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).

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.

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).

The findings from the three trials were presented earlier this week at the American Society of Hematology (ASH) annual meeting in San Diego.

MLN9708 belongs to the same class of drugs as Velcade (bortezomib), called proteasome inhibitors, and it is being developed by Millennium Pharmaceuticals, the same company that developed Velcade.

However, unlike Velcade, which is given by infusion or injection, MLN9708 can be administered orally in capsule form.

The results for MLN9708 that were presented at ASH are promising.  For example, in the small trial with newly diagnosed myeloma patients, 100 percent of the patients had at least a partial response to treatment with a combination of MLN9708, Revlimid, and dexamethasone.

In addition, the rate of peripheral neuropathy among patients treated with MLN9708 appears to be 50 to 75 percent lower than seen among patients treated with Velcade.  Peripheral neuropathy is a condition characterized by pain and tingling in the extremities.

MLN9708 In Combination With Revlimid And Dexamethasone

Dr. Jesus Berdeja from the Sarah Cannon Research Institute in Nashville, Tennessee, reported interim results from a Phase 1 study of MLN9708 in combination with Revlimid (lenalidomide) and dexamethasone (Decadron) in patients with previously untreated multiple myeloma.

Preclinical studies showed that MLN9708 acted synergistically with Revlimid and dexamethasone.

The goal of the Phase 1 study was to determine the safety and maximum tolerated dose of this combination therapy.

Fifteen newly diagnosed patients have been enrolled in the study so far. They received 1.68 mg/m² to 3.95 mg/m² of MLN9708 orally on days 1, 8, and 15 of a 28-day treatment cycle. They also received 25 mg of Revlimid on days 1 to 21 of each treatment cycle and 40 mg of dexamethasone on days 1, 8, 15, and 22 for up to 12 cycles. Transplant-eligible patients could undergo stem cell transplantation after six cycles.

Thus far in the trial, participants have received a median of five treatment cycles. Seventy-three percent of patients are still receiving treatment.

A full 100 percent of the 15 patients enrolled so far in the trial had at least a partial response to the combination treatment after four cycles of treatment.

In addition, 33 percent of the patients achieved a very good partial response and 27 percent achieved a complete response.

Dr. Berdeja pointed out that response to treatment was rapid; 93 percent of patients experienced at least a 50 percent decrease in M-protein, the abnormal protein produced by myeloma cells, after one treatment cycle.

Eighty-seven percent of patients experienced drug-related side effects. The most common severe side effects included vomiting (13 percent), blood clots (13 percent), anemia (13 percent), and rash (13 percent).

Mild peripheral neuropathy was observed in 20 percent of patients.

Twenty-seven percent of patients required Revlimid dose reductions, and 13 percent required MLN9708 dose reductions due to side effects.

The maximum tolerated dose for MLN9708 was found to be 2.97 mg/m². However, Dr. Bereja recom­mended a lower dose (2.23 mg/m²) for the Phase 2 trial because the lower dose was as active as the 2.97 mg/m² dose but better tolerated. In addition, he pointed out that the lower dose did not compromise the dosing of the other two agents.

MLN9708 As A Single-Agent Treatment

Dr. Paul Richardson of the Dana-Farber Cancer Institute in Boston presented results from a Phase 1/2 clinical trial of single-agent MLN9708 in patients with relapsed and treatment-resistant multiple myeloma.

A total of 56 patients, with a median age of 65 years, were enrolled in the study. They had received a median of four prior therapies.

Almost all patients (88 percent) had previously received Velcade, 79 percent had received Revlimid, 59 percent thalidomide (Thalomid), and 4 percent carfilzomib.  Fifty-two percent of patients demonstrated resistance to their last therapy, including 28 percent who were resistant to Velcade.

The purpose of the study was to determine the maximum tolerated dose of MLN9708.

Patients received 0.24 mg/m² to 2.23 mg/m² of MLN9708 on days 1, 4, 8, and 11 of a 21-day treatment cycle.  They received a median of 3.5 treatment cycles.

Of the evaluable patients, 13 percent had at least a partial response to treatment, with 2 percent of patients achieving a complete response. Another 61 percent of patients have reached stable disease.

Overall, 91 percent of patients experienced drug-related side effects including fatigue (46 percent of patients), low platelet counts (39 percent), nausea (30 percent), diarrhea (23 percent), vomiting (23 percent), rash (21 percent), and peripheral neuropathy (11 percent).

Dr. Richardson pointed out that all cases of peripheral neuropathy were mild to moderate; none of the patients experienced severe peripheral neuropathy.

In addition, 32 percent of patients required dose reductions due to side effects, and 9 percent discontinued treatment due to side effects.

The maximum tolerated dose was established at 2.0 mg/m².

Weekly MLN9708 As A Single-Agent Treatment

Dr. Shaji Kumar from the Mayo Clinic in Rochester, Minnesota, presented results from another Phase 1 study of MLN9708 in patients with relapsed and refractory multiple myeloma.

The objective of this study was to determine the maximum tolerated dose and safety of MLN9708 administered once per week.

The study enrolled 32 patients, who had received a median of six prior therapies. The median patient age was 64 years old. Seventy-two percent of patients had previously received a stem cell transplant, and 56 percent were resistant to prior therapy (including 28 percent to Velcade and 41 percent to Revlimid or thalidomide).

Patients received 0.24 mg/m² to 3.95 mg/m² of MLN9708 on days 1, 8, and 15 of a 28-day treatment cycle.

Overall, patients received a median of two treatment cycles. Three patients are currently continuing treatment; all others have discontinued treatment, mainly due to disease progression (69 percent).

Of the 18 patients who have been evaluated thus far for their response to the drug, one reached a very good partial response and one reached a partial response, for an overall response rate of 11 percent.

Another 8 patients (44 percent) achieved stable disease.

The majority of patients (72 percent) experienced treatment-related side effects. The most common treatment-related side effects included fatigue (31 percent), low platelet counts (31 percent), nausea (28 percent), and diarrhea (25 percent).

Nine percent of patients reported peripheral neuropathy. Dr. Kumar pointed that all cases of peripheral neuropathy were mild to moderate in nature.

Nineteen percent of patients required a dose reduction due to side effects, and 11 percent discontinued treatment due to side effects.

The maximum tolerated dose for weekly administration has been determined to be 2.97 mg/m².

For more information about these three trials, please see abstract 301, abstract 479, and abstract 816 on the American Society of Hematology Annual Meeting website.

Also, as a courtesy to The Beacon’s readers, Dr. Richardson has made the slides of his presentation available (pdf) for download and viewing.

Dr. Sagar Lonial from the Winship Cancer Institute at the Emory University School of Medicine in Atlanta presented the updated Phase 2 results at the American Society for Hematology (ASH) annual meeting in San Diego on Monday.

The preceding Phase 1 trial of elotuzumab showed that 82 percent of relapsed/refractory myeloma patients had a partial response or better to the drug in combination with Revlimid (lenalidomide) and dexamethasone (Decadron).

Both the Phase 1 results and initial Phase 2 findings were presented at the American Society of Hematology annual meeting last December, where Dr. Nikhil Munshi from the Dana-Farber Cancer Institute was enthusiastic about trial initial results from the Phase 2 trial (see related Beacon news). “Elotuzumab in combination with Revlimid and low-dose dexamethasone appears to be very promising,” he said.

Elotuzumab was designed to treat myeloma by identifying proteins on the surface of myeloma cells and spurring the body’s immune system to attack the cancer cells.

Among a number of so-called “monoclonal antibodies” being investigated as potential myeloma treatments, elotuzumab is the furthest along in the development process.

Myeloma researchers are excited about the possibility of having monoclonal antibodies as a treatment option.  A new class of treatments generally lengthens the time physicians can keep an average patient’s myeloma under control.

In addition, monoclonal antibodies have made important contributions to the treatment of several cancers, including the blood cancer lymphoma.

Elotuzumab initially was tested as a standalone treatment for myeloma, but it did not show much efficacy when used that way.  Further work indicated, however, that it might work particularly well in combination with Revlimid.

To date, 73 relapsed/refractory myeloma patients have been enrolled and treated in the ongoing Phase 2 trial of elotuzumab.  To participate in the trial, patients had to have received between one and three previous myeloma treatment regimens (the median was two).  A majority of the patients had been previously treated with either Velcade (bortezomib) or thalidomide (Thalomid).

Patients who had been previously treated with Revlimid were not permitted to participate in the trial.

Half of the patients in the trial received 10 mg/kg intravenous elotuzumab, and the other half received 20 mg/kg. Patients received elotuzumab on days 1, 8, 15, and 22 of the first two 28-day treatment cycles and on days 1 and 15 of subsequent cycles.

In addition, trial participants received 25 mg oral Revlimid on days 1 to 21, along with 40 mg dexamethasone once per week or 28 mg dexamethasone orally plus 8 mg dexamethasone by intravenous infusion on elotuzumab dosing days.

In order to prevent several elotuzumab-related infusion reactions observed in the Phase 1 trial, patients were given a steroid (prednisone or dexamethasone), Benadryl (diphenhydramine), Zantac (ranitidine), and Tylenol (acetaminophen) prior to each elotuzumab infusion.

Treatment was discontinued if patients experienced disease progression or severe side effects.

To date, 82 percent of patients have had at least a partial response to the treatment regimen, with 12 percent of patients achieving a complete response and 32 percent a very good partial response.

Even more encouraging to researchers is the fact that, among patients receiving the 10 mg dose, 92 percent had a partial response or better treatment.

Additionally, all patients who had only one prior therapy before entering the trial had a partial response or better to 10 mg/kg intravenous elotuzumab.

The median time to response was one month.

With a median follow-up of just over 11 months, 22 percent of 10 mg/kg treated patients experienced disease progression and 30 percent of patients in the 20 mg/kg group progressed.

The most common severe side effects were low levels of lymphocytes (a type of white blood cell) in 16 percent of patients, low platelet levels (16 percent of patients), low white blood cell levels (15 percent of patients), and low red blood cell levels (11 percent of patients).

In addition, 63 percent of patients experienced infusion reactions, the most common of which were nausea (18 percent), headache (14 percent), fever (14 percent), and dizziness (12 percent).

The lower, 10mg/kg dose of elotuzumab, is being tested further in combination with Revlimid and dexamethasone in two large, Phase 3 trials. One study is being conducted in newly diagnosed myeloma patients, the other in relapsed/refractory patients.

There also are plans to conduct a Phase 2 trial of elotuzumab in combination with Velcade and dexa­methasone as a treatment for relapsed or refractory myeloma patients.

For more information, see abstract 303 on the ASH meeting website.

Also, as a courtesy to The Beacon’s readers, Dr. Lonial has made the slides of his presentation available (pdf) for download and viewing.

The morning presentations about therapies combining current myeloma drugs will be covered in this update.  Morning presentations about potential new myeloma therapies were covered in an update published earlier today, and presentations from the rest of the day will be covered in additional updates.

MPR-R Versus MPR Versus MP

Dr. Antonio Palumbo from the University of Torino in Italy presented the final results of a Phase 3 trial aimed at assessing whether Revlimid (lenalidomide) maintenance therapy is beneficial for newly diagnosed, older myeloma patients ineligible for a stem cell transplant (abstract).

The trial tested three treatment regimens.  Two groups of patients received induction (upfront) therapy consisting of melphalan (Alkeran), prednisone, and Revlimid. Then half of the patients were placed on maintenance therapy with Revlimid (MPR-R), while the other half of these patients received a placebo as “maintenance” therapy (MPR).  A third group received only melphalan and prednisone as induction therapy, then a placebo as “maintenance” therapy (MP).

The results of this trial showed that Revlimid maintenance significantly extends progression-free survival.  Median progression free survival was 31 months for the MPR-R group of patients, 14 months for the MPR patients, and 13 months for the MP patients.

However, Revlimid maintenance therapy has not yet impacted overall survival.  The percentage of patients still alive at the four-year mark was 59 percent for the MPR-R group, 58 percent for the MPR group, and 58 percent, as well, for the MP group.

The latest secondary cancer data from the trial indicated that Revlimid maintenance as well as Revlimid induction therapy noticeably increases a patient’s risk of developing a second cancer.  For instance, there were 12 cases of non-invasive second cancers out of 150 patients who received MPR-R, 10 cases out of 152 patients who received MPR, and 4 cases out of 153 patients who received MP.

Dr. Palumbo argued, however, that the increased risk of secondary cancer associated with Revlimid treatment is far outweighed by the drug’s benefits. Most myeloma specialists agree with this perspective, and it is also the conclusion that the European Medicines Agency reached when it reviewed Revlimid’s secondary cancer risk this past summer.

Dr. Palumbo said recent results, including those from his trial, are moving myeloma in the direction of continuous therapy rather than specific periods of therapy as has typically been the case in the past.

VMP Versus MP

The next presentation was by Dr. Jesús San Miguel from the University Hospital in Salamanca, Spain.  He presented updated results from a Phase 3 clinical trial comparing the three-drug regimen Velcade (bortezomib), melphalan, and prednisone (VMP) to melphalan and prednisone alone (MP) (abstract).

The goal was to determine if a previously reported overall survival benefit for the VMP regimen persisted after five years of follow-up. In addition, the researchers analyzed the risk of secondary cancers in both treatment groups.

The analysis included 655 patients who were previously untreated and also ineligible for stem cell transplants.  Half of the patients received VMP, and the other half received MP alone.

After about five years of follow up, the median overall survival was 56.4 months for VMP patients versus 43.1 months for MP.

The overall survival benefit of VMP versus MP was also observed for several patient subgroups, including patients 75 years old or older (50.7 months versus 32.9 months), patients with stage III multiple myeloma (42.1 months versus 30.5 months), and patients with kidney disease (56.8 months versus 36.7 months). However, no significant difference in overall survival was observed in patients with high-risk chromosomal abnormalities.

Dr. San Miguel concluded that VMP resulted in a substantial long-term overall survival benefit compared to MP across a range of key patient subgroups, and as was discussed in yesterday’s ASH daily update, the risk of increased secondary cancers associated with the treatment is negligible or non-existent.

VT Versus VP Maintenance Therapy

Dr. San Miguel’s colleague Dr. María-Victoria Mateos then presented results from a Spanish trial that was conducted with older, newly diagnosed multiple myeloma patients who were ineligible to receive a stem cell transplant (abstract).

Patients in this study first received induction therapy with either Velcade, melphalan, and prednisone (VMP) or Velcade, thalidomide (Thalomid), and prednisone (VTP).  They then received one of two possible maintenance regimens: Velcade plus thalidomide (VT) or Velcade plus prednisone (VP).  A total of 178 patients started one of those two maintenance therapies.

In this presentation, Dr. Mateos focused on comparing the results of the maintenance therapies, since she and her colleagues previously published results showing that the two induction treatments tested in this trial had very similar efficacy.

After a median follow-up of 34 months, the complete response rate increased from 24 percent after induction therapy to 42 percent after maintenance therapy.  The complete response rate was similar, but slightly higher for VT versus VP (46 percent versus 39 percent).

The median progression-free survival from the start of induction therapy was 35 months.  From the start of maintenance therapy, the median progression-free survival was 30 months for patients receiving VT and 24 months for patients receiving VP.

The median overall survival was 60 months and was similar for both maintenance regimens.

The VT maintenance regimen had slightly higher levels of side effects, but they were generally not an issue.

Dr. Mateos believed that the benefit in terms of progression-free survival seen for the VT regimen supports pursuing that combination as a preferred maintenance regimen.  However, she also believed side effects could be reduced and the regimen further improved if patients were put on a Velcade-Revlimid maintenance regimen.

VD Versus VTD Versus VMP

Dr. Ruben Niesvizky from the Weill Cornell Medical College in New York presented results from a Phase 3 trial involving older, newly diagnosed, transplant-ineligible multiple myeloma patients.

The 502 patients in the study received 24 weeks of induction therapy with one of three regimens: Velcade plus dexamethasone (Decadron) (VD), Velcade plus thalidomide and dexamethasone (VTD), or Velcade plus melphalan and prednisone (VMP).  All three regimens were followed by an extended 25-week Velcade consolidation therapy.

The three Velcade-based induction regimens were effective, with overall response rates of 73 percent, 80 percent, and 69 percent for VD, VTD, and VMP, respectively.

After a median follow-up of 22 months, the median-progression free survival rates were similar for each of the regimens: 13.8 months for VD, 14.7 months for VTD, and 17.3 months for VMP.

Overall survival rates one-year after the start of treatment were also similar: 87.4 percent for VD, 86.1 percent for VTD, and 88.9 percent for VMP.

Patients receiving VTD experienced the most side effects, while those taking VD had the least side effects.

Overall, Dr. Niesvizky concluded that the three regimens were relatively similar in efficacy but yielded encouraging results for the patient population targeted by the trial.

For more detailed coverage of yesterday’s myeloma-related presentations and research at the ASH meeting, see the ASH 2011 Day Three thread in The Myeloma Beacon discussion forum.

The Beacon is publishing updates from Day Four of ASH in the Beacon’s myeloma forums.  As always, the news from each day will also be summarized in daily updates like this one.

Predicting Response To Immunomodulatory Drugs

During an oral presentation and a poster presentation yesterday, researchers discussed the role of the protein cereblon in the treatment of myeloma.  Results from one study (abstract) in myeloma cell lines suggested that cereblon plays a key role in whether multiple myeloma patients respond to the immunomodulatory drugs Revlimid (lenalidomide) and pomalidomide.  Another study (abstract) showed that myeloma patients with higher levels of cereblon in their bone marrow are likely to respond better to treatment with Revlimid and dexamethasone (Decadron).

These studies suggest that, in the future, tests may be developed to allow physicians to easily check a myeloma patient’s cereblon levels.  This, in turn, will help determine whether or not the patient should be treated with an immunomodulatory drug such as Revlimid or pomalidomide.

Velcade And Secondary Cancers

Secondary cancer has been an important topic this year within the myeloma community, with most of the attention focused on the possibility that Revlimid may increase a myeloma patient’s risk of developing a second cancer (see related Beacon news).

A poster presentation yesterday reviewed data from several trials to determine whether there is a link between Velcade (bortezomib) and developing a second cancer (abstract).

In the APEX trial comparing treatment with Velcade to treatment with dexamethasone in relapsed/refractory myeloma patients, Velcade-treated patients had a rate of secondary cancers of 0.88 cases for every 100 patient-years. In contrast, patients treated only with dexamethasone had no cases of secondary cancer.

Similarly, in the VISTA trial in newly diagnosed myeloma patients, which compared Velcade, melphalan (Alkeran), plus prednisone (VMP) as initial therapy versus just melphalan plus prednisone (MP), there were 1.66 cases of secondary cancer for every 100 patient-years of treatment in the VMP arm of the trial versus 1.30 in the MP only arm of the trial.

The two studies indicate that Velcade-treated patients have slightly higher rates of secondary cancer than myeloma patients not treated with Velcade.

However, the researchers who conducted this study noted that the rate of secondary cancers observed in the Velcade-treated patients is similar or lower than the rate of cancer in the general U.S.population similar in age to myeloma patients.

Additionally, a safety review of Revlimid conducted by the European Medicines Agency concluded “that there were 3.98 cases of new cancer for every 100 patient-years in patients receiving Revlimid compared with 1.38 cases in those not receiving Revlimid.”  Therefore, any secondary cancer risk associated with Velcade would appear to be substantially lower than the risk documented thus far for Revlimid.

Potential New Myeloma Therapies

During yesterday’s poster session, there were presentations about several potential new myeloma therapies and new combination therapies.

One presentation discussed the long-term efficacy and safety of pomalidomide in combination with dexamethasone for the treatment of relapsed/refractory multiple myeloma patients (abstract).

The overall response to treatment was 65 percent, including 7 percent stringent complete response, 7 percent complete response, 25 percent very good partial response, and 27 percent partial response.

Half of the patients responded within a rapid 1.7 months, and half responded for more than 21.3 months.

Ninety-one percent of the patients in the study were still alive one year after entering the trial, and 76 percent were alive after two years. Median overall survival has not yet been reached after a median follow-up of about 34 months.

The researchers also noted that standard-risk patients appear to perform better on the combination treatment than higher-risk patients, and the researchers concluded that the treatment is “highly effective” and “well-tolerated.”

Another poster presented results from a Phase 2 trial of ARRY-520 (abstract).  The trial included 32 myeloma patients previously treated with Velcade and at least one immunomodulatory drug (thalidomide or Revlimid).  During the trial, these patients were infused with ARRY-520 on days 1 and 2 of a 14-day cycle.

Overall, 12.5 percent of the study participants achieved a partial response, and another 6 percent achieved a minimal response.  The median time to response was about four months.

The researchers who conducted the study concluded that ARRY-520 “shows promising evidence of single-agent clinical activity and an acceptable safety profile in heavily pretreated patients.”

However, more than 25 percent of the patients treated with the drug experienced serious side effects, such as low white blood cell counts and low platelet counts, despite receiving G-CSF (Neupogen or Neulasta) to help sustain white blood cell counts.

The company developing the drug, Array BioPharma, plans to continue testing the drug in different combinations – with dexamethasone, with carfilzomib, and with Velcade and dexamethasone – in relapsed myeloma patients.

Another study presented during the poster session looked at the safety and efficacy of the so-called “T-BiRD” regimen in 26 newly diagnosed myeloma patients (abstract).  Like the “BiRD” regimen, it is a combination of the antibiotic clarithromycin (Biaxin), Revlimid, and dexamethasone, with the addition of thalidomide.

The overall response rate to the treatment was 77 percent; specifically, 4 percent had a complete response, 31 percent had a very good partial response, and 42 percent had a partial response.  In addition, patients appeared to respond quickly to the regimen.

After about four years of follow-up, overall survival was 84.5 percent. Survival was similar in patients with standard- and higher-risk genetic characteristics. However, there appeared to be a trend toward greater overall survival in standard-risk patients.

Nearly 70 percent of the participants successfully collected enough stem cells and underwent a stem cell transplant in addition to the T-BiRD regimen.  However, 31 percent of the trial participants halted T-BiRD treatment due to side effects.

There was also a poster about a trial studying an investigational cancer vaccine known as Stimuvax (L-BLP25).  The trial involved 34 patients with previously untreated smoldering or active myeloma (abstract).  Although none of the participants responded to the vaccine, the vaccine showed some signs of slowly reducing monoclonal (M)-protein levels over time in the trial participants.  Therefore, the researchers who conducted the study believe the vaccine still warrants further investigation.

Survival Studies

Yesterday evening, Dr. Nicholas Kröger from the University Medical Center in Hamburg, Germany, spoke about the effect “molecular remission” has on a myeloma patient’s survival (abstract).  Molecular remission is a more stringent form of complete response, where a more sensitive test is used to determine whether there is still evidence of myeloma in a patient’s bone marrow.

The study included 73 myeloma patients who were treated during the period from 2000 to 2008. Due to the time period when the study was conducted, patients were initially treated with older treatment regimens, rather than ones involving novel myeloma drugs.

After their initial therapy, patients received high-dose melphalan and an autologous transplant (using their own stem cells).  Two to three months later, the patients went through further treatment with melphalan, fludarabine, and  anti-thymocyte globulin followed by an allogeneic (donor) stem cell transplant.

Overall, 86 percent of participants responded.  Specifically, 60 percent of patients achieved a complete response, 8 percent a very good partial response, and 18 percent a partial response.

Molecular remission was observed in 30 patients, or 46 percent of the patient sample.  Of those 30 patients, 15 had a “sustained” molecular remission, meaning that repeated tests showed no evidence of myeloma. The other 15 had only intermittent molecular remission.

After a median follow-up of seven years, the five-year progression-free survival was 29 percent for the overall study population, 31 percent for those with intermittent molecular remission, and 85 percent for those with sustained molecular remission.

The five-year overall survival was 52 percent.  However, the survival rate was 87 percent for those who achieved intermittent molecular remission and 91 percent for those who sustained a molecular remission.

Dr. Kroeger said during the presentation that, in his opinion, the key is to get patients to a molecular remission if at all possible, but it is not important how or when this is achieved.  Once a patient achieves a molecular remission, he doubts there is a substantial benefit to be gained from further treatment.

The other key takeaway that Dr. Kroeger mentioned is that donor lymphocyte infusions markedly improve the efficacy of donor transplants.  However, he did not fully explore this point in the abstract or talk.

Another poster from yesterday compared survival rates of people diagnosed with multiple myeloma at young ages (45 years or less) to those diagnosed at older ages (abstract).  The analysis included 100 younger patients.  Among those, 45 percent received initial therapy that included a novel agent, 85 percent underwent a transplant using their own stem cells, and 15 percent underwent a donor stem cell transplant.

The median overall survival of the younger patients was 7.8 years as compared to 4.4 years for the older patients.  Also for the patients who were 45 years or younger at the time of diagnosis, the overall survival rates at five and seven years were 69 percent and 59 percent, respectively.

For more detailed coverage of yesterday’s myeloma-related presentations and research at the ASH meeting, see the ASH 2011 Day Two thread in The Myeloma Beacon discussion forum.

The Beacon is publishing regular “as it happens” updates from Day Three of ASH in the Beacon’s myeloma forums.  Similar “as it happens” updates will be provided for Day Four.  As always, the news from each day also will be summarized in daily updates like this one.

The survival outcomes for the patients treated with cyclophosphamide, Velcade, and dexamethasone also are promising.

However, the difference in survival rates between the three treatment regimens is not statistically significant.

This is partly because “the numbers [of patients in the study] were too small to show differences in survival,” explained Dr. Craig Reeder of the Mayo Clinic in Scottsdale, Arizona, and one of the authors of the study.

The study compared data from three independent Phase 2 clinical trials, which – according to the study authors – resulted in additional limitations, including a lack of both consistency in control groups and randomization of participants.

Furthermore, the study authors pointed out that the follow-up time was short, leaving no information on longer-term effects. They suggested that further examination of survival outcomes will require a larger Phase 3 study.

Stem cell transplantation using a patient’s own stem cells has become a standard treatment option for myeloma patients under the age of 65.

For this reason, it is increasingly necessary to have effective induction therapies – used prior to stem cell harvesting and transplantation – that are not toxic to stem cells.

Previous studies have shown that the combinations of cyclophosphamide (Cytoxan) plus Velcade (bortezo­mib) and dexa­methasone (Decadron) (abbreviated CyBorD), Revlimid (lenalidomide) plus dexamethasone (abbreviated RD), and cyclophosphamide plus RD (abbreviated as CRD), are effective as initial therapies for myeloma patients.

According to the study authors, however, there have been no formal comparisons of the efficacy and safety of these three treatment regimens to date.

To make this comparison, researchers from the Mayo Clinic and the University Health Network in Toronto retrospectively analyzed the medical records from 150 newly diagnosed myeloma patients who received one of the three treatments as part of Phase 2 trials in the period from 2004 to 2008.

The median age of the participants was 62.5 years old. Of the 150 patients, 27 percent were defined as high-risk due to genetic abnormalities and 53 percent subsequently received stem cell transplantation.

After four 28-day cycles of treatment, patients who received CyBorD demonstrated greater overall response rates as well as deeper responses than patients receiving the other two combination regimens.

Overall response rates were 89 percent, 88 percent, and 79 percent in the CyBorD, RD, and CRD patient groups, respectively.  These differences were not large enough to be statistically significant.

The differences in depth of response, however, were large enough to be significant.

Patients in the CyBorD group had a combined complete and near complete response rate of 41 percent, and a very good partial response rate of 24 percent.  This compares to 12 percent and 23 percent, respectively, for patients who received the RD regimen, and 2 percent and 28 percent for patients treated with the CRD regimen.

Survival measures were similar across all three treatment groups. The progression-free survival times for CyBorD, RD, and CRD were 2.7 years, 3.2 years, and 2.3 years, respectively, with a median progression-free survival of 2.6 years for all patients.

The three-year overall survival rates by treatment group were 88 percent, 88 percent, and 79 percent, respectively, for the CyBorD, RD, and CRD groups. For all 150 patients, the median four-year overall survival was 80 percent.

Transplanted patients had a higher three-year overall survival rate (95 percent) compared to patients who did not receive a transplant (75 percent).

Trial participants categorized as high-risk relapsed earlier than standard-risk patients, with a median progression-free survival of 2.1 years and 2.7 years, respectively.

Participants receiving CyBorD showed lower rates of either severe or life-threatening side effects (33 percent and 8 percent, respectively) than those receiving RD (50 percent and 6 percent, respectively) or CRD (49 percent and 25 percent, respectively).

However, the CyBorD group had higher rates of peripheral neuropathy (59 percent) than both the RD group (21 percent) and CRD group (15 percent).  Peripheral neuropathy is numbness or tingling, typically in the hands or feet, that can occur as a side effect of myeloma treatment.

According to Dr. Reeder, further studies of these combination therapies in post-stem cell transplantation treatment are planned.

For more information, please see the study in the British Journal of Haematology (abstract).

This Beacon article, the second in a two-part series, summarizes the review’s insights into issues that need to be considered when choosing among relapse treatment options

Part 1 summarizes the review’s perspectives on the use of novel agents in the treatment of relapsed and refractory myeloma.  

According to the authors of the review, the goal at relapse is to select a treatment regimen that maximizes efficacy while minimizing toxicity for each myeloma patient.

Thus, the relapse treatment decision generally depends on both disease-related and patient-related factors.

Disease-Related Factors

Disease-related factors include the duration of the patient’s remission and the timing of the patient’s relapse, as well as the aggressiveness of the disease.

The authors suggest that patients who are disease-free for at least 12 months and have not received treatment during this period of remission may receive the same initial therapy at relapse.

However, they advise that patients who relapse within 12 months, or while they are still receiving initial therapy, should receive a different therapy at relapse because it is likely that their disease has become resistant to the initial therapy.

They point out that stem cell transplantation is a feasible retreatment option in myeloma patients who are disease-free for a long period of time after their first stem cell transplant (at least two years in most cases). However, it is not recommended in myeloma patients who relapse within 18 months after their first stem cell transplant. Patients who relapse early should receive alternative treatments involving combinations of novel agents.

In addition, patients who are disease-free for a long period of time after receiving Velcade (bortezomib)-containing therapies may receive Velcade-containing therapies at relapse. Similarly, patients who respond well to thalidomide (Thalomid)-containing therapies may receive thalidomide- or Revlimid (lenalidomide)-containing therapies at relapse.

According to Dr. Sikander Ailawadhi of the USC Norris Cancer Hospital in Los Angeles, who was not involved in the current review, retreatment with a novel agent should be used only if the novel agent is given in a combination different from the initial combination.

“If the disease escapes initial treatment, then there has to be some amount of initial resistance [that the disease has] developed to it,” explained Dr. Ailawadhi.

“If a patient requires treatment again [after relapse], we will almost never go back to using exactly the same [initial] regimen. We want to use the same drug, but in a different combination so there is some novelty in the anti-cancer effect,” he said.

Patients who have high-risk features such as chromosomal abnormalities or extramedullary disease may also have a more resistant disease that requires different and more aggressive forms of treatment at relapse. For these patients, the French researchers recommend sophisticated combinations of novel agents, donor stem cell transplantation, or enrollment in clinical trials involving new, investigational drugs.

Patient-Related Factors

Patient-related factors include the presence of pre-existing toxicities from initial therapy, as well as patient characteristics such as age and kidney function.

For patients who experience kidney failure after initial therapy, the experts recommend treatment with Velcade-based therapies, which have been shown to have the best safety profile in patients with kidney failure. Modified doses of Revlimid-based therapies may also be feasible in these patients.

Patients who experience blood clots or heart problems after initial therapy should receive Velcade-based or Revlimid-based therapies.

Patients who experience peripheral neuropathy – a condition characterized by pain and tingling sensations in the extremities – after initial therapy should receive Revlimid-based therapies. Therapies containing thalidomide and Velcade should be avoided in these patients.

The authors of the review suggest that patients who are resistant to all novel agents participate in clinical trials involving new, investigational drugs such as the histone deacetylase inhibitors panobinostat, Istodax (romidepsin), and Zolina (vorinostat); antibody therapies such as elotuzumab; new proteasome inhibitors such as carfilzomib; or the new immunomodulatory agent pomalidomide.

Those who do not qualify for inclusion in clinical trials should receive treatment aimed at mitigating symptoms and maintaining quality of life while preventing, as much as possible, the spread of disease.

This may include treatment with alkylating agents such as cyclophosphamide (Cytoxan), a type of chemotherapy that prevents DNA replication in cancer cells, in combination with corticosteroids such as dexamethasone (Decadron) and prednisone.

Long-Term Effects Of Prolonged Treatment With Novel Agents

Currently, novel agents are also used in maintenance treatment strategies with the aim of further improving the efficacy of initial treatment with novel agents. However, according to the review authors, the long-term impact of prolonged treatment with novel agents is still unknown, and its benefits should be evaluated in light of its possible risks.

Thalidomide Maintenance

The authors of the review point out that, of the novel agents, thalidomide has been the most widely investigated in both transplant and non-transplant myeloma patients.

While thalidomide maintenance therapies have been shown to improve response rates and progression-free survival, they have not always translated into improved overall survival. In several studies, the overall survival was shorter in myeloma patients who received thalidomide maintenance therapy than in patients who did not. Therefore, researchers have speculated that prolonged exposure to thalidomide could result in the production of drug-resistant myeloma clones.

However, results of another study showed a survival benefit for patients who received thalidomide maintenance. These findings suggest that other factors may influence the final outcome of myeloma patients who receive prolonged treatment with thalidomide, such as the components of the initial therapy, the intensity of previous therapies, the sequence of drugs, and other patient-related factors.

Revlimid Maintenance

The review authors point out that studies investigating Revlimid maintenance therapy have shown promising results, although the long-term effects of Revlimid maintenance are still unknown.

A sub-analysis of a Phase 3 clinical trial showed that myeloma patients who continued Revlimid therapy had a longer overall survival times (51 months versus 35 months) than patients who discontinued Revlimid therapy.

Results of another Phase 3 clinical trial show that the myeloma patients who relapsed after continuous Revlimid therapy had similar outcomes as patients who relapsed after fixed-duration therapies, suggesting that Revlimid maintenance is not associated with more aggressive relapses.

In another study, researchers found that Revlimid maintenance could improve the very good partial response and complete response rates of elderly myeloma patients from 58 percent after induction therapy to 86 percent after maintenance therapy.

Although Revlimid maintenance may be effective in myeloma patients, there are concerns that it may significantly increase a patient’s risk of developing secondary cancers (see related Beacon news). According to the review authors, this issue requires additional study to better understand the balance between the benefits and risks of Revlimid maintenance.

Velcade Maintenance

According to the review authors, several studies have indicated that Velcade maintenance improves quality of response and increases progression-free survival in myeloma patients. Moreover, the studies have shown that Velcade maintenance is well-tolerated without a large increase in toxicities such as peripheral neuropathy.

The authors also note, however, that Velcade maintenance has not yet been shown to improve overall survival in myeloma patients.

For more information, please see the review in the journal Leukemia (abstract).

This Beacon article, the first in a two-part series, summarizes the review’s perspectives on the use of novel agents in the treatment of relapsed and refractory myeloma.  

A second Beacon article will look at the review’s insights into issues that need to be considered when choosing among relapse treatment options.

The authors of the recent review begin their discussion by noting how use of the novel agents thalidomide (Thalomid), Velcade (bortezomib), and Revlimid (lenalidomide) has changed over time.

The improved treatment outcomes associated with the novel agents has led to their increased use in the upfront treatment of myeloma.  Previously, novel agents had been used mostly to treat relapsed myeloma.

The greater upfront use of novel agents raises questions about their role as treatments for relapsed or refractory myeloma.

In addition, it raises a more general question about the most effective sequence of treatments for myeloma patients.

These are the questions that motivated the French specialists to write their review.

The Goals For Treatment At Relapse

It is generally accepted that treatment with novel agents brings about high-quality responses in newly diagnosed multiple myeloma patients.

Moreover, patients who achieve high-quality responses during initial therapy tend to have longer overall survival than patients who achieve low-quality responses

“Regimens that are giving a better depth of response are likely to translate into better survival if we are able to follow patients long enough,” said Dr. Sikander Ailawadhi of the USC Norris Cancer Hospital in Los Angeles, who was not involved in the current review.

Therefore, the French researchers argue that the goal of initial (“induction”) therapy should be to induce the best possible response in newly diagnosed myeloma patients.

This raises an obvious question: Does the same line of reasoning apply when making treatment decisions for relapsed and refractory myeloma patients?

More specifically, should “depth of response” also be the key goal in relapsed patients?

The authors of the current review admit that the answer to this question is controversial.

One could argue, for example, that duration of response — rather than depth of response — should be the key consideration when treating relapsed myeloma patients.

The French researchers believe, however, that recent research supports that view that depth of response should also be the key factor when choosing a treatment for relapsed and refractory patients.

They write that “for patients with a good performance status who can tolerate aggressive treatments, the ultimate goal at induction as well as at relapse should be to achieve the deepest possible response in order to improve survival.”

Treatment With Novel Agents At Relapse

With novel agents being used so frequently in the treatment of newly diagnosed myeloma patients, it no longer is possible to discuss the efficacy of these agents in relapsed patients without taking into account the previous treatments patients have received.

This is a major reason the authors of the current review typically use the word retreatment when referring to the use of novel agents to treat relapsed and refractory myeloma patients.

Retreatment With Thalidomide and Revlimid

Thalidomide and Revlimid belong to the class of drugs known as immunomodulatory agents.  These drugs work by encouraging a patient’s immune system to destroy myeloma cells.

Currently, most of the clinical trial results describing the efficacy of Revlimid as a “retreatment” are for myeloma patients who have relapsed after thalidomide therapy.

A sub-analysis of two previous Phase 3 clinical trials, for example, shows that retreatment with Revlimid is more effective in myeloma patients who have not had previous thalidomide exposure than in patients who have had thalidomide exposure.

Specifically, patients who did not have previous thalidomide exposure had higher overall response rates, including complete response rates, and longer progression-free survival times compared to patients who had previous thalidomide exposure.

However, patients who had previous thalidomide exposure still achieved better outcomes with Revlimid plus dexamethasone (Decadron) compared to patients who received dexamethasone alone.

Based on these results, the authors of the current review conclude that retreatment with Revlimid can be effective in myeloma patients who have previously received thalidomide, but it is more effective in patients who have not previously been treated with thalidomide.

Retreatment With Velcade

The French researchers next turn their attention to retreatment with Velcade.

They note that there are several studies that have shown that retreatment with Velcade is safe and effective in myeloma patients with previous Velcade exposure.

In fact, results of a Phase 3 clinical trial showed that Velcade is as effective as thalidomide or Revlimid in treating myeloma patients with previous Velcade exposure.

In addition, several studies have shown an overall response rate of up to 50 percent in myeloma patients retreated with Velcade if they had previous Velcade exposure.

Retreatment with Velcade also has been shown not to increase toxicity in patients with previous Velcade exposure. A Phase 2 clinical trial found that 40 percent of myeloma patients who were retreated with Velcade experienced peripheral neuropathy, but most cases were moderate and did not suggest cumulative toxicity.

Reduced-dose or subcutaneous forms of Velcade likewise can limit toxicity during retreatment with the drug (see related Beacon news).

Thus, the authors of the current review believe that “re-using [Velcade] in later lines [of therapy] is feasible and can result in responses in a considerable proportion of patients.”

Response To Previous Therapy With Novel Agents: Does It Matter?

When considering treatment options for myeloma patients who have received several previous therapies, one area of controversy, the review authors write, is whether efficacy of retreatment is influenced by a patient’s response to previous therapy.

Substantial attention has been devoted, in particular, to whether a patient’s response to previous treatment with thalidomide influences response to Revlimid when it is given as relapse therapy.

The French researchers report that there are conflicting results on this point.

Results of one recent study, for example, indicate that Revlimid is equally effective in heavily pre-treated myeloma patients regardless of whether they were resistant to, or responded well to, previous thalidomide therapy.

When treated with Revlimid, thalidomide-resistant and thalidomide-sensitive myeloma patients had similar overall response rates (56 percent versus 62 percent), progression-free survival times (10 months versus 12 months), and overall survival times (17 months versus 18.5 months).

Results of another study, however, show that treatment with Revlimid is more effective in patients who respond well to thalidomide therapy than patients who are resistant to thalidomide therapy.

Thalidomide-sensitive patients had a higher overall response rate (65 percent versus 50 percent) and longer progression-free survival (9.3 months versus 7 months) than thalidomide-resistant patients.

Furthermore, results of another study suggest that the presence of thalidomide-resistant disease may generally predict for poor outcomes in myeloma patients.

In that study, thalidomide-resistant patients had a lower response rate, shorter progression-free and shorter overall survival compared to thalidomide-sensitive patients when the patients were treated with Revlimid-based therapies.

Moreover, the addition of Velcade to these Revlimid-based therapies could not overcome the poor prognosis of thalidomide-resistant patients.

Even here, however, the story is not clear cut.

Results of another study showed that thalidomide resistance affected progression-free survival and overall survival only in myeloma patients who also had been treated with Velcade.  This result led some researchers to wonder whether prior treatment with Velcade might generally make treatment at relapse more challenging.

Stem Cell Transplantation As A Treatment Option

The French researchers close out the first part of their review with a discussion of stem cell treatments and their role as relapse therapy.

According to the review authors, stem cell transplantation can be an effective treatment option for relapsed myeloma in patients who have not previously had a transplant.

Results of one key study show that myeloma patients who receive a stem cell transplant at relapse have similar overall survival outcomes as patients who receive a stem cell transplant at diagnosis. However, patients who received an early stem cell transplant have longer progression-free survival and a longer period of time without symptoms, treatments, and treatment-related toxicities.

The French researchers also note that stem cell transplantation may be an effective option at relapse in myeloma patients who previously received a stem cell transplant as long as the first transplant yielded a disease-free period at least 1.5 to 2 years long.

Several clinical trials have shown that a longer disease-free period after initial transplant is associated with improved progression-free and overall survival in patients undergoing a second transplant.

The value of a third stem transplant seems less certain.  The review authors note that a study looking at the potential benefit of a third transplant found that it “did not contribute to long-term disease control.”

For more information, please see the review in the journal Leukemia (abstract).