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).

Specifically, the researchers found that patients with three or more chromos­omal abnor­malities, a gain in the 1q21 region, or the trans­location t(4;14) have reduced survival compared to patients without such abnormalities.

According to the researchers, their findings highlight the importance of chromosomal abnormalities when considering treatment options for myeloma patients.

They note, however, that their findings need to be confirmed in a pro­spective, randomized trial that includes one or more novel agents.

Chromosomal abnormalities are the result of structural changes in the chromosomes of a patient’s myeloma cells.

These changes may occur through deletions, insertions, duplications, or movement of chromosomal regions. Cells with three or more abnormalities in their chromosomes are considered to have a complex karyotype.

Chromosomal abnormalities have been an area of intensive research.  Some abnormalities can be a sign that a patient’s myeloma may be less responsive to certain treatments (see related Beacon articles).

To determine the frequency of the most common chromosomal abnormalities and their effect on treatment outcomes in newly diagnosed multiple myeloma patients, the Czech researchers retrospectively analyzed data from patients who had participated in the Phase 3 CMG2002 trial.

The CMG2002 trial enrolled 542 newly diagnosed multiple myeloma patients in the Czech Republic from 2002 to 2007.

All patients in the trial received induction therapy with vincristine (Oncovin), doxorubicin (Adriamycin), and dexamethasone (Decadron) followed by high-dose melphalan (Alkeran) and an autologous stem cell transplant.

Patients were then randomized to receive either consolidation therapy and (eventually) maintenance therapy, or maintenance therapy alone.

In the “consolidation plus maintenance therapy” arm of the trial, patients received consolidation therapy consisting of cyclophosphamide, etoposide, and dexamethasone administered for four days in months 4, 8, 12, and 16 after the patient’s transplant, followed by weekly subcutaneous interferon injections beginning in the 18th month after transplant (until relapse).

In the “maintenance therapy only” arm of the trial, patients received weekly subcutaneous interferon injections after their stem cell transplant and until relapse.

Data on chromosomal abnormalities was available for 207 of the 542 study participants. The median patient age was 57 years.

The most common chromosomal abnormality was the deletion del(13q) (53 percent of patients), followed by a gain in the region 1q21 (46 percent), the translocations t(4;14) (23 percent), and t(11;14) (19 percent).

The least common chromosomal abnormality was the deletion del(17p), which was found in 7 percent of patients. Nineteen percent of patients had a complex karyotype.

Overall, the researchers found no difference in overall response rates in patients with chromosomal abnormalities compared to those without them.

However, the differences in survival for certain chromosomal abnormalities were significant.

The researchers found that patients with complex karyotypes had a significantly shorter time to disesase progression (17.5 months) than those with normal karyotypes (32.1 months).  Similarly, the overall survival for patients with complex karyotypes was 17.5 months, while the median overall survival for patients with normal karyotypes has not been reached.

In patients with t(4;14), researchers found a shorter time to disease progression compared to those without t(4;14) (18.0 months versus 36.2 months, respectively).  Overall survival was also negatively affected by t(4;14), with a median of 33.3 months for patients with the translocation compared to 60.7 months for those without it.

Researchers also found that patients with a gain in the region 1q21 had significantly worse outcomes than those without it.  Patients identified with 1q21 had a median time to disease progression of 21.3 months compared to 32.2 months for those without it.  The median overall survival in the gain of 1q21 subgroup was 30.4 months while it had not yet been reached for those without it.

The researchers pointed out that patients with both t(4;14) and complex karyotypes had very poor prognoses, with an median overall survival of 13.2 months.

The authors of the current study believe their results are a useful addition to the literature on chromosomal abnormalities and their impact on myeloma treatment and prognosis.

The authors accept, however, that some caution should be used in interpreting their results.  None of the patients in the Czech trial were treated with novel myeloma treatments such as thalidomide (Thalomid), Velcade (bortezomib), or Revlimid (lenalidomide).  Yet these drugs are now regularly used in the treatment of newly diagnosed myeloma patients.

For more information, please see the study in the journal Leukemia & Lymphoma (abstract).

Additional Information About Chromosomal Abnormalities

Each person’s genetic material is stored in chromosomes. Humans normally have two copies of 22 different chromosomes as well as two sex chromosomes (XX for women and XY for men).

Every chromosome has two regions, a short region (p) and a long region (q), and specific positions on the chromosome are numbered.

Therefore, 17p13 would refer to position 13 of the short region of chromosome 17.

There are a number of different types of chromosomal abnormalities. The most common chromosomal abnormalities related to myeloma include:

Deletion – A part of a chromosome is missing. For example: del(17p13) would mean that on chromosome 17, position 13 of the short arm is missing.

Translocation – A portion of one chromosome is transferred to another chromosome, or two chromosomes swap portions. For example, t(4;14) means that chromosomes 4 and 14 have swapped some of their genetic material.

Gain – There is an extra copy of a chromosome or part of a chromosome. For example: +1q21 would mean that this person has an extra copy of position 21 of the long region of chromosome 1.

“This [study] provides the efficacy of another regimen for use in patients with myeloma,” said the study’s lead author Dr. Shaji Kumar of the Mayo Clinic in Rochester, Minnesota. “It is a fairly safe combination and is quite efficacious,” he stated in an e-mail to The Myeloma Beacon.

According to the study authors, the combination of Revlimid (lenalidomide), cyclophosphamide (Cytoxan) and low-dose dexamethasone (Decadron) (abbreviated as RCd) is suitable as long-term therapy. They stated that the increased side effects associated with RCd, compared to Revlimid plus low-dose dexamethasone (Rd), were manageable.

Previous studies have shown that cyclophosphamide can improve combination therapies containing thalidomide (Thalomid) or Velcade (bortezomib) in newly diagnosed myeloma patients. They have also shown that cyclophosphamide in combination with Revlimid improves responses in relapsed myeloma patients.

The authors wanted to determine if the addition of cyclophosphamide to Rd therapy would also improve outcomes in newly diagnosed myeloma patients.

The trial included 53 previously untreated myeloma patients. Among these patients, 26 percent were considered high-risk based on chromosomal abnormalities.

Participants were treated with 25 mg Revlimid daily for three weeks, 300 mg/m² of cyclophosphamide on days 1, 8, and 15, and 40 mg of dexamethasone on days 1, 8, 15, and 22 of a 28-day cycle. In an effort to reduce side effects, the last 19 patients enrolled in the study received a lower dose of cyclophosphamide (a flat dose of 300 mg). Treatment was continued for a maximum of 12 cycles.

After four cycles of treatment, 79 percent of patients responded, including 2 percent who achieved a complete response and 28 percent who achieved a very good partial response.  Some patients achieved a higher response after longer treatment; the overall response rate during the study was 85 percent.

Additionally, response rates were similar for patients receiving high- and low-doses of cyclophosphamide (77 percent compared to 84 percent).

The median progression-free survival was 28 months, and overall survival was estimated to be 87 percent two years after diagnosis.

Although high-risk patients typically respond similarly or not as well to treatment as standard-risk patients, high-risk patients in this study had a better overall response rate than the standard-risk patients (93 percent compared to 79 percent). Two-year progression-free survival and overall survival were similar for the two groups.

The authors suggested that high-risk patients may respond better to RCd therapy than to Rd alone.  However, Dr. Kumar explained, “[This combination] does not specifically affect the treatment of high-risk patients. They should continue to get Velcade-based treatments,” which currently is the general recommendation for high-risk patients.

Half of all participants experienced low white blood cell counts, which was also the most common cause for treatment delays. Fatigue was the second most common side effect. Side effects were similar among those who received the high- and low-doses of cyclophosphamide.

Dr. Kumar indicated that growth factors could be included with RCd therapy as a way to prevent low white blood cell counts.

The authors stated that RCd therapy is comparable to a number of other new combination therapies with regard to efficacy in newly diagnosed myeloma patients. A comparison of results from this and previous studies showed that the overall response rate for RCd (85 percent) is higher than for Rd alone (70 percent) and comparable to Velcade, cyclophosphamide, and high-dose dexamethasone combination therapy (88 percent).  Survival rates appear to be similar for the three regimens.

The combination of Revlimid, Velcade, and dexamethasone, however, has produced the highest response rate (100 percent) in newly diagnosed myeloma patients, with around half of those patients achieving a complete or near complete response.

According to Dr. Kumar, it is not yet clear when RCd may be investigated in a Phase 3 trial.

For more information, please see the study in the American Journal of Hematology (abstract).

However, patients who received the three-drug combination had comparable overall survival and progression-free survival rates as patients who received melphalan plus prednisone.  Additionally, side effects were more common among patients treated with the three-drug combination.

High-dose chemotherapy followed by autologous stem cell transplantation is the standard of care for transplant-eligible myeloma patients.

Patients who are elderly or who have concurrent illnesses, however, are often ineligible for transplantation and require safer forms of treatment.

One option for these patients is melphalan (Alkeran) plus prednisone, known as MP, a standard initial treatment for myeloma inEurope.

Although not as widely used, the combination of cyclophosphamide, thalidomide (Thalomid), and dexamethasone (Decadron), known as CTD, produces fewer blood-related side effects compared to MP.

A previous study conducted in Polandshowed that CTD is safe and effective both for newly diagnosed myeloma patients prior to stem cell transplantation as well as relapsed and treatment-resistant patients (see related Beacon news).

In the current study, the authors compared the efficacy and safety of a reduced-dose regimen of cyclophosphamide, thalidomide, and dexamethasone, called CTDa, to that of the MP regimen in myeloma patients ineligible for stem cell transplantation.

The study was part of the larger Phase 3 MRC Myeloma IX trial, which compared the efficacy of the bisphosphonates Zometa (zoledronic acid) and Bonefos (clodronic acid) in myeloma patients (see related Beacon news) who were also treated with different myeloma therapies depending on whether they were transplant eligible. Upon completion of the MRC Myeloma IX trial in 2010, the study authors conducted a follow-up analysis comparing CTDa and MP in the subset of patients treated with either of these two regimens.

The analysis included 856 newly diagnosed transplant-ineligible myeloma patients, all of whom were randomized at the start of the trial to receive either Zometa or Bonefos until disease progression. These patients were also randomized to receive either CTDa (419 patients) or MP (418 patients).

The median age of patients in both the CTDa and MP treatment groups was 73 years. In addition, 76 percent of patients in both treatment groups had advanced myeloma. Both treatment groups received a median of six cycles of therapy.

Furthermore, 225 patients in the CTDa group and 215 patients in the MP group were screened for chromosomal abnormalities.

High-risk patients were those who had at least one of the following chromosomal abnormalities: +1q, t(4;14), t(4;14), t(14;2), t(14;16), or del(17p). Standard-risk patients were those who did not have any of these chromosomal abnormalities.

Among those screened for chromosomal abnormalities, the percentage of high-risk patients was similar between the CTDa group and the MP group (43 percent and 42 percent, respectively).

Patients in the CTDa group received 500 mg of cyclophosphamide weekly, escalating doses of thalidomide from 50 mg per day to 200 mg per day, and 20 mg of dexamethasone daily on days 1 to 4 and days 15 to 18 of successive 28-day cycles until maximum response.

Patients in the MP group received 7 mg/m² of melphalan per day plus 40 mg of prednisone per day on days 1 to 4 of successive 28-day cycles until maximum response.

The researchers found that patients in the CTDa group had a significantly higher overall response rate (64 percent) than patients in the MP group (33 percent), with 13 percent of the CTDa group achieving a complete response compared to 2 percent of the MP group. Similarly, 17 percent of patients treated with CTDa achieved a very good partial response rate compared to 2 percent of patients treated with MP.

However, after a median follow-up of 44 months, median progression-free survival (12 months for CTDa versus 13 months for MP) and overall survival (31 months for CTDa and 33 months for MP) were similar for the two treatment groups.

The researchers also found that among patients in the CTDa group, standard-risk patients had a significantly better overall survival than high-risk patients. Based on these findings, they suggested that standard-risk patients were most likely to benefit from the CTDa regimen.

Compared to patients in the MP group, patients in the CTDa group had higher rates of infection (32 percent versus 26 percent), constipation (41 percent versus 18 percent), blood clots (16 percent versus 5 percent), rash (15 percent versus 7 percent), and sensory neuropathy characterized by pain and tingling in the extremities (24 percent versus 6 percent).

Fifty-seven percent of patients in the CTDa group and 62 percent of patients in the MP group died. The most common causes of death were disease progression, infection, treatment, and kidney failure.

For more information, please see the article in the journal Blood (abstract).

 “Low-dose thalidomide was well tolerated, and serious side effects described with high or even intermediate doses were diminished,” said Dr. Anna Dmoszynska, the lead author of the study, in an email to the Beacon.

In recent years, thalidomide (Thalomid) has proven to be an effective therapy for multiple myeloma when given alone or in combination with other drugs. One such combination consists of cyclophosphamide, thalidomide, and dexamethasone (Decadron).

The results of a study published in March showed that this therapy, commonly referred to as CTD, is effective for newly diagnosed multiple myeloma patients (see related Beacon news).

However, treatment with thalidomide is associated with an increased risk of blood clot formation and nerve damage.

The goal of the Polish study was to determine the safety and efficacy of CTD with low-dose thalidomide as a therapy for newly diagnosed multiple myeloma patients prior to stem cell transplantation as well as salvage therapy in relapsed and treatment-resistant (refractory) myeloma patients.

Low-dose thalidomide (100 mg) was used in an attempt to decrease side effects observed at higher doses (300 mg to 800 mg).

A total of 132 patients were included in the study, 64 of whom were newly diagnosed and 68 of whom had received prior treatment.

Patients received cyclophosphamide (625 mg/m² orally on day 1), thalidomide (100 mg orally on days 1 to 28), and dexamethasone (20 mg orally on days 1 to 4 and 8 to 11) in 28-day treatment cycles. The median number of cycles administered was 6, ranging from 3 to 9 cycles.

Of the newly diagnosed myeloma patients receiving CTD, 74 percent achieved a partial response or better.  Forty nine percent of treatment resistant patients and 65 percent of relapsed myeloma patients also achieved a partial response or better during treatment.  

Complete remission was achieved in 9.4 percent of newly diagnosed patients and 3.9 and 5.9 percent of resistant and relapsed patients, respectively.

The median time to disease progression was significantly longer in newly diagnosed patients (21 months) compared to resistant and relapsed patients (15 months and 10 months, respectively).

At 20 months after start of treatment, 73 percent of both newly diagnosed and resistant myeloma patients were alive, compared to 51 percent of relapsed patients. 

CTD with low-dose thalidomide was well tolerated in most patients.  The most common side effect was nerve damage to the extremities, which was observed in 26 percent of patients. Nerve damage was severe enough to stop treatment in 3 percent of patients.

The researchers pointed out that more comparative research is necessary in order to optimize the dosages and administration of the CTD regimen.

However, Dr. Dmoszynska believes the therapy may become important in situations where cost is an issue. “It is not expensive in comparison to other protocols, but it is very effective. The three drugs are also administered orally, so it is ideal for outpatient treatment.”

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

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

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

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

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

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

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

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

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

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

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

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

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

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

High-dose melphalan (Alkeran) is the standard conditioning treatment for multiple myeloma patients who will receive an autologous stem cell transplant. Previous studies have shown that melphalan treatment elicits favorable complete response rates and overall survival. However, the possibility of achieving even better responses was investigated in this study by combining melphalan with other therapeutic agents: Hycamtin (topotecan), which inhibits the replication of DNA in cancer cells, and cyclophosphamide (Cytoxan), which works similarly to melphalan to slow or stop growth of cancer cells.

The study evaluated the safety and efficacy of the Hycamtin-cyclophosphamide-melphalan (HCM) combination in 60 patients with relapsed or refractory multiple myeloma or patients in first remission. HCM was administered intravenously over the course of six days preceding an autologous stem cell transplant.

The overall response rate for the HCM combination was 85 percent: 12 percent of participants achieved complete response, 32 percent very good partial response, and 30 percent partial response. Among the remaining participants, 13 percent had stable disease, and one patient progressed.

Very good partial response and complete response rates were higher in patients who underwent autologous stem cell transplantation within 12 months of their myeloma diagnosis; 68 percent of these patients achieved at least a very good partial response, whereas patients who received stem cell transplants more than 12 months after diagnosis achieved at least a very good partial response rate of 32 percent.

Additionally, very good partial response and complete response rates were higher in patients who achieved at least partial response to HCM therapy before stem cell transplantation. Of those who achieved this preliminary partial response, 63 percent went on to achieve very good partial response or complete response after transplantation. Of those who did not achieve an initial partial response, 31 percent achieved very good partial response or complete response after transplant.

After a median follow-up period of 32 months, the median progression-free survival time was 18.5 months. Five years after the completion of the study, 60 percent of the patients were still alive, and 33 percent were in remission.

Serious blood-related side effects were high, with all patients experiencing low white blood cell counts and low platelet counts. Most other side effects were mild and manageable; the most common were mucositis/stomatitis (inflammation and ulceration of the mouth and digestive tract, 65 percent), nausea (58 percent), and diarrhea (42 percent).

In comparison, past trials have shown that single-agent high-dose melphalan has a complete response rate of 22 to 44 percent, a progression-free survival time of 18 to 30 months, and a median overall survival time of five years, making the HCM combination comparable to, but not an improvement over, melphalan alone.

HCM yielded a lower complete response rate (12 percent) than the standard melphalan regimen, which may be due to a lower melphalan dose used in the combination treatment. Increasing the melphalan dose in HCM could raise the complete response rate, but at the risk of increasing side effects as well.

The side effects of HCM and high-dose melphalan were not directly compared in this study. Dr. Muzaffar Qazilbash of the University of Texas MD Anderson Cancer Center and an investigator of the study explained that side effects were comparable with only a small difference. “Subjectively we felt that the HCM regimen was slightly more toxic in terms of mucositis, diarrhea, and abdominal discomfort than melphalan alone,” said Dr. Qazilbash.

The HCM regimen is also administered over a course of six days, whereas the standard high-dose melphalan treatment is administered over one or two days. Therefore, the HCM treatment would likely be more costly and require longer hospital stays than the standard melphalan treatment.

Aside from complete response rates and treatment times, HCM is comparable to the standard melphalan regimen in terms of overall response rates, progression-free survival rates, and overall survival. However, researchers suggest that a Phase 3 trial directly comparing HCM to high-dose melphalan will be necessary in order to truly determine which treatment regimen is more beneficial.

“Until we can show unequivocal superiority of [HCM] or another regimen, melphalan should remain the standard of care,” suggested Dr. Qazilbash.

For more information, please see the study in Bone Marrow Transplantation (abstract).

Physicians were able to collect almost 50 percent fewer stem cells from patients treated with cyclophosphamide and thalidomide (Thalomid) compared to patients treated with other commonly used myeloma treatments. This combination therapy may prevent stem cells from moving from the bone marrow into the circulating blood, where they are harvested for stem cell transplantation.

Treatment of multiple myeloma typically begins with a combination of drugs that specifically target myeloma cells, known as induction therapy. For young myeloma patients, this treatment regimen is usually followed by autologous stem cell transplantation, in which a patient’s stem cells are harvested and then transplanted back later in the patient’s treatment.

Some drugs, although effective in targeting myeloma cells, are not used in induction therapy for transplant-eligible patients because they reduce the patient’s stem cell count and inhibit stem cell mobilization to the blood, where they can be collected. If not enough stem cells can be harvested, then the patient is unable to receive stem cell transplantation.

Autologous stem cell transplantation has been shown to increase survival and has been an integral part of multiple myeloma treatment in relapsed patients. For patients who are transplant-eligible, physicians, therefore, carefully consider the impact that induction therapies have on stem cell collection.

When used alone and in other combination therapies, thalidomide and cyclophosphamide do not usually disrupt the stem cell harvesting process. However, this study investigated the effect of a combination of these two drugs on stem cell mobilization in multiple myeloma patients.

A group of 67 patients received an induction therapy of oral cyclophosphamide, thalidomide, and dexamethasone (Decadron) (CTD). This group was compared to a control group of 69 patients who received induction therapy with either a vincristine-doxorubicin (Adriamycin)-dexamethasone combination or an oral idarubicin-dexamethasone combination. Both of these control therapies are known to rarely have an effect on stem cell mobilization.

After the completion of induction treatment, patients received stem cell mobilization therapy of oral cyclophosphamide and G-CSF until stem cell collection was complete.

The total number of stem cells collected from patients who received the CTD combination (median 5.0 x 10⁶ cells/kg) was significantly lower than the number of stem cells collected from the patients in the control group (median 9.8 x 10⁶ cells/kg). When evaluated on a per-day basis, the number of stem cells harvested on each day of mobilization was also significantly lower for patients who received CTD.

In the CTD group, almost 40 percent of patients failed to meet the standard target number of stem cells necessary for two stem cell transplants (4 x 10⁶ cells/kg), whereas only 16 percent of the control group did not meet this requirement.

Additionally, 25 percent of patients who received CTD failed to meet even the minimum stem cell count necessary for one transplant (2 x 10⁶ cells/kg), whereas only 8 percent of patients in the control group did not meet the minimum.

An inability to harvest stem cells can sometimes be the result of old age or a higher number of induction treatment cycles. However, it was determined in the study that the age of the participants and the number of induction treatment cycles they underwent did not make a significant difference in the success or failure of stem cell collection.

It has been shown through numerous other studies that thalidomide and cyclophosphamide, when used alone, have little-to-no effect on stem cell mobilization. However, the results of this study suggest that the combination of these two drugs is directly responsible for the negative impact of CTD therapy on stem cell mobilization and subsequent collection.

“We do not really know the precise mechanism by which the combination causes failure of mobilization,” said Dr. Amin Rahemtulla of the Imperial College in London and one of the authors of the study. “We have not studied this.”

As treatment strategies for multiple myeloma shift toward the use of combination therapies, this study highlights the importance of considering the effects drugs may elicit in combination in addition to the effects they elicit independently.

“We should be vigilant about the effect of new treatment regimens on stem cell mobilization,” stated Dr. Rahemtulla.

For more information, please see the study in Nature (abstract) or a related Beacon article about the efficacy of CTD followed by stem cell transplantation.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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