Myeloablative Radioligand Therapy Targeting C-X-C Motif Chemokine Receptor 4 in Advanced Multiple Myeloma

Abstract

Background: Markedly expressed on hematopoietic stem cells, C-X-C motif chemokine receptor 4 (CXCR4)-directed radioligand therapy (RLT) has been used in relapsed/refractory (r/r) MM to prepare for hematopoietic stem cell transplantation (HSCT). We aimed to determine the myeloablative efficacy of CXCR4 RLT in MM patients and assessed the safety profile of this treatment.

Methods: Thirty-eight patients with r/r MM were treated with 40 cycles of CXCR4-targeting [ 90 Y]Y-PentixaTher or [ 177 Lu]Lu-PentixaTher. Myeloablative dynamics were closely monitored by examining hematologic parameters before the application of RLT (day 1), on day 2, and on the start day of conditioning chemotherapy (CON, median day 10). Laboratory parameters evaluating organ toxicity were collected and categorized following the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Cairo-Bishop classification was also applied to identify patients experiencing laboratory tumor lysis syndrome (TLS) caused by RLT. After CON, we determined the rate of patients receiving hematopoietic stem cell transplantation (HSCT) followed by successful neutrophile engraftment.

Results: Forty cycles of CXCR4-directed RLT were applied. Myeloablative effects resulted in an 81.8% decline in leukocytes and a 69.4% decrease in neutrophil levels till the day of CON ( P <0.0001, respectively), followed by platelets (63.1%; P <0.0001) and hemoglobin (9%; P =0.002). We observed 58 AE Events (1/58 [1.7%], ≥ grade 3). CON could be applied successfully after 39/40 (97.5%) cycles. After CON, in 39/39 (100%) of the cycles, HSCT was conducted, and successful neutrophil engraftment was reached after 37/39 (94.9%) of these cycles.

Conclusions: CXCR4-directed RLT exerted relevant myeloablative effects. When performing HSCT after applying additional CON, successful neutrophile engraftment was reached in the vast majority of the cases.

Keywords: C-X-C motif chemokine receptor 4; CXCR4; multiple myeloma; radioligand therapy.

FIGURE 1

Myeloablative dynamics after the application of CXCR4-directed RLT. Boxplots display median % changes from day 0 (day of RLT) to day 2 as well as to the day of CON, whiskers indicating the respective range. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

FIGURE 2

Laboratory-based short-term organ toxicity after CXCR4-directed RLT. Boxplots display median % changes from day 0 (day of RLT) to day 2 as well as to the day of CON, whiskers indicating the respective range. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. GFR indicates glomerular filtration rate; GOT, glutamic-oxaloacetic transaminase; GPT, glutamate-pyruvate transaminase; GGT, γ-glutamyltransferase.

FIGURE 3

Laboratory TLS parameters after CXCR4-directed RLT. Boxplots display median % changes from day 0 (day of RLT) to day 2 as well as to the day of CON, whiskers indicating the respective range. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.