Successful Salvage and Hematopoietic Reconstitution with Bortezomib and Melphalan in Relapsed and Refractory Multiple Myeloma

The management of relapsed and refractory multiple myeloma (RRMM) patients who have failed older conventional and more recent novel agents remains challenging. Patients typically have short response duration, develop prolonged cytopenias and are usually not eligible for clinical trials due to inadequate bone marrow reserve. Furthermore, these patients often have inadequate numbers of stem cells (<3 × 10(6) CD34/kg) remaining for a myeloablative transplant. In patients who have remaining stem cells in storage, we have developed an algorithm to enable the reconstitution of hematopopiesis to allow enrollment in clinical trials. In addition, our algorithm tests the synergy of bortezomib and non-myeloablative doses of melphalan with stem cell boost support. We have treated 6 patients with RRMM who have failed novel agents (including bortezomib) and chemotherapy (dexamethasone, cytoxan, etoposide, cisplatin, and doxil) and who have had limited duration of response previously with high dose melphalan. All patients were cytopenic (ANC < 1000 and/or platelets < 50,000/mcl) and thus not eligible for existing clinical trials. The melphalan was administered intravenously at 30–50 mg/m2 on days 1 and 4, dependent on the patient age and performance status. Bortezomib was administered 1.3 mg/m2 by intravenous push prior to the melphalan on the same schedule. The patients then received 1.5 to 2.2 × 10(6) CD34+ cells/kg. (depending upon the amount of remaining stem cells). All patients were treated in the outpatient clinic. 3 patients required hospitalization for neutropenic fever; the median hospitalization duration was 3 days (range 0 to 6). The overall response (MR, PR, VGPR) was 100% including: 5 PR and 1 VGPR.. More importantly, all patients achieved improved hematopoiesis with WBC > 2000 and platelets > 50,000/mcl. The median duration of response exceeded 2 months. All patients were able to proceed on to new clinical trials. We conclude that the combination of bortezomib and melphalan produces an effective salvage strategy, with hematopoietic reconstitution in RRMM. This non-myeloablative approach serves as a bridge for disease control and hematopoietic reconstitution to allow for subsequent eligibility on clinical trials. We recommend that during stem cell collection that sufficient hematopoietic stem cells be stored to support future myeloablative and similar non-myeloablative chemotherapy regimens.