Abstract
Chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. Based on promising experiences with a radiolabeled CXCR4 ligand (68Ga-pentixafor) for diagnostic receptor targeting, 177Lu- and 90Y-pentixather were recently developed as endoradiotherapeutic vectors. Here, we summarize the first-in-human experience in 3 heavily pretreated patients with intramedullary and extensive extramedullary manifestations of multiple myeloma undergoing CXCR4-directed endoradiotherapy. Methods: CXCR4 target expression was demonstrated by baseline 68Ga-pentixafor PET. Each treatment was approved by the clinical ethics committee. Pretherapeutic 177Lu-pentixather dosimetry was performed before 177Lu-pentixather or 90Y-pentixather treatment. Subsequently, patients underwent additional chemotherapy and autologous stem cell transplantation for bone marrow rescue. Results: A remarkable therapeutic effect was visualized in 2 patients, who showed a significant reduction in 18F-FDG uptake. Conclusion: CXCR4-targeted radiotherapy with pentixather appears to be a promising novel treatment option in combination with cytotoxic chemotherapy and autologous stem cell transplantation, especially for patients with advanced multiple myeloma.
Multiple myeloma is a cancer arising from clonally expanding plasma cells. Despite treatment advances such as proteasome inhibitors and immunomodulatory drugs alone or in combination with stem cell transplantation (SCT), multiple myeloma invariably relapses (1–3) and thus remains incurable. The low response rates to current therapy are in part explained by the emergence of multiple clones, leading to pronounced inter- and intratumor heterogeneity and rapid development of resistance (4,5). Therefore, novel strategies facilitating effective myeloma cell kill are urgently needed.
In cancer, overexpression of chemokine receptor 4 (CXCR4) and its activation by stromal cell–derived factor 1 binding are key triggers for tumor growth, progression, invasion, and metastasis (6–8). CXCR4 is overexpressed in multiple myeloma cells (9,10). Wester’s group has successfully developed a radiolabeled CXCR4 ligand (68Ga-pentixafor) for PET imaging (11,12). Proof of concept for visualization of CXCR4 expression has recently been demonstrated in patients with lymphoma (13) and multiple myeloma (14). To transfer this targeting vector to a therapeutic scenario, derivatives of the compound allowing labeling with various α- and β−-emitters have been developed. Here, we report our first experience with CXCR4-targeted endoradiotherapy in combination with high-dose chemotherapy and autologous SCT applied in 3 patients with advanced and heavily pretreated multiple myeloma.
MATERIALS AND METHODS
Subjects
Three patients (2 men and 1 woman aged 51, 62, and 66 y) with relapsed multiple myeloma were studied. Prior chemotherapies included lenalidomide, bortezomib, pomalidomide, and carfilzomib in various combinations. All patients had undergone autologous SCT and presented with clinically active disease and especially extensive extramedullary disease.
CXCR4 expression was confirmed by imaging in all 3 patients using 68Ga-pentixafor PET/CT. 18F-FDG PET/CT was additionally performed to measure glycolytic activity in active myeloma lesions. The patient characteristics are presented in Table 1. Given the lack of alternative treatments—and in view of the extensive extramedullary disease, documented CXCR4 expression, and availability of bone marrow for marrow rescue—an interdisciplinary board of specialists opted for CXCR4-targeted endoradiotherapy combined with high-dose chemotherapy and autologous SCT. The clinical ethics committee of our institution (Universitätsklinikum Würzburg) approved each individual treatment on a compassionate-use basis (German Drug Act, §13,2b). All subjects gave written informed consent before receiving the therapy.
Patient Characteristics
Dosimetry
As part of this prospective protocol, a preendoradiotherapy dosimetric calculation using SPECT/CT and serial planar imaging was performed on all 3 patients after intravenous injection of approximately 200 MBq of 177Lu-pentixather without nephroprotective medication. This was done to record sites of unexpected tracer accumulation that may denote potential toxicity, determine the organ radiation doses, and estimate the achievable tumor doses. The absorbed doses in tumors and organs were assessed by analyzing regions of interest in multiple planar total-body images to obtain pharmacokinetic data and a single SPECT/CT scan to scale the pharmacokinetic curve. All images were acquired using dual-head γ-cameras (Symbia E for planar imaging, Symbia T2 calibrated from phantom measurements with 177Lu activity standards for SPECT/CT imaging; Siemens) equipped with medium-energy collimators. Pharmacokinetic data were fitted by biexponential functions. SPECT/CT data were reconstructed using 3-dimensional ordered-subsets expectation maximization (6 subsets, 6 iterations, 6-mm gaussian filter) with corrections for scatter and attenuation to obtain absolute activity quantification in voxels sized 0.11 cm3. The 1-mL volume with the highest activity concentration was termed the maxV.
Therapy
Consistent with experience with peptide receptor radionuclide therapy in neuroendocrine tumor patients, preendoradiotherapy dosimetry identified the kidney as the dose-limiting organ. The administered endoradiotherapy activities were chosen to target at 23 Gy in the maxV. Accordingly, patients 1 and 2 were treated by intravenous infusion of 15.2 and 23.5 GBq of 177Lu-pentixather, respectively. Additional posttherapy dosimetry scans were obtained in both patients. In neuroendocrine tumor patients, the high-energy emitter 90Y has been shown to be more effective than 177Lu for treating larger lesions (15,16). Therefore, a 6.3-GBq infusion of 90Y-pentixather was administered in one patient (patient 3) with larger myeloma lesions. In an attempt to further reduce renal toxicity, 25 g of l-arginine and 25 g of l-lysine (pH 7.0, diluted in 2 L of normal saline), were intravenously administered over 4 h beginning 30 min to 1 h before endoradiotherapy as previously recommended for neuroendocrine tumor patients undergoing peptide receptor radionuclide therapy (17). Vital signs, complete blood count, and chemistry including kidney and liver function were documented as acute adverse events during the infusion and within 7 d after administration.
Response Assessment
Nonmetabolic myeloma response was assessed according to the criteria of the International Myeloma Working Group (18). Additionally, assessment by 18F-FDG PET/CT early (within 21 d) after treatment was available in patients 1 and 3. Assessment for minimal residual disease as defined by Munshi and Anderson was not performed (19).
RESULTS
Pentixafor PET and Dosimetry
All patients showed intense CXCR4 expression in the intra- and extramedullary myeloma lesions on 68Ga-pentixafor PET. All hypermetabolic lesions on 18F-FDG PET/CT exhibited concordant 68Ga-pentixafor uptake (Fig. 1A). Intra- and extramedullary manifestations showed no differences in 68Ga-pentixafor positivity.
(A) In patient 3 before pentixather therapy, maximum-intensity projections of 68Ga-pentixafor and 18F-FDG PET/CT indicate high CXCR4 expression in multiple extra- and intramedullary 18F-FDG–avid myeloma lesions. Corresponding 18F-FDG PET/CT image 2 wk after 90Y-pentixather shows complete metabolic response. (B) Scintigraphic images of patient 1 at 24 h and 15 d after 15.2 GBq of 177Lu-pentixather confirm binding to CXCR4 target. Visual difference in tumor-to-background ratios is due to reduced background uptake at later time point and longer emission times due to lower count rates.
Since the bone marrow was one of the main therapeutic targets, a high radiation dose to this organ and myelosuppression were expected. The kidneys were the dose-limiting organs as determined by pretreatment dosimetry (Table 1). In relation to the respective tolerable organ doses, the kidney doses were higher than the liver doses in all 3 patients in pretreatment dosimetry and remained relatively higher in patients 1 and 2 during therapy, although nephroprotective treatment reduced the mean kidney dose by about 45% to 0.57 and 0.50 Gy/GBq, respectively. Therapeutic tumor doses of up to 60 Gy in patient 1 and 71 Gy in patient 2 were determined for the voxels with the highest activity concentration; corresponding maxVs were 53 and 70 Gy, respectively (Table 1). Up to an 84-Gy maximum voxel dose and 71 Gy in maxV were predicted for patient 3 on the basis of pretherapeutic measurements of the 177Lu-pentixather kinetics decay corrected for 90Y-pentixather.
Therapy and Posttherapy Images
No acute adverse effects were associated with 177Lu- and 90Y-pentixather therapy during the first 14 d after infusion. No changes in vital signs occurred. Posttherapeutic scintigraphic imaging after 177Lu-pentixather therapy, including SPECT/CT and serial planar scans, demonstrated high pentixather uptake in all tumor lesions, consistent with diagnostic 68Ga-pentixafor PET/CT and pretherapeutic 177Lu-pentixather dosimetry scans. In one patient, additional imaging could be obtained as late as 14 d after injection of the radiopharmaceutical and demonstrated persistent pentixather retention (Fig. 1B).
Response Assessment with 18F-FDG PET/CT and Serum Parameters
Two of the 3 patients underwent 18F-FDG PET/CT for response assessment 14 and 21 d after treatment. Patient 1 (treated with 177Lu-pentixather) showed a partial response with a reduction of SUVmax by greater than 35% in all lesions. Patient 3 had a complete metabolic response after 90Y-pentixather treatment, showing visual resolution of all previous 18F-FDG–positive lesions (Fig. 1). Consistently, a more than 50% decrease in the difference between involved and uninvolved serum free light chain levels was observed in patients 1 (90.0 mg/L before therapy, 23.0 mg/L after 177Lu-pentixather, and 11.8 mg/L after SCT) and 3 (385.0 mg/L before therapy and 9.1 mg/L after 90Y-pentixather and SCT). Patient 2 presented with sepsis shortly after autologous SCT and therefore did not undergo restaging with 18F-FDG PET/CT. None of the 3 subjects underwent minimal residual disease evaluation with bone marrow examination and fluorescence-activated cell analysis for myeloma.
Outcome
After showing a partial response at the first posttherapeutic assessment by 18F-FDG PET/CT, patient 1 underwent subsequent high-dose chemotherapy with autologous stem cell support. This patient, however, died 6 mo after pentixather therapy from myeloma relapse. Patient 2 died from sepsis 3 wk after pentixather therapy followed by high-dose chemotherapy (BEAM) and autologous SCT. The complete metabolic responder (patient 3) died 3 mo after 90Y-pentixather therapy because of tumor progression with central nervous system disease. In none of the patients were any acute adverse events recorded immediately during or within 1 wk after pentixather therapy; in particular, no nausea or cardiac, renal, or hepatic toxicity occurred.
DISCUSSION
Here, we report the first-in-human administration of CXCR4-targeted radionuclide therapy using 177Lu- and 90Y-labeled pentixather in patients with advanced multiple myeloma. Application of 177Lu- and 90Y-pentixather was safe and well tolerated, without any acute nonhematologic adverse effects despite a prior history of multiple courses of chemotherapy, including novel agents and autologous SCT. However, pentixather treatment resulted in myeloablation in all 3 patients and might have contributed to the leukopenia and sepsis seen in patient 2. As all 3 patients had extensive extramedullary disease manifestations, pentixather was accordingly combined with preemptive autologous stem cell rescue. Even after a single application, pentixather was retained in all multiple myeloma lesions for up to 2 wk after initial treatment (Fig. 1B). Prolonged retention of pentixather will lead to a higher target radiation dose, which might be associated with a higher probability of treatment response.
In the 2 patients evaluable for response by 18F-FDG PET/CT, one partial metabolic imaging response could be documented, as well as one complete response of all extramedullary lesions. All myeloma lesions had been refractory to all standard and novel regimens; thus, CXCR4-directed radiotherapy might prove a powerful new tool in addressing both intra- and extramedullary disease despite the limited progression-free survival documented in the patients (3–6 mo). Because advanced multiple myeloma represents multiclonal disease, the β-emitting endoradiotherapy might also affect cell clones not directly targeted by pentixather because of the radiation-induced bystander effect. This may indeed be one of the key advantages of endoradiotherapy. However, because of the significant radiation dose administered to the bone marrow in these patients, a combination of CXCR4-directed radiotherapy with high-dose chemotherapy and consecutive stem cell support appears mandatory. All patients underwent CXCR4-targeted radiotherapy followed by high-dose conventional chemotherapy and consecutive SCT. In this setting, the therapeutic effects of each individual treatment component could not be dissected. However, because all patients had been heavily pretreated with multiple chemotherapeutic regimens and were presenting with refractory disease with lack of alternative treatments, the observed metabolic response was at least partially due to the CXCR4-directed endoradiotherapy. Nevertheless, this promising proof of principle in 3 patients requires further evaluation, including safety and toxicity studies, as well as prospectively designed clinical trials with well-defined primary and secondary endpoints, especially in view of the pivotal role CXCR4 seems to play in the pathogenesis of not only hematologic malignancies (6,9,10) but also solid tumors (20).
CONCLUSION
CXCR4-directed endoradiotherapy in addition to chemotherapy and autologous SCT is feasible and produced a promising response in our patients, warranting further investigation as a treatment option in heavily pretreated patients with advanced multiple myeloma, especially with extramedullary disease.
DISCLOSURE
The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. Saskia Kropf and Hans-Juergen Wester are CEOs of Scintomics. Ulrich Keller received support from Deutsche Forschungsgemeinschaft SFB 824 and the German Cancer Consortium. Constantin Lapa, Katharina Lückerath, Andreas K. Buck, Hermann Einsele, and Stefan Knop received support from the Wilhelm-Sander-Stiftung (grant 2013.906.1). No other potential conflict of interest relevant to this article was reported.
Acknowledgments
We thank Simone Seifert, Simone Groß, Michael Schulze-Glück (members of the nuclear medicine PET team), Inge Grelle, and the whole staff of Ward M63 for their support and assistance. We further thank Matthias Konrad and Daniel Di Carlo for their dedication and excellent work in the synthesis of pentixather.
Footnotes
- © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
REFERENCES
- Received for publication September 23, 2015.
- Accepted for publication October 26, 2015.
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