved, is subcutaneous administration recommended or preferred compared to intravenous administration?

“I think that the subcutaneous route will be preferred apart from some patients who have a reaction, infection, or bruising after subcutaneous administration, in which case the intravenous route may still be employed,” said Dr. Vij.

About 6 percent of patients who receive subcutaneous Velcade experience a reaction at the injection site.

For more information, see the Velcade prescribing information (pdf).

These articles included interviews with, columns written by, and summaries of treatment guidelines from leading myeloma experts.  They also included articles providing helpful information about rare types of myeloma and exciting new treatment options that are being studied in clinical trials.

All these articles were published in addition to the Beacon’s coverage of the latest myeloma-related news and research results, and in addition to the Beacon’s columns written by myeloma patients and caregivers.

As a service to its readers, The Myeloma Beacon has compiled a list of the resource articles Beacon readers found most interesting during 2011.

Physician Interview

Dr. Kenneth Anderson

Current And Future Approaches To Treating  Myeloma – In an interview with The Myeloma Beacon, Dr. Kenneth Anderson from the Dana-Farber Cancer Institute spoke about his approach to treating multiple myeloma patients.  He also spoke about the future of myeloma treatment, including the possibility of a cure for myeloma. The interview was published as a two-part series.

Physician Columns

Dr. S. Vincent Rajkumar

Promising New Drugs For Myeloma: Will The Future Come Soon Enough? – In one of his regular columns for The Myeloma Beacon, Dr. Rajkumar answered the following questions about myeloma therapies that are currently being developed: What are the most promising potential new drugs that could outsmart myeloma cells? Will they work in patients who have failed other therapies? Will they have a reasonable safety profile?  Will a future filled with many active treatments and options happen soon enough?

The Role Of Autologous Stem Cell Transplantation In Multiple Myeloma – In a different column, Dr. Rajkumar answered the following questions about autologous transplants (that is, a transplant using a patient’s own stem cells):  What is the current role of stem cell transplantation in myeloma therapy? Should I get a transplant? Am I too old for a transplant? Is it better to do one now, or can I wait? One or two transplants? Two back to back, or one now and one later?

Dr. David Vesole

Treating Multiple Myeloma Patients: Optimizing Response While Minimizing Side Effects – Dr. Vesole’s column discusses safer treatment approaches for Velcade (bortezomib) and Revlimid (lenalidomide), the two most commonly used novel agents for the treatment of myeloma.  He wrote that modifications to prior treatment methods can maintain excellent responses and improve survival while decreasing side effects, thereby improving quality of life.

Dr. David Roodman

Recent Advances In The Treatment Of Myeloma Bone Disease – Up to 80 percent of multiple myeloma patients having bone disease.  In his column, Dr. Roodman discussed the latest research about treating myeloma bone disease.  He included a discussion of the promising treatments for bone disease that are under clinical development.

Dr. Bijay Nair

Nonsecretory Multiple Myeloma – Since less than 5 percent of all patients with multiple myeloma have nonsecretory myeloma, these patients often have a hard time finding information about their type of myeloma.  In his column, Dr. Nair discussed the basics of nonsecretory myeloma, how patients with this type of myeloma are diagnosed, followed, and treated, what the prognosis is for these patients, and how secretory myeloma can become nonsecretory.

Guidelines And Reviews Published By Myeloma Experts

Experts Review Current And Future Research Into New Multiple Myeloma Treatments – Earlier this year, an international group of myeloma experts published a review of ongoing research into new myeloma treatments.  This review not only described a wide range of potential new myeloma treatments, but also included the experts’ thoughts on where research into new treatments should go in the future.

Spanish Experts Ask: What Is The Path To A Cure For Myeloma? – In an editorial, Spanish myeloma experts Dr. Jesús San-Miguel and Dr. Maria-Victoria Mateos reviewed the progress that has been made in the treatment of multiple myeloma.  They also proposed several actions they believed will bring the medical community closer to a cure for myeloma, including achieving and maintaining the best possible response early in the treatment of the disease, using advanced tools to evaluate and optimize treatment efficacy, and seeking an appropriate balance between efficacy and the side effects of treatment.

Experts Develop Guidelines For Treating Anemia In Multiple Myeloma Patients (IMW 2011) – A group of leading myeloma specialists, known as the International Myeloma Working Group, collaborated to develop guidelines for the proper management of anemia (low red blood cell counts) in multiple myeloma patients. The group recommended therapy with red blood cell-stimulating agents for anemic myeloma patients receiving chemotherapy in order to improve quality of life and to reduce the need for red blood cell transfusions. They further recommended the use of iron supplements to improve the efficiency of red blood cell-stimulating agents.

Helpful Information For Myeloma Patients

Subcutaneous Velcade – Velcade is currently approved to be used intravenously for the treatment of multiple myeloma.  However, many multiple myeloma patients who take intravenous Velcade experience peripheral neuropathy, a condition characterized by pain and tingling in the extremities due to nerve damage.  Recent studies have shown that administering Velcade subcutaneously may reduce the risk of peripheral neuropathy.  This article summarizes those study results, explains the current usage of subcutaneous Velcade in the United States and in Europe, and describes one myeloma patient’s experience with subcutaneous Velcade.

Extramedullary Myeloma – During the course of their disease, multiple myeloma patients some­times develop what physicians call “extra­medullary disease,” “extra­medullary plasmacytomas,” or “extra­medullary myeloma.”  All of these names refer to myeloma that develops outside of the bone marrow.  This article provides a detailed introduction to extramedullary myeloma, including what it is, how it is diagnosed, and how it is treated.

New Advances In Myeloma Vaccines – This series of articles about emerging vaccines for multiple myeloma describes the concept of a myeloma vaccine, the various types of vaccines that are currently under development for myeloma, vaccines for which clinical trials have been completed, ongoing vaccine research, and a patient’s experience participating in a myeloma vaccine clinical trial.

The Myeloma Beacon also recently published a compilation of the top Myeloma Beacon news articles from 2011 (see the related Beacon article).

Specifically, the results of the study showed that high-risk smoldering multiple myeloma patients who received Revlimid plus dexametha­sone followed by Revlimid maintenance had a longer time to disease progression and better overall survival than patients who did not receive treatment (see related Beacon news).

To help Beacon readers put these results into perspective and better understand their implications, The Beacon asked myeloma specialist Dr. Ola Landgren for his feedback and thoughts on the study.

The resulting discussion was wide-ranging and touched on issues of interest to all multiple myeloma patients — not just those with smoldering myeloma.

Dr. Ola Landgren, who was not involved with the Spanish study, is a Senior Investigator at the National Institutes of Health (NIH) and Chief of the Multiple Myeloma Section at the National Cancer Institute (NCI). He is regarded as an expert on monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma, and he is involved in a number of important studies into potential new treatment regimens for multiple myeloma.

The Myeloma Beacon: How significant are the findings of the Spanish research team, led by Dr. María-Victoria Mateos?

Dr. Landgren:  I find the results by Mateos et al. of major importance. Their data show that treatment of high-risk smoldering multiple myeloma translates into both progression-free and overall survival benefits. These are novel insights. In my opinion, they set the stage for the development of new treatment studies for high-risk smoldering multiple myeloma, aiming to delay and/or prevent progression to multiple myeloma.

Are the findings sufficient to recommend any change in current practice in regard to the treatment of high-risk smoldering myeloma patients?

No, I don’t think so. This study is based on approximately 60 treated and 60 non-treated high-risk smolder­ing multiple myeloma patients. The main reason why I don’t think it is time to change clinical care is that I think we need to see the results replicated in other independent studies. This view is in full accord with that of the investigators of the Spanish study; they emphasize the need for validation.

Another reason is that, until we have better biological markers easily available to define an individual’s risk of progression to symptomatic multiple myeloma, there is a risk of over- and under-treatment of patients diagnosed with smoldering multiple myeloma.

Let me also say that, based on our completed and ongoing research, I personally do not think that smol­dering myeloma truly exists as a disease entity.

I think there are patients in the so called “smoldering multiple myeloma” category that are more like patients with MGUS, while others are what I would call “early myeloma.”

This is not a perspective, however, that you will find in the textbooks (yet).

In our clinic at the NIH, we have assessed a large number of patients diagnosed as smoldering multiple myeloma, with a wide range of tools, including flow cytometry, biomarkers, microRNAs, genetic profiling, molecular / functional imaging, marrow vascularity, early bone changes, and so on.  And we have learned that there is tremendous heterogeneity in terms of biology and the risk of developing symptomatic multiple myeloma.

More importantly, what we have seen is that the biological markers in so-called “high-risk smoldering myeloma” patients are very similar to those seen in patients with symptomatic multiple myeloma. This is why I would rather call high-risk smoldering myeloma “early myeloma.”  The main difference is that the early myeloma patients have not (yet) developed kidney failure, bone fractures, or other symptoms.

[For more information about Dr. Landgren’s studies of precursor diseases and how they progress to active myeloma, see a related Beacon opinion article.]

What caveats do you feel are important to mention in regard to the Spanish research?

In addition to the above mentioned need for validation of the results in other studies, I think a caveat is that the study focused mainly on clinical markers. For example, additional molecular markers and functional imaging would allow a much more detailed investigation into why and how the treatment works in some patients and not in others. That would be a translational / biological approach. I am in favor of translational / biological treatment studies to maximize the possibilities to advance the field.

Of course, I realize that it boils down to resources, and I know it is very expensive to do those types of things. Also it takes a lot of advanced infrastructure. Hopefully, future studies will provide more translational / biological insights.

If you believe the Spanish research argues in favor of early treatment of high-risk smoldering myeloma patients, do you feel that the treatment regimen used in the Spanish trial is the best treatment option, or is there evidence that treatment with other agents might be as effective – or even more effective?

The brief answer is: “nobody knows at this time”. We need to design and conduct clinical treatment studies designed to answer these questions. Until we have clear answers, we can only speculate based on available knowledge.

Here is my thinking: if you buy my arguments above about “early myeloma” – that is, that high-risk smol­dering myeloma is very much like symptomatic myeloma, just with less tumor burden – then you have to ask yourself: Would you treat a younger, newly diagnosed multiple myeloma patient with a Revlimid (lena­lidomide) – dexa­metha­sone (Decadron) combination followed by Revlimid maintenance only (that is, the treatment schedule used in the Spanish study)?

My standard answer would be “No.” So, why don’t we do what we typically do for symptomatic multiple myeloma with these “early myeloma patients”?  Why don’t we use a three-drug combination like Revlimid, Velcade (bortezomib), and dexamethasone (Decadron), or whatever combination we believe is better?

This is why I am so excited about our newest smoldering multiple myeloma study, which will open at the NIH during the spring of 2012. It will examine a treatment regimen involving eight cycles of carfilzomib, Revlimid, and low-dose dexamethasone followed by Revlimid maintenance for a minimum of one year. We are using carfilzomib instead of Velcade in order to increase the efficacy and at the same time reduce the side effects, in particular peripheral neuropathy [a condition characterized by pain and tingling in the extremities due to nerve damage].

Let me stress again, however, the need for more studies before any of these ideas start to be considered “standard of care.”

But isn’t that quite a leap?  Essentially, you are advocating taking patients the medical profession today feels shouldn’t be actively treated, and treating them with one of the more aggressive drug regimens in use for active myeloma. 

Again, the brief answer is: “nobody knows at this time”. We need to design and conduct clinical treatment studies designed to answer these questions.

To me, the whole concept of ‘watch and wait’ for smoldering myeloma is a consequence of multiple factors, including the fact that, until recently, we have not had access to effective drugs with reasonable or low toxicity profiles.

Also the disease monitoring methods have been, and still are, quite limited in standard day-to-day practice.

With toxic and not very effective drugs, it was not justifiable to expose any person to therapy unless there was a compelling need – specifically, clinically active multiple myeloma.

With newer, effective, and less toxic drugs, that way of thinking has to be challenged scientifically, in my opinion. That is what we are doing as we speak.

Looking at other cancers such as early breast cancer and early prostate cancer, much more work has already been done along these lines, and improved survival outcomes have followed.

Even if we assume that high-risk smoldering myeloma is really “early” active myeloma, is it a form of active myeloma that should be treated with a three-drug regimen that includes two novel agents? 

Or, to put it another way, might this “early” myeloma best be considered a relatively “low risk” form of active myeloma.  And, if so, wouldn’t many myeloma specialists be more comfortable using a less aggressive approach for that kind of myeloma?

First of all, I want to stress the need for better terminology and criteria. When we talk about “high risk” in various settings, I think there is a lot of confusion and inconsistency.

For example, “high-risk multiple myeloma” is commonly used as a term for (active) myeloma patients with a poorer prognosis than the average myeloma patient.

However, just to be clear, “high-risk smoldering multiple myeloma” refers to patients at high risk of trans­formation from smoldering myeloma (or early myeloma) to symptomatic multiple myeloma.

As I mentioned before, I think that many high-risk smoldering myeloma patients are already myeloma (that is, “early myeloma”).

Likewise, I would like to be bold and say: High-risk multiple myeloma does not truly exist as one unique biological entity with a given outcome.

Let’s do an intellectual experiment. Let’s say if all multiple myeloma patients were treated only with bisphosphonates such as Zometa (zoledronic acid) or Aredia (pamidronate), then the outcome would be poor for everyone.

In such a scenario, one could call all forms of multiple myeloma “high risk.”

Instead, let’s assume that a drug that cures all forms of myeloma was available. All multiple myeloma patients are treated with this drug, and all are being cured.

Now, all multiple myeloma patients are “low-risk.”

This example emphasizes the obvious.  “Risk” is an interaction between biology and intervention. And intervention is a variable that changes between clinicians and institutions, and it is constantly changing over time.

To me, it suggests that there is another way of looking at multiple myeloma patients currently called “high risk.” I prefer to think of these molecular subtypes of myeloma as “myelomas we have not yet figured out how to treat.”

Again, I don’t like the term “high-risk” myeloma. It think it is misleading in that it sounds like there is one subtype of myeloma that is inherently bad, and it does not respond to therapy.

That is not true. We know there are several molecular subtypes hidden in that group and they likely require different treatments for successful outcomes. We need to figure out the biological underpinnings, identify the treatment targets, and develop the right therapies for these subtypes soon!

Regarding your last question, where you assume that “early” myeloma best be considered a relatively “low risk” form of active myeloma. I don’t think there is any data to back that up; that is a theoretical assumption.

In fact, based on our ongoing research, there seem to be “early myeloma” patients with different disease biology. Consequently, as part of a clinical treatment study, I think it is reasonable to catch low disease burden and use powerful treatment strategies.

Just to be very clear; before we have these and other related answers sorted out in clinical treatment studies, in my opinion, we should not start treating early myeloma patients in standard, day-to-day practice.

Those are great points on terminology.  Can you explain a bit more, though, why you feel an aggressive approach with “early myeloma” (high-risk smoldering myeloma) may turn out to make the most sense?

If we think about “early myeloma” as a state of less tumor burden, it is theoretically possible that the less aggressive disease is curable, at least in some patients, with more effective therapy, while more aggressive disease will only be controlled (converted into chronic disease) using early therapy.

If we can cure a patient with early myeloma, that would be a huge thing for us. Of course, the pros and cons of treatment have to be balanced. We cannot accept side effects that are not in accord with the projected outcome.

In the coming years, I envision that some myeloma patients will be cured and others will have extended remission. Likely, many patients will have their disease controlled, which could be viewed as a “functional cure” — similar, for example, to successfully treated hypertension.

Before we reach this point, a lot of work remains to be done. I think key future strategies will be (1) more rational therapies / drugs (precision medicine), (2) earlier start of therapy in many patients, and (3) better monitoring before, during, and after therapy.

Again, these are ideas and concepts based on our research. It is not meant to be implemented in any clinical standard-of-care setting at this time.

However, I am very optimistic about the future. We have many new clues and tools to advance the field. We will continue working hard for our patients. Our ultimate goal is to find a cure for myeloma. It is an exciting time to develop new strategies for myeloma and its precursor states!

Specifically, the results showed that high-risk smoldering multiple myeloma patients who received Revlimid plus dexamethasone had a longer time to disease progression and better overall survival than patients who did not receive treatment.

However, the Spanish researchers acknowledged that these results should be confirmed by long-term follow-up data, especially regarding the difference in overall survival.

Dr. Ola Landgren of the U.S. National Institutes of Health, who has done extensive research on smoldering myeloma, described the results of the Spanish study as “very important.”

“This is the first treatment study of high-risk smoldering multiple myeloma showing that treatment is associated with improved overall survival,” he added.  “In my opinion, it has the potential to influence and change the way high-risk smoldering myeloma patients are being managed in the clinic. It could potentially lead to more advanced therapies for high-risk smoldering myeloma, and maybe some patients will be cured while others will have a significant delay in the progression of the disease.”

Dr. María-Victoria Mateos from the Hospital Clinico Universitario in Salamanca, Spain, presented the updated Phase 3 results at the American Society for Hematology (ASH) annual meeting in San Diego last month.

Dr. Mateos discussed initial results of this trial during a debate with Dr. Sagar Lonial of Emory University at the International Myeloma Workshop earlier this year (see related Beacon news and detailed coverage of the debate in the Beacon’s discussion forum).

Smoldering, or asymptomatic, multiple myeloma is a blood disorder characterized by an excess of monoclonal protein in the blood and urine. A diagnosis of smoldering multiple myeloma is given when a patient’s monoclonal protein level is at least 30 g/L or the proportion of plasma cells in the bone marrow is at least 10 percent, but the patient experiences none of the symptoms typically associated with multiple myeloma (elevated calcium levels, kidney failure, anemia, or bone lesions). Patients with smoldering multiple myeloma generally receive no treatment until their disease progresses.

Certain factors have been shown to increase the risk of progression to symptomatic disease in patients with smoldering multiple myeloma. These include a monoclonal protein level exceeding 30 g/L, plasma cells exceeding 10 percent in the bone marrow, abnormal plasma cells exceeding 95 percent, or the presence of small parts of antibodies (as indicated by an abnormal free light chain ratio).

Several past clinical trials have investigated the effects of melphalan (Alkeran) plus prednisone, thalidomide (Thalomid), and bisphosphonates in patients with smoldering multiple myeloma. According to the study authors, however, these clinical trials did not distinguish between standard-risk and high-risk smoldering multiple myeloma patients. The authors explained that standard-risk patients would probably not benefit from treatment, whereas high-risk patients may benefit from early treatment to delay the progression of the disease.

In this Phase 3 clinical trial, researchers investigated whether treatment with Revlimid (lenalidomide) plus dexa­methasone (Decadron) would prolong the time to progression to symptomatic disease in high-risk smoldering multiple myeloma patients.

A total of 119 patients were randomly assigned to either the treatment arm (57 patients) or the non-treatment arm (62 patients). The patients had a median age of 61 years and 65 years, respectively.

Patients in the treatment arm received an initial therapy consisting of nine four-week cycles of Revlimid plus dexamethasone. During each cycle, they received 25 mg of Revlimid daily on days 1 to 21 and 20 mg of dexamethasone daily on days 1 to 4 and 12 to 15. They then received maintenance therapy consisting of 10 mg of Revlimid on days 1 to 21 every month until disease progression or two years of treatment.

Patients in the non-treatment arm did not receive any form of treatment during the study.

Of the 57 patients in the Revlimid-dexamethasone treatment group, 86 percent achieved a partial response or better, including 14 percent of patients who achieved a complete response.

Fifty of the 57 patients went on to receive Revlimid maintenance therapy. The complete response rate increased to 25 percent after a median of 15 cycles of maintenance therapy.

After a median follow-up of 32 months, 15 percent of patients who received the Revlimid-dexamethasone therapy progressed to symptomatic disease, compared to 59 percent of patients who did not receive treatment.

The median time to disease progression was 23 months for patients in the non-treatment arm; the median has not yet been reached for patients treated with Revlimid-dexamethasone.

The estimated three-year overall survival rate is 93 percent for patients who received Revlimid-dexamethasone and 76 percent for patients who did not.

The most common side effects for patients in the treatment arm during initial therapy were mild to moderate infections (46 percent), rash (33 percent), low red blood cell counts (28 percent), and diarrhea (24 percent). Severe side effects included loss of strength (7 percent), infections (6 percent), and low white blood cell counts (5 percent).

For more information, see abstract 303 on the ASH meeting website. The Myeloma Beacon will also publish later this week an interview with Dr. Landgren about the results of the study by Dr. Mateos and her colleagues and the implications of those results for the treatment of smoldering myeloma.

As a service to its readers, The Myeloma Beacon has compiled a list of the news articles and topics that Myeloma Beacon readers found most interesting during 2011.

#1: Revlimid And Secondary Cancers – Results from three studies presented in late 2010 first showed that long-term maintenance therapy with Revlimid (lenalidomide) may increase a myeloma patient’s risk of developing a second cancer.  Throughout 2011, safety reviews and additional analyses were conducted to shed further light on the safety of Revlimid and other myeloma therapies.  Beacon readers were particularly interested in the U.S. Food and Drug Administration’s safety review, the difference in opinions among myeloma experts about the risks and benefits of Revlimid, and a statement from European myeloma researchers about Revlimid and secondary cancers.

#2: Gene Therapy Advance In Leukemia Suggests New Treatment Options For Multiple Myeloma – A promising experimental method for treating advanced leukemia may point the way to important new treatment options for multiple myeloma. The new method used genetically altered versions of patients’ own immune cells to treat three patients with very advanced cases of chronic lymphocytic leukemia.  Two of the patients have been left free of any signs of cancer, and the other achieved a partial response.  The researchers said that they would like to expand their study to include other types of cancer.

#3: Genetic Differences Linked To Increased Risk Of Multiple Myeloma – Researchers have identified specific areas of the human genome that consistently differ between people with multiple myeloma and people who do not have the disease.  These findings help explain why the risk of developing myeloma seems to be higher in some families than in others.

#4: Transplantation Versus Novel Agents For Myeloma: Study Supports Transplantation (EHA 2011) – As the myeloma community continues to investigate whether stem cell transplantation or treatment with novel agents is the best way to treat newly diagnosed myeloma patients, results from a Phase 3 clinical trial indicate that stem cell transplantation may lead to longer disease-free survival. The results also show, however, that transplanted patients may experience more severe side effects compared to non-transplanted patients.

#5: Complete Response After Stem Cell Transplant For Myeloma Indicates Best Prognosis – Long-term follow-up results confirm that a complete response following stem cell transplantation in multiple myeloma patients increases overall and progression-free survival compared to a very good or partial response.

#6: Results Of PET/CT Scans May Predict Survival In Multiple Myeloma Patients – According to a study, the results of PET/CT scans conducted at diagnosis, after induction therapy, and after stem cell transplantation may predict survival in multiple myeloma patients.  Specifically, patients with PET/CT scans negative for cancer cells, bone lesions, or other signs of active cancer had longer progression-free and overall survival times than patients with positive PET/CT scans.

#7: Study Finds Early And Delayed Stem Cell Transplants Have Comparable Efficacy In Newly Diagnosed Multiple Myeloma Patients – Results of an analysis suggest that newly diagnosed multiple myeloma patients receiving Revlimid or thalidomide (Thalomid) as initial therapy have similar prognoses regardless of whether they receive an early stem cell transplant or delay the transplant and continue their initial treatment.

#8: Fatigue And Multiple Myeloma: Study Highlights Role Of Mood, Reevaluates Role Of Pain – A study found that fatigue in multiple myeloma patients is associated with sleep and mood disturbances, reduced abilities to complete simple physical activities, and elevated levels of physical pain.

#9: MLN9708, “Son of Velcade,” Shows Promising Initial Results In Multiple Myeloma (ASH 2011) – The initial results from three early-phase clinical trials suggest that the investigational drug MLN9708, either alone or in combination with Revlimid and dexamethasone (Decadron), may be an effective treatment for both newly diagnosed multiple myeloma patients and patients with relapsed and/or treatment-resistant disease. MLN9708 belongs to the same class of drugs as Velcade (bortezomib).  However, it can be administered orally in capsule form instead of being given by injection or infusion.

#10: NCCN Modifications To Multiple Myeloma Guidelines – In 2011, the National Comprehensive Cancer Network (NCCN) announced two sets of updates and changes to its guidelines for the diagnosis and treatment of multiple myeloma.  The NCCN guidelines are followed closely by physicians and by many U.S. health insurance companies when making reimbursement decisions about different cancer treatments.

However, results of a key Phase 3 trial involving the drug were disappointing, and they call into question whether the drug will receive formal FDA approval as a treatment for myeloma.

Zolinza (vorinostat), which is marketed by the U.S. pharmaceutical company Merck (NYSE: MRK), is an oral drug already approved in the United States for a certain type of lymphoma. It also is approved for a similar use in Canada and Australia, but not in Europe.

Zolinza belongs to a class of drugs called histone deacetylase (HDAC) inhibitors, which work by increasing the production of proteins that slow cell division and cause cell death. Two other drugs that have been investigated as potential myeloma treatments – panobinostat and Istodax (romidep­sin) – belong to the same class of drugs.

Details of the key ASH oral presentations about Zolinza – as well as two related poster presentations – are summarized below.

Zolinza Plus Velcade – Phase 3 Trial Results

Two clinical trials, including a Phase 2b study called Vantage 095 and a Phase 3 study called Vantage 088, are investigating the combination of Zolinza and Velcade (bortezomib) in relapsed/refractory multiple myeloma patients. Preliminary data for these studies were presented at the ASH 2010 annual meeting (see related Beacon news).

Updated results of the key, large-scale Phase 3 trial were presented at the 2011 ASH meeting by Dr. Meletios Dimopoulos from the University of Athens in Greece.

The Phase 3 study included 637 patients from 174 treatment centers across 33 countries. The median patient age was 62 years. Patients in the study had received a median of two prior therapies; 24 percent of patients had previously received Velcade, 56 percent thalidomide (Thalomid), 13 percent Revlimid (lenalido­mide), 56 percent melphalan (Alkeran), and 35 percent a stem cell transplant.

Half of the participants in this study received received 400 mg Zolinza on days 1 to 14 and 1.3 mg/m² Velcade on days 1, 4, 8, and 11 of a 21-day treatment cycle.  The other half Velcade plus a placebo.

Among the patients who received Velcade in combination with Zolinza, 56 percent achieved at least a partial response, compared to 41 percent of patients who received Velcade plus placebo.

In addition, progression-free survival was longer (7.6 months) in patients who received Velcade plus Zolinza than in patients treated with Velcade plus placebo (6.8 months).

Although the 25-day difference in these time spans is statistically significant, it was not clear to many of the physicians attending the presentation that it is clinically significant.

Dr. Adam Cohen from the Fox Chase Cancer Center in Philadelphia told The Beacon that the results are unlikely to change day-to-day treatment decisions.

Dr. Craig Hofmeister from the Ohio State University went one step further and indicated in a published report that he was not convinced the 25-day progression-free survival advantage would be sufficient for the FDA to grant Zolinza approval for use in multiple myeloma.

Additionally, the difference in overall survival between the two groups of patients in the study was not statistically significant.  Dr. Dimopoulos noted, however, that there is a trend toward a survival advantage for the Velcade-Zolinza combination.

Side effects were more frequently observed in the patients who received the Velcade-Zolinza combination.  About half of the patients who received the combination had to reduce their dose or discontinue treatment as a result of side effects.  Only a quarter of the patients who received Velcade plus placebo had to reduce their dose or discontinue treatment.

Full details of the Phase 3 trial results presented by Dr. Dimopoulos are not available because the abstract for the presentation includes neither efficacy nor safety results, and Merck, the company that markets Zolinza, is not making copies of the presentation available to the press or the public.

Zolinza Plus Velcade – Phase 2 Trial Results

Final results of the Phase 2 study investigating combination treatment with Zolinza and Velcade were presented at the 2011 ASH meeting by Dr. David Siegel from the John Theurer Cancer Center in Hackensack, New Jersey.

The study included 143 patients with a median age of 63 years and a median of four prior therapies. All patients had previously received Velcade, 85 percent thalidomide, 71 percent Revlimid, 4 percent pomalidomide, and 74 percent a stem cell transplant.

As in the Phase 3 trial of the Zolinza-Velcade combination, participants in the Phase 2 trial received 400 mg Zolinza on days 1 to 14 and 1.3 mg/m² Velcade on days 1, 4, 8, and 11 of a 21-day treatment cycle for a median of six cycles. Patients who did not respond to the treatment could add 20 mg dexamethasone (Decadron) on the day of and day after each dose of Velcade.

No patients in the Phase 2 trial received treatment with a placebo.

Of 142 evaluated patients who participated in the Phase 2 trial, 17 percent achieved a partial response or better. The median duration of response was 6.3 months.

The median overall survival was 11.2 months, with a two-year overall survival rate of 32 percent.

The most common severe side effects included low platelet counts (68 percent of patients), low red blood cell counts (38 percent), low white blood cell counts (32 percent), and diarrhea (17 percent). Peripheral neuropathy, a condition characterized by pain and tingling in the extremities due to nerve damage was infrequent, with severe peripheral neuropathy occurring in 2 percent of patients.

Zolinza In Combination With Velcade And Doxil

In a poster presentation, Dr. Peter Voorhees from the University of North Carolina at Chapel Hill summarized results from a Phase 1 study of Zolinza plus Velcade and Doxil (pegylated liposomal doxorubicin) in patients with relapsed and refractory multiple myeloma. Interim results from this study were presented at ASH 2010 (see related Beacon news).

The purpose of this trial was to determine the maximum tolerated dose and efficacy of Zolinza in this combination regimen. The study included 32 patients, who had received a median of two prior therapies.  Three-quarters (78 percent) had previously received Velcade, 56 percent Doxil, 91 percent thalidomide and/or Revlimid, and 66 percent a stem cell transplant. Of the patients with prior exposure to Velcade, 44 percent were treatment-resistant.

Participants received 1.3 mg/m² Velcade on days 1, 4, 8, and 11, 30 mg/m² Doxil on day 4, and 200 mg to 400 mg Zolinza on days 4 to 11 or days 1 to 14 of a 21-day treatment cycle. They received a median of six cycles.

Among the 31 patients evaluated, 65 percent achieved at least a partial response.

Notably, of the 11 patients with Velcade-resistant disease, 45 percent achieved a partial response or better. Furthermore, 71 percent of Velcade-sensitive patients and 83 percent of patients without prior exposure to Velcade also reached a partial response or better.

The maximum tolerated dose of Zolinza in this treatment regimen was 400 mg on days 4 to 11. The most common side effects included fatigue as well as blood and gastrointestinal problems. Peripheral neuropathy was observed in 38 percent of patients (6 percent severe).

Zolinza Plus Revlimid And Dexamethasone

In another poster presentation, results of a recent Phase 1 study of Zolinza in combination with Revlimid and dexamethasone were summarized.  The results suggest that the combination is well tolerated and effective in patients who are refractory to Revlimid and dexamethasone alone.

The study included 29 patients with a median of four prior therapies, all of whom were refractory to Revlimid and dexamethasone. Additionally, 76 percent were refractory to at least one Velcade regimen, and 48 percent were resistant to the combination of Velcade, Revlimid, and dexamethasone. Ninety percent had undergone stem cell transplantation.

The participants received 300 mg or 400 mg Zolinza on days 1 to 7 and 15 to 21, 10 mg to 25 mg Revlimid on days 1 to 21, and 20 mg to 40 mg dexamethasone on days 1, 8, 15, and 22 of a 28-day treatment cycle.

Of the 29 participants, 24 percent achieved at least a partial response. The median overall survival time was 11 months.

Common side effects included diarrhea and fatigue. Severe to life-threatening side effects included low white blood cell counts (45 percent) and low platelet counts (34 percent).

Researchers are planning Phase 2 studies of the Zolinza-Revlimid-dexamethasone combination.

For more information, please see abstract 811, abstract 480, abstract 3985, and abstract 3986 on the ASH 2011 annual meeting website.

The Beacon asked exactly this question of its Medical Advisors — the myeloma specialists who generously share their knowledge and expertise in the Beacon’s myeloma discussion forum.

And the responses from the Advisors were surprising.

Surprising, because they were so similar.

The three Advisors who responded to the Beacon’s question indepen­dently picked the same “hidden gem” – specifically, the research presented at the meeting showing that the protein known as “cereblon” affects whether or not myeloma patients respond to certain myeloma treatments.

These findings were mentioned in the Beacon’s update for the second day of the ASH meeting.  The findings indicate that myeloma patients with high levels of cereblon in their bone marrow respond better to the class of drugs known as immunomodulatory agents (“IMiDs”) than myeloma patients with little or no cereblon in their bone marrow.

The IMiD class of drugs includes thalidomide (Thalomid), Revlimid (lenalidomide) and the potential new myeloma treatment pomalidomide.

The rest of  this article passes along the feedback the Beacon received from its Medical Advisors about the ASH meeting’s “hidden gem.”

A related article published last week here at The Beacon presented the Advisors’ thoughts regarding the top myeloma-related research findings of the ASH meeting.

Dr. Peter Voorhees from the University of North Carolina at Chapel Hill:

A target has finally been established for the IMiDs!

Investigators had previously published findings showing that the binding of thalidomide to a protein called cereblon was necessary for its teratogenicity [tendency to cause birth defects].

Now, Dr. Keith Stewart and his colleagues at the Mayo Clinic in Scottsdale, Arizona, have discovered that Revlimid and pomalidomide must bind to cereblon to achieve their anti-myeloma effect (abstract).

In fact, when cereblon levels are low in myeloma cells, the drugs do not work as well.

With this new information, we can better determine how these drugs work in myeloma, study the basis of resistance to this class of drugs, and develop novel therapies that can restore sensitivity to the IMiDs.

Dr. Adam Cohen from the Fox Chase Cancer Center in Philadelphia:

I think one of the most important research findings, reported by Dr. Keith Stewart and colleagues from Mayo Arizona and two other groups at this year’s ASH meeting, involves a protein called cereblon and its potential ability to predict responsiveness to IMiDs such as thalidomide and Revlimid.

First identified as the primary target protein through which thalidomide causes teratogenicity, cereblon has now been shown to be activated in myeloma cell lines and in primary patient myeloma samples, and the level of activation seems to correlate with whether the cells can be killed by thalidomide or lenalidomide.

Much more research needs to be done to understand the exact function cereblon plays in myeloma and how its binding by IMiDs leads to myeloma cell death, but its discovery offers the tantalizing possibility of a predictive biomarker for IMiD sensitivity that could help guide the choice of therapy, bringing us closer to truly personalized therapy for our patients.

Dr. Ken Shain from the Moffitt Cancer Center in Tampa:

I feel that one of the topics in myeloma research that deserves a lot of attention was the conversation around the potential IMiD target cereblon.

I am not sure where or what the role of cereblon will be in the future of myeloma therapy.

However, building on the seminal 2010 article (abstract) by Ito et al. published in the journal Science  – a piece of work that initially identified cereblon as a potential teratogenic target of thalidomide – Dr. Keith Stewart and colleagues from the Mayo Clinic in Scottsdale, Arizona, further demonstrated that cereblon activation was also important for the effects of the thalidomide derivatives Revlimid and pomalidomide.

The authors demonstrated that cereblon activation was associated with sensitivity to Revlimid and pomalidomide in myeloma cell lines.

The specific role of cereblon was examined using shRNA technology to chronically decrease the activation of cereblon.  This down regulation correlated with resistance to both IMiDs.

These findings may have significant applications to the treatment of myeloma and possibly other tumors.

The possibility exists that patients with high activation of cereblon are more sensitive to thalidomide, Revlimid, or pomalidomide and that patients with low activation may be less sensitive or resistant.  As such, cereblon may be an important marker for a patient-specific, personalized treatment paradigm.

A rationale was further highlighted at the ASH meeting by the work presented by Heintal et al. (abstract).  These authors begin to address the issues of levels of cereblon activation and response to IMiD therapy by examining the activation of cereblon in 44 myeloma samples treated with Revlimid and dexamethasone (Decadron) relative to normal bone marrow samples.

The authors demonstrated that increased cereblon activation (relative to normal bone marrow) correlated with a significantly better response to Revlimid and dexamethasone (minor response or better).  In patients with stable or progressive disease, cereblon activation was less than normal in the bone marrow.

These data, again, provide significant rationale for the further study of cereblon in myeloma and perhaps other Revlimid, pomalidomide-, and thalidomide-sensitive diseases.

However, it is important to note that these were lab studies and need to be further developed in patient specimens and incorporated into clinical trials to correlate with outcomes (response, progression-free and overall survival, etc.) before we can state anything definitively about a role for cereblon in myeloma or other diseases.

For the short term, more study is needed and I don’t see any direct impact on myeloma patients today.  Hopefully, with more examination it will impact how we approach patients in the future.

I think that there is a reason for excitement in this line of research.  However, as always, our enthusiasm needs to be tempered until supportive data is presented.

Furthermore, with history as a guide, drug target activation does not always correlate with response, especially drug targets that do not appear to facilitate disease progression.

Note: The Advisor responses summarized above have been edited slightly for length, flow, and adherence to Beacon conventions (regarding, for example, drug names).