Low/Intermediate Doses of Melphalan in the Treatment of Triple-Exposed/Refractory Multiple Myeloma: A Case Series from a Reference Center for the Treatment of Multiple Myeloma in Colombia
Authors: Martinez-Cordero Humberto , Mantilla Juan-Carlos , Valdes-Cespedes Jaime , Ospina Juan , Spirko Maria , Alcala Sebastian , Prada-Serrano Mayra , Leon-Chavez Fabian , Pereira-Garzon Mario 
Published: December 2024

Background
The treatment of relapsed/refractory (RR) multiple myeloma (MM) has evolved dramatically over the past ten years with novel therapies, including proteasome inhibitors (PIs), second- and third-generation immunomodulators (IMiDs), and anti-CD38 monoclonal antibodies (mAbs). This has led to an increasing number of triple-class-exposed (TCE) patients who may also achieve triple-, quadruple-, and penta-refractory status. Data on real-world outcomes for the spectrum of advanced and heavily pretreated RRMM patients are limited, where the most effective therapeutic options appear to be T-cell redirection therapies, chimeric antigen receptor T-cell therapy (CAR T), and bispecific antibodies (BiTES) not widely available in low- or middle-income countries. We present a case series of 5 patients treated with low/intermediate doses of intravenous melphalan. This work demonstrates that low- or intermediate-dose melphalan could be a therapeutic alternative to rapidly control triple-exposed/refractory multiple myeloma in patients without immediate access to more novel therapies.
Methods
We present a case series of consecutive patients treated at the National Cancer Institute of Colombia with a diagnosis of triple-exposed multiple myeloma who had also been refractory to at least four drugs, including bortezomib, lenalidomide, daratumumab, carfilzomib, and pomalidomide, without access to CAR T-cell therapy, bispecific antibodies, or antibody conjugates; or to clinical trials. The institutional ethics committee approved this work, and all patients signed informed consent for treatment and data collection.
Results
Five patients were included, three women and two men, with a median age of 67 years (55-80). Two patients had an ECOG score of 1, and three had an ECOG score of 2. The time they have elapsed since myeloma diagnosis was, on average, 5.2 years. All patients had received at least three lines of therapy; three patients had undergone autologous transplantation whose duration of response had been greater than three years. All patients were triple-class exposed; four patients were penta-refractory, and one patient was quadruple-refractory and was not a candidate for the use of carfilzomib.
All patients had measurable disease, two IgG kappa, one IgA lambda, one IgA kappa and one for lambda free light chain. Three patients achieved at least a very good partial response (VGPR) after administration of low/intermediate dose IV melphalan (25 mg/m2), one patient achieved a partial response, and one patient had stable disease. The average M protein reduction percentage in patients with at least VGPR was 96.7%. The reduction in M protein in the patient who achieved partial response was 61%. This patient received two low/intermediate doses of melphalan, initially achieving a percentage reduction in M protein of 32% with the first dose. One patient has had progressive biochemical disease at month 5, two at month 4, and one patient has not relapsed and has sustained a response for two months as of the date of this report. No patient has had a clinical relapse with CRAB.
The average duration of neutropenia after melphalan infusion was 4.4 days (1-14). Only one patient developed uncomplicated febrile neutropenia. Red blood cell transfusion was not required, but three patients required platelet transfusion. Hematologic recovery occurred in all patients. All received Granulocyte colony-stimulating factor (G-CSF) from day +6 after melphalan infusion.
Discussion
Low/intermediate dose melphalan is a safe and effective therapeutic option to rapidly control multiple myeloma in patients who do not have access to novel treatment strategies such as CAR T cell therapy, BiTES or antibody-drug conjugates (ADCs), especially in low- and middle-income countries. This therapy should be considered in patients who have not been previously exposed to melphalan, patients exposed to high doses of melphalan and autologous transplantation with a reasonable duration of response.