Researchers from the Moffitt Cancer Center recently published results from a Phase 2 clinical trial that investigated the combination of Revlimid plus Doxil and low-dose dexa­metha­sone as initial therapy for patients with newly diag­nosed multiple myeloma.

Although the results show an overall re­sponse rate of 77 per­cent, a medi­an progression-free survival time of 28 months, and a one-year overall survival rate of 98 per­cent for the Revlimid ^[1] (lenalidomide), Doxil ^[2] (doxo­ru­bi­cin liposomal), and dexa­metha­sone ^[3] (Decadron) combination, the re­search­ers indicate that this combination is not an improvement on ini­tial therapies currently available for newly diagnosed myeloma patients.

In fact, several other three-drug combinations have achieved better re­sults in newly diagnosed patients than the Revlimid-Doxil-dexa­metha­sone combination.

For example, the combination of Revlimid, Velcade ^[1] (bortezomib), and dexa­metha­sone, commonly abbre­vi­ated as RVD or VRD, achieved a 100 per­cent re­sponse rate in newly diagnosed multiple myeloma patients (see related Beacon ^[4] news).

Similar results (98 per­cent overall re­sponse rate) were observed with a combination of Kyprolis ^[5] (carfilzo­mib), Revlimid, and low-dose dexa­metha­sone, commonly abbreviated as CRd (see related Beacon ^[6] news).

In addition, 89 per­cent of newly diagnosed patients receiving cyclophosphamide ^[7] (Cytoxan) plus Velcade and dexa­metha­sone, commonly abbreviated as CyBorD or VCD, responded to treatment (see related Beacon ^[8] news).

“The reported re­sponse rates for VRD and CRd are numerically higher than seen here with deeper re­sponses as well,” said Dr. Shaji Kumar from the Mayo Clinic, who was not involved in the study.

The overall survival rate was also lower in the Revlimid-Doxil-dexa­metha­sone trial (98 per­cent at 12 months and 80 per­cent at 24 months) compared to the VRD trial (97 per­cent at 18 months), CRd trial (92 per­cent at 24 months), and CyBorD trial (88 per­cent at 36 months).

In addition, the Revlimid-Doxil-dexa­metha­sone combination caused more severe and life-threatening side effects than previously found after treatment with Revlimid and dexa­metha­sone alone. For this reason, the study in­vesti­gators decreased the starting dose of Doxil from 40 mg/m² to 30 mg/m² after half of the patients started treatment.

The lower Doxil dose resulted in a lower rate of severe to life-threatening side effects. After changing to the lower dose, 47 per­cent of patients had low white blood cell counts versus 59 per­cent before, 11 per­cent had anemia versus 21 per­cent before, and 4 per­cent had fatigue versus 21 per­cent before.

Surprisingly, the overall re­sponse rate was higher among patients who started Doxil at 30 mg/m² (82 per­cent), compared to those who began with Doxil at 40 mg/m² (72 per­cent).

Based on the findings, the study’s lead in­vesti­gator, Dr. Rachid Baz, indicated that the Revlimid-Doxil-dexa­metha­sone combination does not offer a clear advantage over other currently-available regimens for the initial treatment of newly diagnosed myeloma patients.

“It is hard to see a clear advantage of this combination over Revlimid-Velcade-dexa­metha­sone, except possibly sparing neuropathy related to Velcade,” Dr. Baz said. However, he pointed out that Kyprolis-Revlimid-dexa­metha­sone also does not have the neuropathy concern.

Given the number of different induction therapy options for newly diagnosed multiple myeloma patients, Dr. Baz believes the role of the Revlimid-Doxil-dexa­metha­sone combination in this patient population is not clearly defined.

“We do not have further plans for this combination,” said Dr. Baz. “It is important to note that in the past five to seven years there have been considerable advances in the field that are more interesting to investigate.”

Dr. Kumar points out, though, that the combination might be useful for patients with highly proliferative or extramedullary disease where an anthracycline, such as Doxil, may have a benefit.

According to Dr. Baz, there are nevertheless lessons to be learned from the current study.

“The tolerability of therapy is more important than the dose intensity. Specifically, when we reduced the dose of Doxil, the toxicities decreased significantly and the efficacy was not compromised. This is a theme identi­fied in several myeloma studies,” he explained.

Background

Common induction therapies for newly diagnosed myeloma patients include low-dose dexa­metha­sone combined with Revlimid, Velcade, or thalidomide ^[9] (Thalomid).

The combination of Revlimid, Velcade, and dexa­metha­sone is increasingly being used as induction therapy due to its high efficacy, particularly for patients with high-risk myeloma.

Velcade, however, has been linked to high rates of peripheral neuropathy, damage to nerves that often causes pain, tingling, and loss of sensation in the extremities. Researchers believe that the replacement of Velcade with another drug, such as Doxil, in the three-drug combination may result in less severe side effects.

Doxil kills myeloma cells by damaging their DNA. It has the same active ingredient as the chemotherapy agent doxorubicin ^[10] (Adriamycin), but in Doxil the active ingredient is coated so that it stays in the body longer.

Based on previous Phase 2 and Phase 3 studies in relapsed and refractory myeloma patients that dem­on­strate the addition of Doxil to two- or three-drug regimens can improve re­sponse rates or deepen re­sponses, particularly when used in combination with Revlimid. the in­vesti­gators wanted to test the efficacy and safety of Doxil in combination with Revlimid and low-dose dexa­metha­sone in newly diagnosed multiple myeloma patients.

Study Design

The Phase 2 study was conducted at the Moffitt Cancer Center in Tampa, Florida. Patient enrollment began in February 2008 and continued through February 2011.

The study included 57 previously untreated multiple myeloma patients with a median age of 63 years; 22 per­cent of patients carried high-risk chromosomal abnormalities.

The first half of the study participants began treatment receiving 25 mg of Revlimid on days 1 to 21, 40 mg of dexa­metha­sone on days 1 to 4, and 40 mg/m² of Doxil on day 1 of a 28-day treatment cycle.

Many of these patients experienced severe to life-threatening side effects, including 48 per­cent with dangerously low white blood cell counts and 20 per­cent with fatigue. Overall, 24 per­cent required Doxil dosage reductions and 14 per­cent discontinued therapy after just one cycle.

Based on these initial findings, the in­vesti­gators decreased the starting dose of Doxil from 40 mg/m² to 30 mg/m².

The remaining patients were treated from the beginning according to the new protocol. Of these patients, 36 per­cent required further Doxil dosage reductions, but only 7 per­cent discontinued the therapy after one cycle. The in­vesti­gators also found that the rate of severe to life-threatening side effects decreased.

The 57 patients received a median of six cycles of Revlimid-Doxil-dexa­metha­sone induction therapy.

After induction therapy, 32 per­cent of patients proceeded with maintenance therapy that consisted of 25 mg of Revlimid on days 1 to 21 and 40 mg of dexa­metha­sone on days 1 to 4 of a 28-day cycle. The standard Revlimid dose of 25 mg is now considered high for maintenance therapy; more recent studies use 10 mg of Revlimid for maintenance therapy.

Forty-seven per­cent of patients proceeded to stem cell transplantation with high-dose melphalan ^[11] (Alkeran).

The remaining 21 per­cent of patients either had stable or progressive disease and received other drug therapies or withdrew consent.

Results

Overall, 77 per­cent of patients responded to treatment, with 7 per­cent achieving a stringent com­plete re­sponse, 7 per­cent a com­plete re­sponse, 28 per­cent a very good partial re­sponse, and 25 per­cent a partial re­sponse.

Of the patients who started treatment at 40 mg/m² of Doxil, 72 per­cent responded, with 3 per­cent achieving a stringent com­plete re­sponse, 14 per­cent a com­plete re­sponse, 31 per­cent a very good partial re­sponse, and 24 per­cent a partial re­sponse. Surprisingly, more patients who received 30 mg/m² of Doxil as a starting dose responded (82 per­cent), with 0 per­cent achieving a stringent com­plete re­sponse, 11 per­cent a com­plete re­sponse, 25 per­cent a very good partial re­sponse, and 46 per­cent a partial re­sponse.

The median progression-free survival was 28 months.

Among the 22 per­cent of patients with high-risk chromosomal abnormalities, the progression-free survival time was 18 months, compared to 31 months for patients without high-risk chromosomal abnormalities. Although this difference was not statistically significant due to the limited number of patients, the in­vesti­gators point out that these results indicate that the Revlimid-Doxil-dexa­metha­sone combination is not strong enough to overcome high-risk factors.

Patients who proceeded with stem cell transplantation had a median progression-free survival of 28 months, while patients who deferred transplantation and received maintenance therapy had a median progression-free survival of 35 months. According to the in­vesti­gators, these results further dem­on­strate the success of Revlimid maintenance therapy after induction therapy.

The in­vesti­gators point out that overall survival has not been reached yet. However, 98 per­cent of patients were alive one year after induction therapy and 80 per­cent were alive at two years.

Overall, 49 per­cent of patients experienced severely low white blood cell counts, which according to the in­vesti­gators, is a large increase over the 20 per­cent of patients treated with Revlimid and dexa­metha­sone alone who developed this side effect.

“At this time, it does not appear that the addition of Doxil offers an advantage over the Revlimid-dexa­metha­sone backbone,” said Dr. Baz. “It certainly increases the toxicities, but the efficacy is not obviously better.”

In addition, 16 per­cent of patients experienced severe anemia and 14 per­cent experienced severe fatigue during induction therapy.

The in­vesti­gators were able to control side effects by decreasing the Doxil dose from 40 mg/m² to 30 mg/m² . After the change in the treatment protocol, the induction therapy was better tolerated.

For example, severe low white blood cell counts decreased from 59 per­cent in the 40 mg/m² dosing group to 47 per­cent in the 30 mg/m² dosing group, severe anemia decreased from 21 per­cent to 11 per­cent, and fatigue decreased from 21 per­cent to 4 per­cent.

According to the in­vesti­gators, maintenance therapy with Revlimid and dexa­metha­sone was well tolerated. Although 44 per­cent of patients had severely low white blood cell counts, the in­vesti­gators consider the therapy safe because no significant new cancer formation occurred in any of the patients. Two patients developed skin carcinomas, but they were removed surgically.

“The main point of this study is that maintenance was very well tolerated despite the higher standard Revlimid dose, and we did not have an issue with second primary cancers,” said Dr. Baz.

For more information, please refer to the study in the American Journal of Hematology ^[12] (abstract).