Chemokine (C-X-C motif) receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer including multiple myeloma (MM). Proof-of-concept of CXCR4-directed ...radionuclide therapy in MM has recently been reported. This study assessed the diagnostic performance of the CXCR4-directed radiotracer
GaPentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies. Thirty-five patients with MM underwent
GaPentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases,
FFDG-PET/CT for correlation was available. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with standard clinical parameters of disease activity.
GaPentixafor-PET detected CXCR4-positive disease in 23/35 subjects (66%). CXCR4-positivity at PET was independent from myeloma subtypes, cytogenetics or any serological parameters and turned out as a negative prognostic factor. In the 19 patients in whom a comparison to
FFDG was available,
GaPentixafor-PET detected more lesions in 4/19 (21%) subjects,
FFDG proved superior in 7/19 (37%). In the remaining 8/19 (42%) patients, both tracers detected an equal number of lesions.
FFDG-PET positivity correlated with
GaPentixafor-PET positivity (p=0.018).
GaPentixafor-PET provides further evidence that CXCR4 expression frequently occurs in advanced multiple myeloma, representing a negative prognostic factor and a potential target for myeloma specific treatment. However, selecting patients for CXCR4 directed therapies and prognostic stratification seem to be more relevant clinical applications for this novel imaging modality, rather than diagnostic imaging of myeloma.
C-X-C-motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. We have recently reported promising first-in-man experience with ...CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM). Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles). ERT was administered in combination with chemotherapy and autologous stem cell support. End points were occurrence and timing of adverse events, progression-free and overall survival. ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs. With absorbed tumor doses >30-70 Gy in intra- or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission. Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome. Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313). During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive. CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease. Further assessment of this novel treatment option is highly warranted.
Summary
Overexpression of the transcription factor interferon regulatory factor‐4 (IRF4), which is common in multiple myeloma (MM), is associated with poor prognosis. Patients with higher IRF4 ...expression have significantly poorer overall survival than those with low IRF4 expression. Lenalidomide is an IMiD® immunomodulatory compound that has both tumouricidal and immunomodulatory activity in MM. This study showed that lenalidomide downregulated IRF4 levels in MM cell lines and bone marrow samples within 8 h of drug exposure. This was associated with a decrease in MYC levels, as well as an initial G1 cell cycle arrest, decreased cell proliferation, and cell death by day 5 of treatment. In eight MM cell lines, high IRF4 levels correlated with increased lenalidomide sensitivity. The clinical significance of this observation was investigated in 154 patients with MM. Among MM patients with high levels of IRF4 expression, treatment with lenalidomide led to a significantly longer overall survival than other therapies in a retrospective analysis. These data confirm the central role of IRF4 in MM pathogenesis; indicate that this is an important mechanism by which lenalidomide exerts its antitumour effects; and may provide a mechanistic biomarker to predict response to lenalidomide.
In this prospective study (NCT01595295), 272 patients treated with azacitidine completed 1456 EuroQol 5-Dimension (EQ-5D) questionnaires. Linear mixed-effect modelling was used to incorporate ...longitudinal data. When compared with a matched reference population, myeloid patients reported more pronounced restrictions in usual activities (+28%,
< 0.0001), anxiety/depression (+21%,
< 0.0001), selfcare (+18%,
< 0.0001) and mobility (+15%,
< 0.0001), as well as lower mean EQ-5D-5L indices (0.81 vs. 0.88,
< 0.0001), and lower self-rated health on the EuroQol Visual Analogue Scale (EQ-VAS) (64 vs. 72%,
< 0.0001). After multivariate-adjustment, (i) the EQ-5D-5L index assessed at azacitidine start the predicted time with clinical benefit (TCB) (9.6 vs. 6.6 months;
= 0.0258; HR = 1.43), time to next treatment (TTNT) (12.8 vs. 9.8 months;
= 0.0332; HR = 1.42) and overall survival (OS) (17.9 vs. 12.9 months;
= 0.0143; HR = 1.52); (ii) Level Sum Score (LSS) predicted azacitidine response (
= 0.0160; OR = 0.451) and the EQ-5D-5L index showed a trend (
= 0.0627; OR = 0.522); (iii) up to 1432 longitudinally assessed EQ-5D-5L response/clinical parameter pairs revealed significant associations of EQ-5D-5L response parameters with haemoglobin level, transfusion dependence and hematologic improvement. Significant increases of the likelihood ratios were observed after addition of LSS, EQ-VAS or EQ-5D-5L-index to the International Prognostic Scoring System (IPSS) or the revised IPSS (R-IPSS), indicating that they provide added value to these scores.
Since the introduction of first-generation proteasome inhibitors and immunomodulatory agents, the multiple myeloma (MM) treatment landscape has undergone a remarkable development. Most recently, ...immunotherapeutic strategies targeting the B cell maturation antigen (BCMA) entered the clinical stage providing access to highly anticipated novel treatment strategies. At present, numerous different approaches investigate BCMA as an effective multi-modal target. Currently, BCMA-directed antibody–drug conjugates, bispecific and trispecific antibodies, autologous and allogeneic CAR-T cell as well as CAR-NK cell constructs are either approved or in different stages of clinical and preclinical development for the treatment of MM. This armamentarium of treatment choices raises several challenges for clinical decision making, particularly in the absence of head-to-head comparisons. In this review, we provide a comprehensive overview of BCMA-targeting therapeutics, deliver latest updates on clinical trial data, and focus on potential patient selection criteria for different BCMA-targeting immunotherapeutic strategies.
Osteoblastic activity is severely impaired in active myeloma, contributing to the development of myeloma bone disease. Although several drugs reducing osteoclast-mediated bone degradation are in ...clinical use, approaches to specifically augment bone formation are at an early stage of development. Novel antimyeloma drugs not only directly act on myeloma cells, but impact on the microenvironment as well. Proteasome inhibitors were previously shown to have bone anabolic properties. Here we investigated the impact of immunomodulatory drugs (IMiDs) on bone formation. Treatment with thalidomide and lenalidomide significantly inhibited osteoblast development in vitro, as reflected by a reduction of alkaline phosphatase activity and matrix mineralization. The effects were upheld in combination with bortezomib. The IMiDs upregulated Dickkopf-1 (DKK1) and inhibin beta A, but blocking these molecules was not able to restore regular osteoblast development. We therefore performed gene expression profiling to reveal other osteoblast regulatory factors that might be involved in the IMiD-mediated effect on osteoblast development. Our data indicate that osteoblast inhibition is possibly an IMiD-class effect mediated by downregulation of major osteoblast regulators (e.g., runt-related transcription factor 2, distal-less homeobox 5, pleiotrophin) and concurrent induction of secreted inhibitors of osteoblast formation (e.g. DKK1, activin A, gremlin 1). Our results highlight the need for bone anabolic therapeutics in myeloma, counteracting the negative impact of prolonged IMiD exposure on bone metabolism.
Azacitidine is the treatment backbone for patients with acute myeloid leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia who are considered unfit for intensive chemotherapy. ...Detailed reports on adverse events in a real-world setting are lacking.
To analyze the frequency of adverse events in the Austrian Registry of Hypomethylating agents. To compare real-world data with that of published randomized clinical trials.
A total of 1406 patients uniformly treated with a total of 13,780 cycles of azacitidine were analyzed. Hematologic adverse events were the most common adverse events (grade 3-4 anemia 43.4%, grade 3-4 thrombopenia 36.8%, grade 3-4 neutropenia 36.1%). Grade 3-4 anemia was significantly more common in the Registry compared to published trials. Febrile neutropenia occurred in 33.4% of patients and was also more common in the Registry than in published reports. Other commonly reported adverse events included fatigue (33.4%), pain (29.2%), pyrexia (23.5%), and injection site reactions (23.2%). Treatment termination due to an adverse event was rare (5.1%).
The safety profile of azacitidine in clinical trials is reproducible in a real-world setting. With the use of prophylactic and concomitant medications, adverse events can be mitigated and azacitidine can be safely administered to almost all patients with few treatment discontinuations.
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