Busulfan Plus Melphalan for ASCT in Myeloma

Susan Mayor

September 30, 2015

ROME ― Early results from a study investigating intravenous busulfan (multiple brands) plus melphalan (Alkeran, GlaxoSmithKline) as enhanced conditioning therapy before autologous stem cell transplantation (ASCT) in patients newly diagnosed with multiple myeloma are encouragingand show good safety.

Several approaches have been proposed to improve the outcome of ASCT: incorporating novel agents into the induction regimen, enhancing the conditioning regimen immediately before transplantation, and using maintenance therapy following ASCT.

The Myeloma Canada Research Network (MCRN)-001 Trial is investigating all three approaches. Newly diagnosed myeloma patients who are eligible for ASCT are being treated with standard novel- agent induction regimens containing bortezomib (Velcade, Millennium Pharmaceuticals, Inc). They are then given a combination of busulfan and melphalan as the pretransplant conditioning regimen, followed by lenalidomide (Revlimid, Celgene Corporation) maintenance therapy until disease progression after ASCT.

The latest results reported here at International Myeloma Workshop (IMW) 2015 for 71 evaluable patients (median age, 57 years) show that no ASCT-related deaths have occurred during a median follow-up period of 18.8 months (range, 5.9-27.4 months). Five patients experienced disease progression during this period.

Serious adverse events were reported in 15 patients in the study. These included atrial fibrillation (grade 2-3) in two patients; acute kidney injury (grade 3) in three patients; bacteremia/sepsis (grade 3-4) in two patients, and febrile neutropenia (grade 3) in two patients.

Mucositis was the most common adverse event overall, with 46 events occurring (38 grade 2; seven grade 3; one grade 4). Five events of liver toxicity of grade 3-4 were reported.

"Busulfan/melphalan conditioning treatment followed by lenalidomide maintenance is well tolerated, with no deaths to date," reported lead author Donna Reece, MD, director of the program for myeloma and related disorders at the Princess Margaret Hospital, Toronto, Canada, at a poster session during the workshop.

Improving Myeloma Status Assessment

Researchers are using the trial to try out a new approach with the aim of determining myeloma status more accurately by using both serial bone marrow minimal residual disease (MRD) detection by multiparameter flow cytometry and a newly developed serum assay, the Hevylite chain (HLC) assay, to monitor evidence of myeloma throughout the study.

The HLC assay provides an automated evaluation of the serum heavy-to-light chain ratio of the involved and uninvolved immunoglobulins in myeloma.

Results reported from the Canadian trial showed that fewer than half (43%) of evaluable patients tested negative for marrow minimal residual disease at day 100. All of these results were less than or equal to partial response (PR) by conventional parameters. The strongest correlation between MRD and HLC status was observed in MRD-negative patients. In nearly two thirds (62%) of these patients, the involved HLC ratio was normalized.

The best conventional immunoglobulin response post induction in 71 patients was complete response (CR), seeb in 5 (7%) patients; very good partial response (VGPR), seen in 26 (37%) patients; partial response (PR), in 31 (44%) patients; minimal response (MR), in 4 (5.5%) patients; and stable disease (SD), in 1 (1%) patient (see Table 1).

Table 1. Best Conventional Response (EBMT Modified Criteria)

Response Post Induction, 71 Evaluable Patients, No. (%) Day 100, 60 Evaluable Patients, No. (%) Maintenance, 59 Evaluable Patients, No. (%)
Complete response 5 (7) 10 (17) 19 (32)
Very good partial response 26 (37) 30 (50) 33 (56)
Partial response 31 (44) 18 (30) 7 (12)
Minimal response 4 (5.3) 1 (1.5) 0
Stable disease 1 (1.4) 1 (1.5) 0


In the 60 patients who have reached day 100 post ASCT, with regard to immunoglobulin response, CR was seen in 10 (17%), VGPR in 30 (50%), PR in 18 (30%), MR in 1 (1.5%), and SD in 1 (1.5%).

Table 2. Comparison of Response Rates by Marrow Flow Cytometry for MRD and Serum Hevylite Assay After Induction Chemotherapy and at Day 100 Post ASCT

  No. Evaluable No. MRD Negative No. MRD Negative (%) No. MRD Negative (%) No. MRD Positive (%) No. MRD Positive (%) No. MRD Positive (%)
    Total Hevylite Abnormal Hevylite Abnormal Total Hevylite Abnormal Hevylite Abnormal
After induction chemotherapy 71 19 15 (79%) 1 (5.3%) 47 20 (43%) 14 (30%)
At day 100 post ASCT 60 26 16 (62%) 2 (8%) 33 17 (52%) 11 (33%)


"Further follow-up is required to determine the long-term outcomes, the dynamics, and prognosis of MRD negativity and the relationships between MRD status and involved HLC ratio," Dr Reece suggested.

The MCRN-001 trial is funded by Myeloma Canada, Otsuka, Celgene, and the Binding Site. Dr Recce has received research funding and honoraria from Otsuka, Millennium, and Novartis; has served as a consultant and has received honoraria and research funding from Celgene and Janssen; has received research funding from BMS and Merck; and has received honoraria from Amgen.

International Myeloma Workshop (IMW) 2015: Abstract BP-014. Presented September 24, 2015.


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