First-in-human experience of radiopharmaceutical therapy with [177Lu]Lu-DOTATATE in patients with advanced multiple myeloma.

Introduction

Theranostics in nuclear medicine represents a transformative leap forward in precision oncology, integrating diagnosis and treatment through a targeted approach. By leveraging radiopharmaceuticals, radiotheranostics enables both the detection of diseases at a molecular level and the precise delivery of therapeutic radiation [ 1 ]. This concept has gained broad clinical acceptance, particularly with the success of somatostatin receptor (SSTR)-targeting agents in neuroendocrine tumours (NETs) through Peptide Receptor Radionuclide Therapy (PRRT) [ 2 ], and of prostate-specific membrane antigen (PSMA)-targeting agents in prostate cancer [ 3 ]. Notably, the latest generation PRRT agent, [ 177 Lu]Lu-DOTATATE, is now routinely used in managing gastroenteropancreatic NETs [ 4 ].

Multiple myeloma (MM), the second most common haematological malignancy, accounts for approximately 10% of all haematological malignancies and has seen a 126% increase in global incidence between 1990 and 2016 [ 5 ]. Despite substantial therapeutic progress, particularly with the advent of immunotherapies, MM remains incurable, necessitating new therapeutic approaches. SSTR expression in MM has been demonstrated through molecular imaging [ 6 – 8 ], positioning these receptors as promising targets within the radiotheranostics framework. Evidence suggests that SSTR expression may be enhanced in advanced disease stages, prompting investigation in relapsing and refractory MM patients. As part of the SCARLET trial ( NCT04379817 ), a prospective phase II study, we assessed SSTR expression using [ 68 Ga]Ga-DOTATATE PET imaging to evaluate the feasibility of SSTR-targeted therapy in this patient population. The results confirmed SSTR expression in MM and identified 60% of patients as potential candidates for PRRT [ 9 ]. Here, we report the world’s first administration of [ 177 Lu]Lu-DOTATATE in two patients with advanced MM enrolled in the SCARLET trial.

Methods

Subjects

Two heavily pretreated patients diagnosed with MM according to the International Myeloma Working Group (IMWG) received [ 177 Lu]Lu-DOTATATE on an off-label basis following their inclusion in the SCARLET trial ( NCT04379817 ). Both patients met the PRRT eligibility criteria defined in the study: identification of ≥ 3 [ 68 Ga]Ga-DOTATATE-positive lesions, absence of [ 18 F]F-FDG-avid lesions without corresponding [ 68 Ga]Ga-DOTATATE uptake, and no diffuse bone marrow uptake on [ 68 Ga]Ga-DOTATATE PET/CT. Patient characteristics are described in Table 1 . Both patients had adequate baseline haematological values (platelets > 150 × 10³/µl, lymphocytes > 0.9 × 10³/µl, hemoglobin > 12 g/dL). The treatment was approved by the multidisciplinary tumour board and the local ethics committee of Jules Bordet Institute (CE3817 and CE3493). Written informed consent was obtained from both patients.

Table 1 Patient characteristics Patient 1 Patient 2 Gender Male Female Age at diagnosis (y) 67 47 Durie-Salmon stage IIIA IIIA Immunoglobulin type IgA κ Light chains κ Cytogenetics Hyperdiploid t(11;14) ISS stage 2 Unknown R-ISS stage Unknown Unknown Number of prior treatment lines 4 4 Bone marrow transplant No Yes (autologous stem cell transplantation) Previous treatments Radiotherapy, bortezomib, melphalan, ixazomib, lenalidomide, pomalidomide, cyclophosphamide, belantamab Radiotherapy, bortezomib, lenalidomide, pomalidomide, cyclophosphamide, daratumumab Glomerular filtration rate ([ 99m Tc]Tc-DTPA) (mL/min/1.73 m²) 57.61 95.23 Para- or extramedullary involvement No No Number of lesions identified on baseline [ 18 F]F-FDG PET/CT 17 2 Number of lesions identified on baseline [ 68 Ga]Ga-DOTATATE PET/CT 18 6

[ 177 Lu]Lu-DOTATATE Treatment

A standard treatment protocol, as applied for NETs [ 10 ], was used. Standard activities of 7.4 GBq of [ 177 Lu]Lu-DOTATATE were administered intravenously following premedication with antiemetics (ondansetron 8 mg, methylprednisolone 40 mg and metoclopramide 20 mg) and nephroprotective perfusion of an amino acid solution (Aminosteril N-Hepa 8% (Fresenius Kabi)). Dosimetry of organs at risk was performed as previously described [ 11 ] (see Supplemental Material).

Case descriptions

Case 1

This patient received four injections of [ 177 Lu]Lu-DOTATATE, administered 8 to 9 weeks apart. The tolerance to the treatment was excellent, with no clinically significant adverse events. On the contrary, the patient described a gradual and marked improvement in overall clinical condition and quality of life, noticeable as early as after the first injection. He regained appetite, experienced reduced pain and fatigue, and showed improved mobility. His performance status improved from an ECOG score of 2 at baseline to 1 by the end of the treatment.

A transient, asymptomatic decrease in platelet and lymphocyte counts—typical adverse events associated with PRRT—was observed. Platelet count dropped to grade 3 after the third and fourth cycles, with nadirs occurring 4 to 6 weeks post-injection, followed by recovery to grade 1 within 2 months after the last injection. Lymphocyte counts declined to grade 4 after the second and subsequent cycles, with nadirs at 2 to 4 weeks post-injection (Figure S1 ), and had recovered to grade 2 at the last follow-up (7 months after the last administration).

Conventional serum and urine paraprotein measurements were not informative due to the non-secretory nature of the disease at this stage. The patient initially presented with an IgA κ secretory myeloma, which subsequently evolved into a non-secretory form. Imaging, however, demonstrated a gradual decrease in [ 18 F]F-FDG uptake across all lesions over the four treatment cycles, indicative of a continuous partial metabolic response at each assessment, with no new lesions detected (Fig. 1 A-B). Serial [ 68 Ga]Ga-DOTATATE PET/CTs performed after each PRRT cycle showed stable disease throughout the treatment course (Fig. 1 C-D).

At the most recent follow-up, 12 months after PRRT initiation, the patient remained free of both clinical and metabolic signs of disease progression.

Compared to dosimetric historical controls from PRRT in NETs, absorbed doses to the kidneys, liver, spleen, and red marrow were slightly elevated (Figure S4 and Table S3 ). This is likely attributable to infra-normal baseline kidney function, which may have prolonged the circulating time of [ 177 Lu]Lu-DOTATATE in the blood. Tumour dosimetry could not be performed due to the small volume of target lesions in this patient.

Case 2

This patient received two injections of [ 177 Lu]Lu-DOTATATE, administered 9 weeks apart. The treatment was generally well tolerated, with grade 1 nausea, bone pain and alopecia, and grade 2 fatigue reported. Lymphocyte counts dropped to grade 3 following both [ 177 Lu]Lu-DOTATATE injections, with nadirs occurring 7 days post-injection. Platelet counts also declined to grade 3 but were considered clinically non-significant and have remained stable since (Figure S2 ).

During the treatment phase, light chain levels remained stable according to IMWG response criteria (Figure S3 ). In terms of imaging, the first injection of [ 177 Lu]Lu-DOTATATE resulted in a partial metabolic response on [ 18 F]F-FDG PET/CT, with decreased uptake of [ 68 Ga]Ga-DOTATATE in 5 out of the 6 lesions described at baseline. No new lesions were detected on any imaging modality. The second injection led to a complete metabolic response on [ 18 F]F-FDG PET/CT in the metabolically active baseline lesions (Fig. 1 E-F). [ 68 Ga]Ga-DOTATATE PET/CT showed normalization of SSTR expression in all baseline lesions (Fig. 1 G-H). However, some previously silent/residual cranial lesions demonstrated discrete uptake on[ 68 Ga]Ga-DOTATATE PET/CT. Among them, only one—the posterior right cranial parietal lesion—became metabolically active (Figure S5 ). This was associated with a subtle biological disease progression at the end of treatment (Figure S3 ), and the lesion was subsequently treated with external beam radiotherapy 4 months after PRRT completion.

Despite a persistent complete metabolic response 3 months after the last [ 177 Lu]Lu-DOTATATE administration, the patient experienced continued biological progression, requiring a new line of systemic therapy. Treatment with teclistamab—a bispecific antibody that had become commercially available at that time—was initiated, leading to a complete and durable biological remission, ongoing for 27 months at the time of writing.

Absorbed doses to the kidneys, liver, spleen, and red marrow were within historical control values from PRRT in NETs (Figure S4 and Table S3 ). Similar to patient 1, tumour dosimetry could not be performed due to the small volume of target lesions.

Fig. 1 [ 18 F]F-FDG and [ 68 Ga]Ga-DOTATATE PET/CT MIP images at baseline and post [ 177 Lu]Lu-DOTATATE treatment. In patient 1 ( A-D ), a partial metabolic response was observed on [ 18 F]F-FDG PET/CT ( A-B ) and [ 68 Ga]Ga-DOTATATE PET/CT showed overall stable disease ( C-D ). In patient 2 ( E-H ), a complete metabolic response was obtained on [ 18 F]F-FDG PET/CT ( E-F , red arrows indicate the two metabolically active baseline lesions, black arrow indicates a [ 18 F]F-FDG stasis on the port-a-cath) and a normalization of [ 68 Ga]Ga-DOTATATE uptake was observed in all the baseline lesions ( G-H )

Discussion

To the best of our knowledge, this case series is the first documented use of [ 177 Lu]Lu-DOTATATE for the treatment of advanced MM, highlighting its promising safety profile and therapeutic potential in two patients. Most importantly, both patients experienced and maintained a significantly improved quality of life, comparable to that observed in NET patients after PRRT, thereby further strengthening the favourable tolerability and symptomatic benefit of [ 177 Lu]Lu-DOTATATE. In addition, the PRRT regimen, requiring only one injection every 8 to 12 weeks, stands in sharp contrast to the intensive and frequent administration schedules of most therapies in this setting, offering a meaningful advantage in terms of patient convenience and treatment burden.

The administration of [ 177 Lu]Lu-DOTATATE at standard activities of 7.4 GBq per cycle resulted in transient and reversible myelotoxicity, in line with safety findings from the NETTER-1 and NETTER-2 trials [ 2 , 12 ]. Myelotoxicity nadirs occurred at 1–4 weeks post-injection for white blood cells and 4–6 weeks for platelets, with (partial) recovery observed before subsequent cycles. In contrast to myeloablative approaches—such as CXCR4-targeted therapies, which require high-dose administration and stem cell transplantation, and are associated with significant toxicity, including sepsis [ 13 , 14 ]—PRRT appears to preserve quality of life while maintaining efficacy.

The efficacy of PRRT was evident in both patients, as shown by a progressive reduction in the metabolic activity of lesions after each treatment cycle, suggesting a cumulative therapeutic effect, and achieving at least biologically stable disease. Patient 1 showed a durable response, which is remarkable given the typical overall survival of 7–8 months in that setting [ 15 ]. Importantly, although [⁶⁸Ga]Ga-DOTATATE uptake in MM is typically lower than in NETs [ 9 , 10 ], it was sufficient to achieve a therapeutic response, aligning with our preclinical findings [ 16 ].

Discontinuation of treatment after 2 cycles in one patient was prompted by the complete suppression of SSTR2 expression, emphasizing the importance of timely reassessment for optimal therapy duration.

These first-in-human results suggest that PRRT could serve as an additional therapeutic modality in selected MM patients based on molecular imaging, expanding the PRRT theranostic paradigm beyond NETs. For example, PRRT could be considered as a bridging strategy to Chimeric Antigen T-cell Therapy (CART) in heavily pretreated MM patients, typically lacking treatment options at this particular stage. Alternatively, PRRT could be considered as a complementary approach to systemic therapies, targeting selected focal lesions.

In conclusion, the application of [ 177 Lu]Lu-DOTATATE in MM demonstrates encouraging efficacy and safety, with manageable toxicity and meaningful improvements in quality of life. Further clinical investigation is needed to validate these findings, and potentially extend PRRT indication to refractory MM. To this end, a phase II trial is currently being developed at our institution.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Abbreviations

Chimeric Antigen T-cell Therapy

International Myeloma Working Group

Multiple myeloma

Neuroendocrine tumour

Peptide receptor radionuclide therapy

Prostate-specific membrane antigen

Somatostatin receptor

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Wendy Delbart and Marie Vercruyssen contributed equally to this work.

Erwin Woff and Ioannis Karfis share last authorship.

Change history

8/13/2025

The authors corrected a spelling in the Abstract.

Acknowledgements

Not applicable.

Author contributions

MV, IK and EW evaluated the patients in consultation and ensured follow-up. RD and CM performed the dosimetric analyses. WD, IK and EW wrote the manuscript and analysed the data. ZW, PF and NM revised the manuscript. All authors read and approved the final manuscript.

Funding

Not applicable.

Data availability

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The treatment was approved by the local ethics committee of Jules Bordet Institute (CE3817 and CE3493). Written informed consent was obtained from both patients.

Consent for publication

Both patients gave consent for the publication of their data.

Competing interests

The authors declare that they have no competing interests.

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