More than 25,000 clinical specialists from all over the world are expected to attend the five-day meeting to discuss the current research in cancer treatment and care. The theme for this year’s meeting is “Collaborating to Conquer Cancer.”

The meeting will include many presentations and seminars focused specifically on multiple myeloma. The ASCO website currently lists nearly 50 myeloma-based presentations (included under “lymphoma and plasma cell disorders”).

The ASCO meeting is one of three annual scientific meetings where important new myeloma-related research findings are usually reported. The other two key conferences are the annual meetings of the American Society of Hematology (ASH) and the European Hematology Association (EHA).

As in previous years, The Myeloma Beacon will be covering the ASCO 2012 meeting in detail.  So readers can expect many articles during and after the meeting about the key myeloma findings.

Organization Of The Meeting

Research findings presented at ASCO and other scientific meetings are generally communicated in either oral presentations or poster summaries.

Oral presentations are usually done for research that is considered particularly important, either because the subject itself is important, or the results are based on substantial amounts of evidence (for example, a sizable clinical trial).

Poster research summaries are made available during specific “poster sessions,” when researchers make available their summaries in a large exhibition hall with small exhibits for each poster.

Compared to the research summarized during oral presentations, the findings in poster summaries generally are in earlier stages of development, and may involve only laboratory research or clinical trials with just a small number of patients.

Treatments Under Development

Several of this year’s ASCO presentations will unveil results from Phase 1 and Phase 2 clinical trials of potential new drugs under development for the treatment of multiple myeloma. In particular, there will be many presentations on carfilzomib (Kyprolis), pomalidomide, elotuzumab, Treanda (bendamustine), and several newer drugs that are in the early stages of clinical testing.

On June 3, there will be eight oral presentations about potential new anti-myeloma drugs.

The first three talks will be about carfilzomib studies.

First, Dr. Brigitte Kolb will present results from a Phase 1/2 study evaluating the combination of carfilzomib, melphalan (Alkeran), and prednisone in elderly patients with multiple myeloma.

Afterward, Dr. Joseph Mikhael will present results from a Phase 1/2 study of a new carfilzomib combination regimen.  The regimen is known as “CYCLONE,” and it involves carfilzomib, cyclophosphamide (Cytoxan), dexamethasone, and thalidomide (Thalomid) in patients with newly diagnosed myeloma.

The last carfilzomib presentation will be one by Dr. Andrzej Jakubowiak, in which he will present an analysis of stringent complete responses in newly diagnosed patients treated with carfilzomib, Revlimid (lenalidomide), and dexamethasone.

Next, Dr. Melissa Alsina will present results from a Phase 2 study of elotuzumab in combination with Velcade (bortezomib) and dexamethasone in relapsed / refractory myeloma patients who previously did not respond to Velcade.

Dr. A. K. Stewart will give the presentation after Dr. Alsina’s, and it is likely to be met with a great deal of interest.  Dr. Stewart will discuss results of a Phase 1 study of obatoclax, a potential new myeloma drug, in combination with Velcade for relapsed myeloma patients.  This will be the first time an oral presentation about clinical trial results for obatoclax as a myeloma treatment will be made at a major medical meeting.

Dr. Phillipe Rodon will then present results from a clinical trial studying the combination of Treanda, Velcade, and dexamethasone in elderly relapsed and refractory myeloma patients.

Later in the session, Dr. Ravi Vij will present results from a study of pomalidomide in patients relapsed and refractory to Revlimid and/or Velcade.

The final presentation will be by Dr. Sagar Lonial, in which he will present results from a Phase 1 study of the oral proteasome inhibitor MLN9708 in relapsed and refractory myeloma patients.

On June 4, myeloma experts will give three talks about immunotherapy for multiple myeloma.  The first two presentations will summarize trial results for potential new myeloma treatments — siltuximab and daratumumab – that are not particularly well known among myeloma patients.

First, Dr. Robert Orlowski will present results from a Phase 2 study comparing siltuximab plus Velcade to Velcade alone in relapsed and refractory myeloma patients.

Next, Dr Torben Plesner will present preliminary efficacy results from a Phase 1/2 study of daratumumab in relapsed and refractory myeloma patients.

Dr. Phillipe Moreau will give the final presentation of the session.  His talk will be about a Phase 2 study of elotuzumab in combination with Revlimid and dexamethasone in relapsed and refractory myeloma patients.  Preliminary results from this trial were presented at the 2011 ASH meeting and were considered quite promising (see related Beacon news).

During poster sessions on June 2 and 4, researchers will also present results from several studies investigating potential new treatments for multiple myeloma, including pomalidomide, elotuzumab, panobinostat, MLN9708, SNS01-T, and a myeloma vaccine, as well as metronomic therapy (low-dose, daily chemotherapy).

Controversies In Myeloma

During an education session on June 2, myeloma experts will discuss several of the current controversies in the treatment of multiple myeloma.

Dr. Vincent Rajkumar will first give a presentation titled, “Upfront Therapy for Myeloma: Tailoring Therapy across the Disease Spectrum,” in which he will discuss the many treatment options available to newly diagnosed myeloma patients.  Dr. Rajkumar will review results from major Phase 3 trials and present a risk-adapted individualized approach to myeloma therapy. (Dr. Rajkumar also discusses a risk-adapted approach to treating myeloma in this Beacon column that he wrote.)

During the second presentation, Dr. Amrita Krishnan will give a talk titled, “Stem Cell Transplantation for Multiple Myeloma: Who, When, and What Type?”  She will address the multitude of questions that clinical trials are addressing in regard to stem cell transplantation for multiple myeloma.  For instance:  In the era of novel agents, should stem cell transplantation be done upfront or at the time of relapse?  Are transplants feasible for older patients?  Are allogeneic (donor) transplants better than autologous (self) transplants for high-risk patients?  What approaches can be taken to reduce the risk of relapse?

Finally, Dr. Michel Attal will give a presentation titled, “Maintenance Therapy for Myeloma: How Much, How Long, and at What Cost?”  Dr. Attal will also address the many questions surrounding the use of maintenance therapy in myeloma.  For instance, what are the optimal dose and duration?  Is the risk of side effects, second cancers in particular, acceptable?  Will the disease be more aggressive at relapse?

Revlimid And Secondary Cancers

During the poster sessions on June 2 and 4, there will be several presentations about myeloma patients’ risk of developing secondary cancers.

In the June 2 session, one poster will present an analysis of second cancers among patients included in a multiple myeloma disease registry.  Another poster will be about the risk factors for the development of second cancers after stem cell transplantation for multiple myeloma.

The June 4 session will also include a poster about a retrospective analysis of second cancers in myeloma patients.

For more information on ASCO’s 48th Annual Meeting, including the final presentation schedule and information on attending, please see the American Society of Clinical Oncology meeting website.  Abstracts for the presentations will be available at 6 p.m. this evening.

For most of the 15 cycles I’ve been receiving treatment, I haven’t had much in the way of side effects related to the dexamethasone (Decadron).  I certainly haven’t experienced some of the significant issues that a lot of others have.

Recently however, the effects have been getting more noticeable.

Still, I hadn’t planned on using it as a subject for a column, but as fate would have it, I had a “dex” night following treatment last week.

I was fairly exhausted and fell asleep by about 10 p.m., then woke up shortly after midnight with my mind in overdrive.  I ended up getting out my computer and put in over four hours of work.

In addition to the work, I also went on several mental side trips, including coming up with the following story.  I think it reflects, in a somewhat twisted sense, how unpredictable and absurd our lives can get as we deal with treating our disease and the associated side effects.

I don’t want this to be another dex rant, so I hope everybody takes it for the tongue-in-cheek analogy of my changing dexamethasone world that it’s meant to be.

────────────────────────────

Who knows when this war first started.

I expect sleeper cells were in place long before there was evidence the enemy had invaded my homeland, though I can only guess at how long the cells festered before revealing themselves.

Once the war was engaged, however, I could see that it was going to be a fight to the death, that it would be fought on several fronts, and that it could go on for a long time.

I had several options available to try and combat the enemy’s first incursion, and I chose what I hoped would provide the best counterassault – one that would provide an effective, decisive response and force the enemy back for some time.

I ended up going with a tactical insurgence team and recruited agent C, agent R, and agent D, more commonly known as team CRD (sort of like recruiting the Men in Black).^†

Agent D had been around for some time and had taken on this enemy many times before, whereas agent R had only some recent experience, and agent C was basically a newcomer.

To date, the team has more than met my expectations, and it looks like they have the enemy on the run for now.  However, recent developments made me question the loyalty of the team and I wondered whether one or more of the agents may have their own agenda.

I originally thought the issue might be with one of the newer agents, but evidence suggests it’s most likely agent D, because some weeks I utilize the entire CRD team, other weeks agent R and D, and once a month just agent D, yet the issues occur every week.

There’s been nothing outright insubordinate in agent D’s actions and he’s still doing his job, but he seems to be getting more difficult to deal with and our relationship recently has been more strained.

I find myself getting more irritable after dealing with agent D and can pretty much count on losing my voice for a day or two after meeting with him.

He also has a knack for getting my heart rate up, and my face gets flushed to the point it looks like I was on an all-night drinking binge.

It’s even to the point now where I’m losing sleep over the situation and stay awake for hours after our mission briefings.

I suppose I shouldn’t be surprised with these developments since I had heard rumors of others having similar issues with agent D.  I guess I may have been a bit too overconfident though, thinking I was immune to his maneuverings or could keep him under control. I’ll just have to hope that things don’t get worse.

And if that’s not trouble enough, I’m now also hearing concerns that agent R may have been compromised.  It appears there’s evidence to suggest that, although he may be effective fighting the enemy, secondary assault teams are crossing the borders to the homeland in his wake – but that’s a story for another time.

────────────────────────────

Peace, and live for a cure.

^†Editor’s Note: Most of our readers will probably recognize who the agents C, R, and D are in Kevin’s column.  For those, however, who like things a bit more explicit, we will add that there are rumors the agents might be carfilzomib, Revlimid (lenalidomide), and dexamethasone.

sCD105 Protein May Be An Indicator For Myeloma Severity – Results of a recent study show that levels of the protein sCD105 circulating in the blood are higher in multiple myeloma patients than in healthy individuals. Higher levels of sCD105 also were associated with more advanced stages of disease. sCD105 is known to play a role in the growth of new blood vessels and may thus contribute to tumor progression in myeloma. Researchers believe these findings warrant further study of sCD105 levels as an indicator for disease activity. For more information, please see the study in the European Journal of Internal Medicine (abstract).

Whole Body MRI Adds Limited Value To Routine Myeloma Remission Testing After Transplantation – A recent study found that the use of whole body magnetic resonance imaging (MRI) to detect persisting or relapsing multiple myeloma post transplant offers little added value compared to current routine laboratory tests. The results of the whole body MRI and routine laboratory tests were in agreement in 79 percent of the patients assessed. For more information, please see the study in European Radiology (abstract).

IMF Myeloma Workshop For Patients And Families – The International Myeloma Foundation (IMF) will be hosting a workshop for multiple myeloma patients and their families on May 19 in Indianapolis, IN. Dr. Rafat Abonour from the Indiana University Bone Marrow and Stem Cell Transplantation Program and nurse Kena Miller from the Roswell Park Cancer Institute in Buffalo, NY, will speak about topics including treatment options, managing side effects, and local clinical trials. For more information or to register, please visit the IMF website.

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

The articles were accompanied by an editorial summarizing the study findings and discussing their significance for the treatment of multiple myeloma patients.

All three clinical trials involved newly diagnosed multiple myeloma patients.  The patients in the trials first underwent initial treatment that in some cases included Revlimid (lenalidomide).  In two of the three trials, the initial treatment also included a stem cell transplant.

After the initial treatment, patients were randomly assigned to take either Revlimid or a placebo on a regular basis until they relapsed.  This kind of extended treatment, given after a more intensive initial course of therapy, is known as maintenance therapy.

All three trials found that Revlimid maintenance therapy significantly delays the progression of multiple myeloma.  In younger newly diagnosed myeloma patients who had undergone a stem cell transplant, for example, Revlimid maintenance therapy nearly doubled the time to relapse.

Only one of the three trials, however, found that Revlimid maintenance therapy improved the overall survival of patients. In the other two trials, patients who were on Revlimid maintenance therapy typically lived no longer than those who took the placebo.

In addition, all three trials revealed that the patients taking Revlimid were significantly more likely to experience a second cancer than those who took a placebo.

Prior to the publication of yesterday’s articles, findings from the three trials already had been presented and discussed at several conferences in recent years.  The findings are therefore well known among myeloma specialists (and long-time Beacon readers).

Nevertheless, publication of the results in a major peer-reviewed medical journal is a clear signal that the medical community views the findings as significant and relevant to the treatment of myeloma patients.

At the same time, the publication of the articles in unlikely to settle the important questions many physicians and patients still have about the value of maintenance therapy with Revlimid.

Among those questions, perhaps the most important is whether delaying disease progression is worthwhile when it requires long-term treatment, often with side effects, with an uncertain benefit in terms of overall survival.

Details Of The Three Trials

The trial results that were published yesterday were from three multi-center Phase 3 clinical trials being carried out in the United States and in Europe.

Two of the trials, known as the CALGB and IFM trials, were carried out with younger newly diagnosed multiple myeloma patients who also underwent a stem cell transplant as part of their initial myeloma therapy.

Patients in the third trial, known as the MM-015 study, were newly diagnosed myeloma patients as well.  However, they were at least 65 years of age and not eligible for a transplant.

CALGB Study

The CALGB trial registered patients between April 2005 and July 2009 at centers across the United States.  Patients had to be newly diagnosed and under the age of 70 years.  A specific induction treatment was not required for the trial, although more than 90 percent of the patients were treated with Velcade (bortezomib) alone or as part of a combination regimen.  All patients had to undergo a stem cell transplant after their initial treatment.

After their transplants, patients in the trial were randomly assigned to receive either 10 mg of Revlimid (231 patients) or a placebo (229 patients) as daily maintenance therapy.  The study was “double blind,” meaning that neither patients nor their physicians knew which patients were receiving Revlimid and which were receiving a placebo.

In December 2009, an interim analysis of the trial results showed a statistically significant difference in the rate of disease progression between the two patients groups.  The study was therefore unblinded, and patients who had been receiving the placebo were given the option to start taking Revlimid.  Of 128 patients eligible to make this switch, 86 chose to do so.

Patients who received Revlimid maintenance therapy during the study stayed on the maintenance regimen until their disease progressed.

IFM Study

The IFM trial was conducted in France, Switzerland, and Belgium, registering patients between July 2006 and August 2008.  Participants in the trial had to be newly diagnosed myeloma patients under the age of 65.

Most of the participants were initially treated with one of two treatment regimens: Velcade and dexamethasone (Decadron), or vincristine (Oncovin), doxorubicin (Adriamycin), and dexamethasone.  About a quarter of the patients also had their initial treatment augmented with additional combination therapy involving the DCEP regimen: dexamethasone, cyclophosphamide (Cytoxan), etoposide, and cisplatin.

After their initial therapy, patients underwent a stem cell transplant.  One fifth of the patients also went on to receive a second transplant.

After patients had completed their transplants, they received two 28-day cycles of treatment consisting of 25 mg of Revlimid, administered on days 1 to 21 of each cycle.  Then, patients were randomly selected to receive either 10 mg Revlimid daily (307 patients) or a placebo (307 patients) until disease relapse.  As in the CALGB trial, the administration of Revlimid and the placebo was double blind, and was intended to continue until disease relapse.

In July 2010, the study was unblinded after a data analysis showed a statistically significant benefit to Revlimid treatment in terms of delaying disease progression.  However, no patients were switched from the placebo-treated group to the Revlimid treated group.

In January 2011, an interim analysis of the trial data revealed a significant difference in the rates of second cancer between the two patient groups.  The researchers leading the study therefore decided to halt all further dosing of Revlimid during the trial.

MM-015 Study

The third and final trial, the MM-015 study, was conducted in Europe, Australia, and Israel.  Patients were recruited from February 2007 until September 2008, and they had to be 65 years of age or older and transplant ineligible.

Each MM-015 trial participant was randomly assigned to one of three treatment groups.

The first group (154 patients) – denoted “MP” – received nine 4-week cycles of treatment with melphalan (Alkeran), prednisone, and a placebo as initial therapy, followed by “maintenance” therapy with a placebo.

The second group (153 patients) – denoted “MPR” – received nine 4-week cycles of treatment with melphalan, prednisone, and Revlimid (10 mg on days 1 to 21 of the cycle), followed by “maintenance” therapy with a placebo.

The third group (152 patients) – denoted “MPR-R” – received the same upfront treatment as the second group (melphalan, prednisone, and Revlimid), but received Revlimid as maintenance therapy.  The Revlimid maintenance dose was 10 mg on days 1 to 21 of a 28 day cycle.

As in the CALGB and IFM trials, the dosing of Revlimid and a placebo in the MM-015 also was double blind.  The trial was unblinded in May 2010 after a data analysis showed patients receiving Revlimid maintenance therapy had a longer time to disease progression than patients on placebo.  As in the IFM trial, however, no patients were switched during the trial from the placebo group to the Revlimid group.

Progression-Free Survival

Patients receiving Revlimid maintenance in all three studies experienced significantly longer progression-free survival times than patients who did not receive Revlimid maintenance therapy.

CALGB Study

In the CALGB-study, patients on Revlimid maintenance had longer progression-free survival times and rates, even after the study was unblinded in December 2009 and patients in the placebo group were allowed to begin Revlimid maintenance.

(Click here or on the image to the right to see a graph of the key CALGB progression-free survival results.)

At a median follow-up time of 34 months, 37 percent of patients receiving Revlimid maintenance had progressed or died, compared to 58 percent of patients who did not receive Revlimid maintenance.

The three-year progression-free survival rate was 66 percent among patients receiving Revlimid maintenance, compared to 39 percent among patients not receiving Revlimid maintenance.

The median time to disease progression was 46 months for patients on Revlimid maintenance, compared to 27 months for patients not receiving Revlimid maintenance.

IFM Study

When the study was unblinded at a median follow-up time of 30 months, the median time to disease progression was almost double (41 months) for patients on Revlimid maintenance, compared to patients not receiving Revlimid maintenance (23 months).

The three-year progression-free survival rate was 59 percent among patients receiving Revlimid maintenance, compared to 35 percent among patients not receiving Revlimid maintenance.

At a median follow-up time of 45 months, the four-year progression-free survival rate was still significantly higher for patients receiving Revlimid maintenance (43 percent) than for patients who did not receive Revlimid maintenance (22 percent).

MM-015 Study

As previously reported for the MM-015 study, the median progression-free survival time from the start of the trial was significantly longer for patients receiving Revlimid maintenance (MPR-R, 31 months) than for patients receiving MPR (14 months) or MP (13 months).

When the researchers compared progression-free survival times from the start of maintenance therapy, they found that the median was 26 months with Revlimid maintenance, compared to 7 months without maintenance.

The progression-free survival benefit associated with Revlimid maintenance, however, was not found to be statistically significant in patients over the age of 75 years: median progression-free survival times in this patient population were 19 months with MPR-R, 12 months with MPR, and 15 months with MP.

Overall Survival

The CALGB study showed an overall survival benefit for patients treated with Revlimid maintenance, but the other two studies did not.

CALGB Study

After a median follow-up time of 34 months, 85 percent of the patients receiving Revlimid maintenance and 77 percent of the patients in the placebo group were still alive.

(Click here or on the image to the right to see a graph of the key CALGB overall survival results.)

The estimated three-year overall survival rate was higher for the Revlimid group (88 percent) than the placebo group (80 percent), even though most of the placebo group began Revlimid maintenance when the study was unblinded.

A subgroup analysis showed that patients treated with Revlimid induction therapy had significantly longer survival if they received Revlimid maintenance, compared to those who received a placebo.  The same analysis also showed that Revlimid maintenance did not provide a survival advantage for: patients who were treated with thalidomide induction therapy; patients who had elevated beta-2 microglobulin levels; or patients who achieved a complete response prior to the start of maintenance therapy or placebo.

IFM Study

Unlike the CALGB study, the estimated four-year overall survival rate was similar for the Revlimid maintenance (73 percent) and placebo (75 percent) groups.  The study investigators pointed out that these rates are high and could be due to the use of intensive treatment as well as effective therapies at relapse.

(Click here or on the image to the right to see a graph of the key IFM overall survival results.)

The researchers also stated that a longer follow-up is needed to fully assess the effect of Revlimid maintenance on overall survival.

The investigators of the CALGB study wrote in their article that the difference in survival results between the CALGB and IFM trials may be due to differences in induction and consolidation therapies, the use of one versus two transplants, and the discontinuation of maintenance therapy.  They suggested that longer follow-up and additional studies might clarify the difference in results.

MM-015 Study

As was the case with the IFM study, Revlimid maintenance did not extend overall survival in the MM-015 study.

After a median follow-up time of 30 months, the estimated overall survival time was 42.5 months for the MPR-R group and was not yet reached for the MPR and MP groups.

The three-year overall survival rate was similar for all three treatment groups.  Specifically, the survival rates were 70 percent for the MPR-R group, 62 percent for the MPR group, and 66 percent for the MP group.

Second Cancers

In all three studies, patients receiving Revlimid maintenance experienced higher rates of second cancer than patients not receiving Revlimid maintenance.

The rate of second cancer in these studies is a key reason U.S., Canadian, and European authorities recently added warnings to Revlimid’s prescribing information about the risk of second cancer associated with the drug (see related Beacon news articles).

In the CALGB study, 8 percent of patients receiving Revlimid maintenance experienced secondary cancers, compared to 3 percent of patients who did not receive Revlimid maintenance. Of the 8 percent in the Revlimid maintenance group, 4 percent were blood-related cancers and 4 percent were solid tumors (excluding non-melanoma skin cancers).

In the IFM study, the researchers observed 32 cases of second cancers in 26 patients receiving Revlimid maintenance and 12 cases in 11 patients not receiving Revlimid maintenance. Based on these cases, they calculated that 3.1 percent of patients receiving Revlimid maintenance developed a second cancer each year and 1.2 percent of patients not receiving Revlimid maintenance developed a second cancer each year.

In the MM-015 study, the rate of second cancers at three years was reported to be 7 percent for patients receiving MPR-R, 7 percent for patients receiving MPR, and 3 percent for patients receiving MP.

Implications Of The Three Studies

As one might expect, the authors of the three studies are relatively positive, overall, about the benefits of Revlimid maintenance therapy.

The MM-015 investigators, for example, write in their conclusion that “MPR-R is an effective treatment for patients with newly diagnosed multiple myeloma who are ineligible for transplantation.

Similarly, the authors of the IFM article believe that their data, along with the CALGB data, “support the use of [Revlimid] maintenance therapy” after stem cell transplantation in patients with myeloma.

The IFM investigators also add, however, that the “impressive benefits” of Revlimid maintenance therapy “must be weighed against the increased risk” associated with that therapy.

An independent perspective on the three articles that were published yesterday is available in the form of an editorial that accompanied the articles. The editorial was written by Professor Ashraf Badros of the University of Maryland’s Greenbaum Cancer Center.

Prof. Badros notes in his editorial that the three studies provide “compelling evidence” that Revlimid maintenance therapy delays relapse. He adds, however, that there still are important questions relevant to this therapy that need to be answered.

For example, is delaying disease relapse actually what is important when testing a maintenance therapy?

With maintenance therapy, delaying relapse is achieved by continuously treating patients with a drug that, for some patients, will involve frequent side effects. Thus, even if the therapy results in some additional overall survival, will it be enough to be worthwhile given the side effects patients experience during the maintenance therapy?

Similarly, can physicians be certain there actually is a survival benefit to maintenance therapy? Is it possible that, by treating a patient continuously with low-dose Revlimid, the patient’s myeloma evolves such that, when relapse occurs, the disease is more resistant to treatment and there is no net survival benefit to the maintenance therapy?

Prof. Badros finds it difficult to come to a clear conclusion at the end of his editorial. “Whether these data establish a new standard of care for myeloma may be debatable,” he writes. He then starts a concluding sentence that sounds like a strong endorsement of Revlimid maintenance therapy … until one gets to a key qualifying statement at the end.

“The data on progression-free survival,” he said, “provide support for the use of [Revlimid] maintenance therapy after careful assessment of the risks and benefits.”

For more information, see the studies (CALGB, IFM, and MM-015) and the accompanying editorial in the New England Journal of Medicine (abstracts).

Note: The graphs that are included with this article are from the original journal articles and are copyrighted property of the Massachusetts Medical Society. For copyright reasons, only a limited number of graphs have been included. The ones that have been selected were chosen because they more fully describe important data, and because they permit more complete comparisons of important results from the different trials.

These were the unanswered questions of my universe in the early autumn of 2009.

During that time, my family and I all became very familiar with the cancer center.  Lovely artwork, all donated or on loan, brightened the walls of the hallways.  Volunteers served tea in bone china teacups and biscuits every afternoon to the patients.  Staff were friendly, and a daily riddle was posted at the unit’s clerk station. ’Chemo brain’ or not, I could rarely figure it out!

It was a busy, bustling place, but some of the waiting patients looked tense and sad. We probably looked that way too.

Being ushered to a reclining chair and having an IV inserted into my hand soon became a familiar procedure for me.  The chemo nurses always wore heavy purple synthetic gloves to prevent ‘needle stick’ injuries, a nurse’s nightmare because it requires testing for hepatitis, HIV, and other diseases as a result of a small pinprick.

Some of the treatment cubicles were near a window, which I really appreciated because it gave view to the beautiful Bow River Valley.  The leaves of the aspens were turning a lovely gold color, and the river gleamed an intense shade of blue.  It was a very serene sight and made the whole treatment process easier for me.  I could reflect on the fact that I had enjoyed many wonderful walks and bike rides in that area, in all seasons.

That fall, I spent most of my time between doctor appointments and twice-weekly Velcade (bortezomib) infusions at home.  Participating in the usual activities, such as working out at the gym, hiking, gardening, singing in my choir, attending meetings of the needlework guild, or travelling, either near or far, was not possible.  I only managed to keep up with some work at home, which took a lot of concentration, considering the medications I was taking.  Otherwise, I found myself talking to visitors who came by, reading, doing crafts, and occasionally venturing out to a nearby mall.

The effects of dexamethasone (Decadron) were intensifying.

I found myself blurting out details of my struggles to anyone who would listen.  Once at a mall, I was drawn to a kiosk of jewelry, convinced that turquoise was a healing stone.  I wanted to buy up the entire lot of that stone set in silver but fortunately I didn’t. Instead, I bought a heavy strand of the beads later when the effects of dex had worn off.

I sewed many wall hangings during that time.  One design, called ‘Blowin’ in the Wind’, showed a picture of kites with long strings,  That design particularly suited my mood:  I felt like I was just being blown around by the winds of fate, with no answers.  Another design, sea turtles swimming on a very turquoise fabric sea, reminded me of snorkeling over a coral reef.  One of my sisters recalls it as ‘turtles on steroids’ because I was under the influence of steroids when I was sewing it.

I also was fascinated by the ancient Etruscan goddess Minerva, patroness of medicine, music,and crafts.  The owl was sacred to her, so I put an ornament of an owl in our garden.

At that time, I was also terrified of catching the H1N1 virus, which was circulating in the east of the country and expected to arrive in Calgary at any time. My mind wandered in many directions, quite un-tethered.

It wasn’t the best of times, but my friends and family continued to rally around me, and it was their good feelings and the cheerful medical staff that got me through it all.

I received hand-knitted ‘prayer shawls’ from members of two different churches.  I wrapped myself up in them while watching TV.  We watched a lot of movies at home that fall!  My husband’s sister flew in from Connecticut for a few days, which was very heartening for both of us.  It is not easy being a caregiver, and my husband Dilip was going all out in this role.

We had two interesting events occur that fall that related to our new preoccupation of myeloma.

The first was a myeloma conference that we attended at a downtown hotel here in Calgary. It was organized by the Southern Alberta Myeloma Patient Society in cooperation with Myeloma Canada.  The conference included scientific talks on myeloma given by hematological oncologists and workshops for myeloma patients and caregivers. The event was a huge success; it was sold out and hundreds of people attended from all over western Canada.  I talked with many people about their experiences with myeloma.  It was interesting but also sobering to hear their stories.

Another nice event was one that my daughters and their friends organized. They got a team together to participate in the ‘Light the Night’ walk by the Leukemia and Lymphoma Society.  They were carrying red and white balloons which had little lights attached that twinkled in the twilight.  We attended the evening walk/run with these terrific young people and were touched by the outpouring of love and support.

With regard to my treatment, I received Velcade twice a week for two weeks, followed by a week off.

By the sixth treatment, my blood protein levels had fallen significantly.  By the tenth treatment, my monoclonal protein level was at 6.4 g/L – it had been at 59 g/L in July.  After 14 treatments, it was at 3.3 g/L (or 0.33 g/dL, the units commonly used in the States when measuring a patient’s M-spike).

This was very good news.  I was sure that I could feel the ‘tumor burden’ lifting away, as though a heavy curtain that had been occluding my thoughts was being pulled back.

By the last treatment, number 16, there was no doubt that I felt a lot better.  My protein levels had fallen by over 90 percent.  My bone marrow had been 50 percent full of tumor cells at the time of diagnosis, and I am sure that it had been dragging me down both physically and mentally to have to try to cope with that amount of diseased cells.

I did experience some neuropathy towards the end of the four Velcade treatment cycles; it came as a feeling of pins and needles in my feet.

Although afraid of the whole process, I decided to stay the entire course of treatment and undergo a stem cell transplant because I wanted to delay the possibility of a relapse.   This was what my oncologist recommended, and so far his advice had been excellent.  My next hurdle would be the stem cell transplant.

In my mind, I hailed Velcade as a real wonder drug.  No wonder the three scientists who had discovered the biological processes behind it had won the Nobel Prize for Chemistry in 2004!

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The quotation for this month is from Pythagoras (c. 570 BC – c. 495 BC), who wrote, “Above the cloud with its shadow is the star with its light.”

The study investigators conclude that these findings warrant further studies to determine whether blood clot prevention measures can extend the survival of myeloma patients.

“There are effective ways to prevent venous and arterial thrombosis in myeloma patients; e.g, aspirin, heparin, warfarin (Coumadin), and Pradaxa (dabigatran),” said Dr. Edward Libby of the University of Washington School of Medicine in Seattle, who was not involved with the study. “Hopefully this important and well-conducted study will shed light on the topic and contribute to a decrease in the frequency of this preventable and potentially catastrophic complication in myeloma patients.”

Previous studies have shown that multiple myeloma patients are at risk of developing blood clots in the veins, called venous thromboembolism. Patients treated with Revlimid (lenalidomide) or thalidomide (Thalomid) in combination with dexamethasone (Decadron) are at an even greater risk of developing blood clots (see related Beacon news).

Whether blood clots affect the survival of myeloma patients remains unclear because the results of the current study contradict those of three previous smaller retrospective studies designed to examine this issue. All three previous studies reported no significant differences in survival outcomes between patients with and without venous blood clots.

The researchers note important differences in the studies that may have contributed to the varying results.

First, the current study included patients diagnosed with multiple myeloma within one particular population and followed them for a long period of time.  In contrast, prior analyses used data from clinical trials that excluded patients with poor overall health or focused on relapsed and/or refractory patients who have a lower risk of developing blood clots compared to newly diagnosed patients.

Additionally, the patients included in the current study (median age 71 years) were older than those in previous studies (57 years and 63 years).

Lastly, the majority of patients in the current study were not treated with thalidomide and very few were treated with Revlimid because these agents were not yet available during a large portion of the study period.

The current study included data from 9,399 Swedish multiple myeloma patients who were diagnosed between 1987 and 2005.

Among the myeloma patients included in the study, 724 developed venous blood clots and 1,572 developed arterial blood clots after their myeloma diagnosis.

The study investigators found that myeloma patients who developed blood clots had poorer survival outcomes compared to patients who did not develop blood clots.

Those who developed venous blood clots had a 2.9-fold higher risk of death within one year of their myeloma diagnosis, a 1.6-fold risk within five years, and a 1.6-fold risk within 10 years, compared to patients who did not develop blood clots.

Patients who developed arterial blood clots had a 3.4-fold higher risk of death within one year after diagnosis, a 2.2-fold risk after five years, and a 2.1-fold risk after 10 years.

Since myeloma patients are at a higher risk of developing blood clots soon after diagnosis, the researchers specifically investigated the impact that blood clots soon after diagnosis have on survival.

The researchers found that patients who survived arterial blood clots that developed within the first six months of diagnosis had an increased risk of death at one year (1.5 fold), five years (1.4 fold), and 10 years (1.4 fold) compared to that of patients who did not develop blood clots. This was not the case for venous blood clots.  Patients who survived venous blood clots during the first six months after diagnosis had a risk of death that was similar at one year (1.4 fold), five years (1.1 fold), and 10 years (1.0 fold) to that of patients who did not develop blood clots.

Blood clots had a similar effect on the survival of those diagnosed before and those diagnosed after 2000 when thalidomide became available for use in Sweden.  This result confirms that blood clots in multiple myeloma patients remain a serious complication even with the incorporation of novel agents into current treatment regimens.

For more information, please see the study in the journal Haematologica (pdf).

As we were facing our demon, multiple myeloma, last year at this time, I began suggesting a grand plan for Deana’s 40^th birthday – a party at the restaurant Deana has chosen for my pre-race carbo load, family and friend participation in the Saturday 5K race, and the marathon/half-marathon on Sunday.   This was at a time when I still held on to the belief that Deana might consider giving running another try.

(For those concerned about Darrie being left out, fret not – Darrie ran the Inaugural Disney Princess Half Marathon with me in 2009.  She said, “Never again,” and has assumed the role of pit crew chief, whereby she meets me at points along the course to cheer me on and to see if I need anything.  She’s a good sport – and tremendous support to me.  As a bonus, we have had some grand adventures along the way, in cities she has wanted to visit.)

But back to Deana… Apparently, Deana did not share my idea of a fun birthday weekend, even though I proposed going on a cruise following the race.  So, I gave in to Deana’s desire to be in control of her own destiny.

My sisters are with me in spirit wherever I go, and on race day, though Deana was not with me in body, I was pleased to be a part of a group that continues to mean a great deal to her.  I was with the team from Gilda’s Club of Western Pennsylvania, a place where Deana has found community as she is on her journey with multiple myeloma.  She has attended numerous programs offered at the Club and has become particularly fond of a guided relaxation class.  Her multiple myeloma support group meets there as well – I am staying in Pittsburgh to serve as the guest speaker for today’s meeting.

As you can probably tell, my family acknowledges and puts importance on birthdays and anniversaries.  Many myeloma survivors and their families have shared that there are myeloma-related dates one does not forget – the date of diagnosis, the new “birthday” (date of transplant), and the day remission was proclaimed.  We just had our first anniversary of diagnosis, a date we can never forget, as it is also Gregory’s birthday; Gregory is Deana’s youngest.

Gregory turned 3 on April 27, and I had the pleasure of calling to wish him a happy birthday while on a business trip toTaiwan.  Deana was astonished when she answered the phone.  I told her that there probably wouldn’t be many times I would be in a position to call from such an exotic destination.  Truth be told, I was more interested in talking to her, in hearing her voice on that day.

I will never forget April 27, 2011, and the myriad feelings – fear, resolve, a touch of anger, frustration – but overwhelmingly, fierce love for my sister and absolute determination that we would not be beaten by multiple myeloma.

I am filled with thanksgiving that one year later, her voice was clear and happy.  She had planned an over-the-top birthday for Gregory, filled with balloons and most importantly, a new tractor. The following day, she departed on a cruise for her significant birthday.

Life is good.

The update comes on the heels of a change the Food and Drug Administration (FDA) made to the prescribing information for Revlimid (lenalidomide) in March of this year.

The change involved the addition of a warning that patients being treated with Revlimid have an increased risk of developing a second cancer (see related Beacon news).

Today’s update by the FDA includes more specific details of the agency’s analyses of Revlimid and second cancers.

In the update, the FDA says that it continues to recommend that physicians monitor patients being treated with Revlimid for the development of second cancers, and that physicians take into account both the potential benefit of the drug and the risk of second cancers when they consider treating a patient with Revlimid.

The FDA also urges patients to contact their health care professional if they have any questions or concerns about Revlimid.

Revlimid is marketed by the U.S. pharmaceutical company Celgene (NASDAQ: CELG).  Representatives from Celgene did not respond to requests for comment on today’s FDA update.

The new Food and Drug Administration’s analyses show that newly diagnosed multiple myeloma patients treated with Revlimid maintenance therapy after stem cell transplantation are three times more likely to develop a second cancer than patients who do not receive Revlimid maintenance.

Data from three ongoing clinical trials show so far that 7.9 percent of newly diagnosed patients receiving Revlimid maintenance have developed a second cancer, compared to 2.8 percent of patient who received a placebo.  Patients receiving Revlimid were more likely to develop acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin’s lymphoma.  The median time from start of Revlimid treatment till diagnosis of a second cancer was two years.

The analyses also show that relapsed and refractory myeloma patients treated with Revlimid and dexa­methasone (Decadron) are more likely to develop a second cancer than patients treated with dexamethasone alone.

Specifically, data from the two clinical trials that supported the FDA’s approval of Revlimid show that 3.98 percent of relapsed and refractory myeloma patients developed a second cancer during each year of treatment with Revlimid and dexamethasone, compared to 1.38 percent of patients treated with dexa­metha­sone and placebo.   A key contributor to the different rates of second cancer was a noticeably higher rate of non-melanoma skin cancer among the patients treated with Revlimid.

However, when FDA adjusted its analysis of non-melanoma skin cancer rates to account for differences in how long patients were observed on treatment during the clinical trials, it found that 1.71 percent of Revlimid-treated patients developed a non-melanoma skin cancer per year of treatment, as compared to 0.91 percent of patients who did not receive Revlimid.  The FDA stated that these two rates are statistically similar.

The FDA also suggested in today’s update that the prescribing information for Revlimid has been further updated to reflect the agency’s newly released analyses.  The Beacon has not been able to confirm with either the FDA or Celgene whether or not this actually is the case, and there is no evidence on the FDA’s website of newly revised prescribing information for Revlimid. (See important update below.)

Today’s FDA update follows an announcement last week by regulators in Ottawa that information about the risk of secondary cancer has been added to Revlimid’s Canadian prescribing information (see the related Health Canada announcement).

European regulators concluded their review of Revlimid and second cancers last September by reporting that “the benefits of Revlimid, particularly improved survival, continue to outweigh the risks” (see related Beacon news).

At the same time, the regulators moved to include in Revlimid’s European prescribing information language about second cancers that is more detailed than what has been included thus far in the drug’s U.S. and Canadian prescribing information.

The current European prescribing information for Revlimid, for example, states that “In clinical trials of newly diagnosed multiple myeloma, a 4-fold increased incidence of second primary malignancies has been observed in patients receiving Revlimid (7.0%) compared with controls (1.8%).”

For further coverage of developments related to Revlimid and second cancers, please see the compilation of Beacon articles about relevant research findings and announcements.

The full text of today’s FDA update can be found at the FDA website.  The key parts of the statement are included below for the convenience of the Beacon’s readers.

Update (May 9, 2012; 10:30 a.m.):  A spokesperson for the FDA has informed The Beacon that the agency is not currently planning additional revisions to Revlimid’s prescribing information beyond those made public by the FDA in March. Thus, the Revlimid prescribing information currently available on the FDA website is up to date.

The spokesperson further clarified that the FDA update discussed in the Beacon article above was intended, in part, to explain the agency’s rationale for the changes to Revlimid’s prescribing information published on the FDA website in March.

Key Text of FDA Drug Safety Communication:
Safety review update of cancer drug Revlimid (lenalidomide) and risk of developing new types of malignancies

Safety Announcement

The U.S. Food and Drug Administration (FDA) is informing the public of an increased risk of second primary malig­nancies (new types of cancer) in patients with newly-diagnosed multiple myeloma who received Revlimid (lenalidomide). Clinical trials conducted after Revlimid was approved showed that newly-diagnosed patients treated with Revlimid had an increased risk of developing second primary malignancies compared to similar patients who received a placebo. Specifically, these trials showed there was an increased risk of developing acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin lymphoma.

This safety information has been added to the Warnings and Precautions section of the Revlimid drug label. The patient Medication Guide is also being updated to inform patients about this risk.

Healthcare professionals should consider both the potential benefit of Revlimid and the risk of second primary malignancies when deciding to treat patients with this drug, and monitor patients for this risk.

Patients should contact their healthcare professional if they have any questions or concerns about Revlimid …

Data Summary

FDA reviewed controlled clinical trials of Revlimid as maintenance therapy in patients with newly-diagnosed multiple myeloma and for the treatment of relapsed/refractory multiple myeloma, to evaluate the risk of developing a second primary malignancy with Revlimid.

Second primary malignancies in patients with newly diagnosed multiple myeloma

In three prospective, randomized trials, patients with newly-diagnosed multiple myeloma received initial chemotherapy or chemotherapy plus blood stem cell transplantation followed by treatment with Revlimid or a placebo. This treatment protocol was used to study the effect of Revlimid as maintenance therapy. A pooled analysis of the three ongoing trials, as of February 28, 2011, showed 65 second primary malig­nancies among 824 patients in the Revlimid treatment arms compared to 19 second primary malig­nancies among 665 patients in the treatment arms that did not include Revlimid maintenance (7.9% vs. 2.8%; p<0.001). This difference is almost a three-fold increase in new malignancies for the groups receiving Revlimid versus the groups that did not receive Revlimid. The second primary malignancies noted included acute myelogenous leukemia (AML), myelodysplastic syndromes (MDS), and B-cell malignancies. Overall, 30 (3.6%) second primary hematologic malignancies were reported in the Revlimid treatment arms (22 MDS/AML, 5 Hodgkin lymphoma, 3 B-cell acute lymphoblastic leukemia) compared with 2 (0.3%) cases of AML in the study arms not receiving Revlimid. The median time from start of Revlimid to a diagnosis of a second primary malignancy was two years. Based on the available data, there appears to be no difference in the incidence of non-melanoma skin cancers or of solid tumors between the patients who received Revlimid and those who did not.

Second primary malignancies in patients with relapsed/refractory multiple myeloma

A retrospective pooled analysis of second primary malignancies also was conducted on data derived from the two clinical trials that supported the initial FDA approval for relapsed multiple myeloma. These were multicenter, double-blind, placebo-controlled, parallel-group trials of Revlimid plus high-dose dexa­methasone therapy versus dexa­methasone alone in the treatment of patients with relapsed or refractory multiple myeloma. The incidence rates of developing a second primary malignancy during the treatment phase of these trials were 3.98 and 1.38 per 100 person-years for patients in the Revlimid / dexa­metha­sone and the placebo / dexamethasone groups, respectively. The higher incidence rate of second primary malignancies in the Revlimid / dexa­metha­sone group was largely accounted for by the higher incidence of non-melanoma skin cancers with Revlimid (2.4 vs. 0.91 per 100 person-years for the Revlimid / dexa­metha­sone and placebo / dexamethasone groups, respectively). The patients in the Revlimid / dexa­metha­sone group had longer on-study treatment time compared to the placebo / dexamethasone group (467 person-years vs. 218.7 person-years, respectively). When adjusted for the differences in observation time on-study, the incidence rate of invasive non-melanoma skin cancers was not substantially different between the two groups (1.71 vs. 0.91 per 100 person-years, respectively).

Speculation arose last month that an ongoing Phase 3 trial of perifosine in myeloma might be canceled due to disappointing results from a Phase 3 trial of perifosine in colorectal cancer.

Perifosine (KRX-0401) is an orally administered drug that belongs to a new class of anti-cancer drugs known as “Akt-inhibitors.” Akt is a protein believed to play an important role in the development and growth of cancer cells.

The Canadian biotech company Aeterna Zentaris (NASDAQ: AEZS) licensed the rights to develop and market perifosine in North America to the U.S.-based pharmaceutical company Keryx Biopharmaceuticals (NASDAQ: KERX) in 2002. However, Aeterna Zentaris regained those rights on Friday, after the two companies announced the termination of their license agreement.

Results of the Phase 3 clinical trial in colorectal cancer, which were released April 2, showed that perifosine in combination with chemotherapy did not extend survival of patients with refractory advanced colorectal cancer, compared to chemotherapy alone.

Following the release of the colorectal cancer results, the stocks of both Keryx and Aeterna Zentaris lost two-thirds of their value.

The ongoing Phase 3 trial in multiple myeloma is comparing the combination of perifosine, Velcade (bortezomib), and dexamethasone (Decadron) to Velcade and dexamethasone alone in relapsed and refractory multiple myeloma patients.  Keryx indicated that recruitment for the trial may become difficult given the lack of positive results in the colorectal cancer study.

Dr. Paul Richardson, from the Dana-Farber Cancer Institute and lead investigator of the Phase 3 myeloma study, said in today’s press release, “We believe there is a strong rationale for the use of perifosine as part of combination therapy in multiple myeloma, both pre-clinically and clinically. The promise of perifosine as an effective therapeutic agent given the size, strength, and maturity of the Phase 2 results to date is very considerable, and clearly warrants further study.”

For more information, see the Aeterna Zentaris press release, previous Beacon news articles about perifosine, and the clinical trial description for the Phase 3 perifosine trial in multiple myeloma.

The tumor, also called a plasmacytoma, occurs when abnormal plasma cells originating in the bone marrow accumulate on the interior surface of the bone. However, in patients with solitary bone plasmacytoma, these malignant plasma cells are typically not present throughout the bone marrow itself or in the soft tissues surrounding the bone.

The following article provides a detailed introduction to solitary bone plasmacytoma, including what it is, how it is diagnosed, how it is treated, and how it relates to multiple myeloma.

What Is Solitary Bone Plasmactyoma?

In patients with solitary bone plasmacytoma, abnormal plasma cells in the bone marrow aggregate to form a single tumor in any bone in the body.

Most commonly, the tumor develops in a bone along the spinal column. In order of decreasing frequency, the tumor may also develop in the pelvis, ribs, upper extremities, face, skull, femur, and sternum.

Unlike multiple myeloma, solitary bone plasmacytoma does not include the presence of abnormal plasma cells throughout the bone marrow or in the soft tissues surrounding the bone, a condition known as extramedullary myeloma (see related Beacon news). In some cases, however, patients with solitary bone plasmacytoma may also have a small amount of abnormal plasma cells in the bone marrow (see “Diagnosis”).

According to Dr. Vincent Rajkumar of the Mayo Clinic in Rochester, Minnesota, experts do not fully understand how abnormal plasma cells (which originate in the bone marrow) are able to travel from the bone marrow to the surface of the bone and form a tumor in patients with solitary bone plasmacytoma.

It is likely, however, that the location of the bone tumor is the same location at which the abnormal plasma cells initially originated in the bone marrow.

“That is why in roughly 50 percent of cases, solitary bone plasmacytoma is curable by radiating that one site alone,” said Dr. Rajkumar.

Patients with solitary bone plasmacytoma do not have the typical features of myeloma, which include low red blood cell counts, elevated calcium levels in the blood, or kidney deficiencies, although patients with solitary bone plasmacytoma may eventually progress to multiple myeloma (see “Prognosis“).

Diagnosis

A patient is diagnosed with solitary bone plasmacytoma when a biopsy reveals a single tumor inside the bone comprised of abnormal plasma cells.

However, bone surveys and positron electron tomography (PET) or magnetic resonance imaging (MRI) must show no other lesions in the bone or in the soft tissues. Physicians recommend PET or MRI scans of the entire spine and pelvis in order to confirm that there are no abnormal plasma cell tumors anywhere other than the single site. Past studies have shown that one-third of patients suspected to have solitary bone plasmacytoma actually have evidence of other plasma cell tumors in other parts of the skeleton, as detected by PET and MRI scans.

In addition, blood tests must also reveal none of the typical myeloma-related features, such as low red blood cell counts, elevated calcium levels in the blood, or kidney deficiencies, in patients with solitary bone plasmacytoma.

The presence of monoclonal proteins in the blood or urine may be present in 30 percent to 75 percent of patients with solitary bone plasmacytoma. Monoclonal proteins are produced by abnormal plasma cells and are often measured in blood tests to track the progress of plasma cell disorders such as multiple myeloma.

Patients with solitary bone plasmacytoma who also have monoclonal proteins in the blood or urine are diagnosed differently but treated the same way as patients who do not have monoclonal proteins.

If the patient has less than 10 percent of abnormal plasma cells in the bone marrow, he or she is diagnosed with solitary bone plasmacytoma plus monoclonal gammopathy of undetermined significance, a common myeloma precursor disease.

However, if the patient has more than 10 percent of abnormal plasma cells in the bone marrow, he or she is diagnosed with stage 1 multiple myeloma.

Prevalence

Approximately 5 percent of all plasma cell disorders are solitary bone plasmacytomas. In the United States, roughly 450 new cases of solitary bone plasmacytoma are diagnosed each year. Men are diagnosed twice as often as women. Solitary bone plasmacytoma occurs most commonly in African-Americans and least commonly in Asians and Pacific Islanders.

The median age at diagnosis is 55 to 65 years, compared to a median age of 71 years for patients diagnosed with multiple myeloma.

Symptoms

The most common symptom of solitary bone plasmacytoma is pain at the tumor site as a result of bone destruction from the infiltrating plasma cells.

Some patients may also experience a fracture at the tumor site. Patients with compression fractures in the spine often experience severe spasms and back pain.

According to Dr. Rajkumar, pain or fractures at the tumor site are characteristic symptoms of solitary bone plasmacytoma, but more specific symptoms depend on which bone is involved.

“For example, a solitary bone plasmacytoma in the back may grow out of the vertebra to cause spinal cord compression and paralysis, while a solitary bone plasmacytoma in the rib may cause pain while breathing,” said Dr. Rajkumar.

Treatment

Radiation Therapy

The primary mode of treatment for patients with solitary bone plasmacytoma is radiation therapy localized to the tumor site.

A previous retrospective study involving 206 patients with solitary bone plasmacytoma indicated that patients who received localized radiation therapy had a lower rate of relapse (12 percent) than patients who did not receive radiation (60 percent).

However, according to the literature, the ideal radiation dose is controversial. Published studies have reported ideal doses ranging from 30 gray (Gy) to 60 Gy, although most radiation oncologists recommend doses between 40 Gy and 50 Gy. Gray is the radiation dose expressed in terms of absorbed energy per unit mass of tissue.

“Our radiation therapy specialists advise 40 Gy, similar to most practices elsewhere,” said Dr. Raymond Alexanian of the MD Anderson Cancer Center in Houston.

Evidence-based guidelines published by the United Kingdom Myeloma Forum recommend at least 40 Gy over the course of 20 radiation sessions. They also recommend that radiation should encompass the entire tumor plus a margin of at least 2 cm beyond the tumor region detected by MRI. For tumors larger than 5 cm, a higher dose (up to 50 Gy over 25 sessions) may be used.

Surgery

Surgery is rarely necessary but may be required for patients who have structural instabilities or deformities in the bone resulting from the tumor.

In these cases, radiation therapy may be delayed but is still administered after the surgery.

Chemotherapy

According to the literature, the use of chemotherapy as an additional or preventative measure, also called adjuvant chemotherapy, is controversial for patients with solitary bone plasmacytoma. While some studies have shown no benefit, others have suggested that adjuvant chemotherapy prevents or delays the time to progression to myeloma.

A small, retrospective study of 32 patients with solitary bone plasmacytoma revealed that adjuvant chemotherapy delayed the median time to progression to myeloma from 29 months to 59 months. However, chemotherapy did not decrease the frequency of progression to myeloma.

Another small study involving 53 patients with solitary bone plasmacytoma showed that patients who received radiation therapy plus chemotherapy had a significantly higher rate of disease-free survival after nine years than patients who received radiation therapy alone.

However, because these studies are small and therefore inconclusive, some physicians believe that there is currently no role for chemotherapy in the treatment of solitary bone plasmacytoma. Instead, they recommend observing patients after the initial radiation therapy.

According to Dr. Rajkumar, there are currently no data from randomized trials that support the use of adjuvant chemotherapy in the treatment of solitary bone plasmacytoma.

“We are planning clinical trials of adjuvant chemotherapy [in patients with solitary bone plasmacytoma]. But as with everything else in medicine, our treatments can either harm or help; that is why we need Phase 3 data with appropriate endpoints before embarking on new treatments in routine practice,” said Dr. Rajkumar.

Dr. Alexanian agreed that adjuvant chemotherapy should not yet be administered alongside radiation therapy as frontline treatment for solitary bone plasmacytoma.

“Since radiation therapy is curative for approximately one-third of properly staged patients [with solitary bone plasmacytoma], I do not favor adjuvant chemotherapy. [It] should be reserved for recurrent disease if or when it develops,” commented Dr. Alexanian.

Follow-Up

The Mayo Clinic recommends that patients with solitary bone plasmacytoma should have their blood and urine protein levels as well as their blood counts, creatinine and calcium levels tested every four to six months for one year after completion of radiation therapy. Thereafter, patients should continue to receive blood and urine tests on an annual basis.

A bone survey, MRI scan of the spine, or whole-body PET/CT scans should be administered if blood or urine tests reveal the presence of monoclonal protein in the blood, or if existing monoclonal protein levels increase.

Prognosis

The median overall survival time of patients with solitary bone plasmacytoma is 10 years. Approximately 75 percent of patients are alive after five years, and 45 percent of patients are alive after 10 years. Disease-free survival rates at five years and 10 years are 45 percent and 25 percent, respectively.

Approximately 50 percent to 60 percent of patients who are diagnosed with solitary bone plasmacytoma progress to multiple myeloma even after receiving radiation therapy.

According to Dr. Rajkumar, patients who are cured after radiation therapy are likely patients with true solitary bone plasmacytoma. On the other hand, patients who progress even after treatment with radiation therapy may have had myeloma prior to therapy.

“[The solitary bone tumor] is likely the first bone lesion of myeloma [in patients who relapse after radiation therapy]. However, this is not obvious given the limits of the radiologic tests that can be done,” said Dr. Rajkumar.

Previous retrospective studies have also found that two-thirds of patients with solitary bone plasmacytoma develop multiple myeloma within the first four years, although progression can occur as late as 13 years following diagnosis.

Progression to myeloma is thought to arise either from undetectable, abnormal plasma cells that were outside the field of radiation or from abnormal plasma cells that survive after radiation therapy.

In addition, the presence of monoclonal protein in the blood is a prognostic factor associated with progression to myeloma.

“Persistence of monoclonal proteins after radiation therapy obviously signifies residual disease outside of the radiation field,” said Dr. Alexanian.

One study showed that patients with solitary bone plasmacytoma whose monoclonal protein disappeared after radiation therapy had a 10-year progression-free survival rate of 91 percent, compared to 29 percent for patients who still had monoclonal protein following radiation therapy.

Another study involving 116 patients with solitary bone plasmacytoma showed that two risk factors predicted disease progression after five years. These included a persistent blood monoclonal protein level of above 0.5 g/dl one to two years after solitary bone plasmacytoma diagnosis, as well as an abnormal free light chain ratio at the time of diagnosis.

Patients who had neither of these risk factors had a 13 percent chance of progressing to myeloma after five years. Patients who had one risk factor had a 26 percent chance, and patients who had both risk factors had a 62 percent chance.

Other factors that increase the likelihood of progression to myeloma include a tumor size of at least 5 cm, old age, low bone density (osteopenia), and fast-growing blood vessels in the tumor sample (high-grade angiogenesis).

For additional information, see the related discussion in the Beacon forums.