Results from a small Phase 2 study conducted in Italy demon­strate that se­quen­tial treatment with novel agents and au­tol­o­gous stem cell trans­plan­ta­tion with intermediate-dose melphalan is a safe and ef­fec­tive treat­ment for older, newly diagnosed myeloma patients.

“This is the first study with a sequential approach of Velcade in­duc­tion, autol­o­gous stem cell trans­plan­ta­tion, and Revlimid main­te­nance,” said the study’s lead investigator, Dr. Antonio Palumbo of the University of Torino in Italy.

The regimen was safest in patients under the age 70; patients aged 70 years and older ex­peri­enced more treatment-related side effects and deaths, which were mostly due to infections.

Dr. Palumbo and his colleagues suggest a need for more care­ful selection of this treat­ment in elderly pa­tients, such as ex­clud­ing patients with other diseases in addi­tion to myeloma. They also suggest that the use of pre­venta­tive antibiotics and weekly administration of dexamethasone (Decadron) might reduce the fre­quen­cy of infections.

Background

The introduction of novel agents such as thalidomide (Thalomid), Revlimid (lenalidomide), and Velcade (bortezomib) revolutionized the treatment of multiple myeloma within the last decade, both as upfront as well as consolidation and maintenance treatments. Research has shown that these new drugs significantly improve treatment outcomes, especially when used in combination therapies.

Currently, myeloma patients who are eligible for and choose to undergo stem cell transplantation receive a sequential treatment regimen that begins with induction therapy, followed by high-dose chemotherapy and autologous stem cell transplantation, and often ending with consolidation and maintenance therapies.

The first treatment given for myeloma is referred to as induction therapy. In this study, researchers used a combination of Velcade, Doxil (doxorubicin liposomal), and dexamethasone, which has resulted in high response rates in multiple previous clinical trials (see related Beacon news).

After induction therapy, patients collect stem cells for a future transplant. After receiving high-dose chemo­ther­a­py, which often kills off both tumor cells and healthy cells, patients undergo an autologous stem cell transplant, in which they are infused with the previously collected healthy stem cells to begin producing cells again.

Following transplantation, patients may receive consolidation therapy and/or maintenance therapy.  Con­sol­i­dation therapy is a short course of treatment used to improve a patient’s response to previous treat­ments. In contrast, maintenance therapy is a prolonged, often low-dose, form of treatment given after a patient’s initial therapy. It is used to prevent disease pro­gres­sion while also maintaining a favorable quality of life.

Study Design

In the current study, Italian researchers assessed the long-term efficacy and safety of sequential treatment with Velcade-based induction therapy, two back-to-back autologous stem cell transplants with intermediate-dose melphalan, followed by Revlimid-based consolidation and maintenance therapy.

The researchers enrolled 102 myeloma patients at 17 centers in Italy between October 2005 and July 2007. In order to be eligible for the study, patients must have had newly diagnosed disease and must have been between 65 and 75 years old, or younger but unable to receive high-dose chemotherapy. The median patient age was 67 years.

Patients received induction therapy with four 21-days cycles of Velcade, Doxil, and dexamethasone. In order to mobilize stem cells for collection, patients received cyclophosphamide (Cytoxan) and granulocyte colony-stimulating factors. Patients then underwent two autologous stem cell transplants, each preceded by intermediate-dose (100 mg/m²) melphalan (Alkeran) chemotherapy.

For patients whose disease did not progress at two to four months after the second transplant, con­soli­da­tion therapy was given as four 28-day cycles of Revlimid and prednisone, followed later by Revlimid alone as maintenance therapy until disease progression.

Physicians assessed the efficacy of the treatment every four weeks. Safety was assessed every two weeks during consolidation therapy and then every four weeks during maintenance therapy.

The median follow-up time was 66 months.

Study Results

Of the 102 patients enrolled in the study, 95 percent completed at least three cycles of induction therapy, 78 percent completed the stem cell transplantation phase, 72 percent received at least three cycles of con­soli­da­tion therapy, and 65 percent received maintenance therapy.

Among the 102 patients that the researchers intended to treat, 55 percent achieved at least a very good partial response after induction therapy. The share increased to 76 percent after transplantation, 80 percent after consolidation therapy, and 82 percent after maintenance therapy.

More specifically, 12 percent achieved a complete response after induction therapy and 33 percent after transplantation. According to the researchers, the complete response rates seen after induction therapy and after transplantation are similar to those seen in younger patients with other Velcade-based three-drug regi­mens.

Additionally, the researchers observed that consolidation and maintenance therapy further improved outcomes. The complete response rate increased to 49 percent after consolidation therapy and 54 percent after maintenance therapy, which according to the researchers is a clear sign that the sequential approach increased the depth of response.

Overall, the median progression-free survival was 48 months, and the five-year progression-free survival rate was 43 percent. The median overall survival was not reached, and the five-year overall survival rate was 63 percent.

Achievement of a complete response was associated with improvements in both progression-free and overall survival. The median progression-free survival was 63 months and the five-year overall survival rate was 83 percent in patients who achieved a complete response.

The results also showed that patients diagnosed with Stage I disease, according to the International Stag­ing System, and who did not have t(4;14) or del17 chromosomal abnormalities, which are associated with poor prognosis, had reduced risk of progression and death, compared to patients with more advanced disease or poor chromosomal profiles.

The most common severe side effects included low platelet counts (91 percent), low white blood cell counts (90 percent), infections (33 percent), peripheral neuropathy (numbness and pain in hands and feet ) (18 percent), gastrointestinal issues (18 percent), skin-related side effects (10 percent), and blood clots (7 per­cent).

At the time of analysis, 10 patients had died during treatment and 30 had discontinued treatment, primarily due to side effects. All side effect-related deaths occurred during the induction and transplantation phases.

The rate of transplant-associated deaths was significantly higher in patients over the age of 70 (19 percent versus 5 percent).  Therefore, the researchers suggest that better patient selection may lead to reduced death rates.

For more information, please refer to the study in the journal Blood (full text) and a related commentary (full text) in the same journal.