PET/CT Imaging for Therapy Assessment in Multiple Myeloma Including MRD

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article is well-written, the topic is interesting, and the review is performed in a good manner.

I suggest minor improvements:

1) Please deepen the discussion regarding negative MM patients at FDG PET. I also suggest that you discuss the so-called "salt-n-pepper" MRI appearance of multiple myeloma (neither focal nor diffuse disease at MRI, but multiple very small <5mm bone marrow lesions), considering it as a potential pitfall for PET-CT

2) Please, deepen the discussion regarding the MRI vs PET comparison

3) Increasing the iconography of the paper with more cases illustrated in other key aspects of the manucript would be very appreciated

Author Response

We thank the Reviewer for the positive assessment of our work and for these constructive suggestions, which we have addressed as detailed below.

Comment 1: Please deepen the discussion regarding negative MM patients at FDG PET. I also suggest that you discuss the so-called "salt-n-pepper" MRI appearance of multiple myeloma (neither focal nor diffuse disease at MRI, but multiple very small <5mm bone marrow lesions), considering it as a potential pitfall for PET-CT

Response 1: We thank the Reviewer for this valuable suggestion. We have expanded the discussion of FDG-negative disease in Section 3.1.1 by addressing two distinct mechanisms of false negativity. First, we now describe the micronodular, or "salt-and-pepper", pattern of marrow infiltration. Second, we discuss intrinsically low glucose-avid disease, so that PET/CT may appear negative despite active disease being detectable by MRI. The relevant references have been added.

 

Comment 2: Please, deepen the discussion regarding the MRI vs PET comparison.

Response 2: We agree with the Reviewer and have added a summarizing paragraph at the end of Section 3.1.1 that synthesizes the comparative evidence.

 

Comment 3:  Increasing the iconography of the paper with more cases illustrated in other key aspects of the manucript would be very appreciated

Response 3 : We thank the Reviewer for this suggestion. Instead of adding more cases we chose to replace the cases we initially included with ones having improved quality images and covering extra-medullary disease as well as a FDG-PET/CT false-negative in a « salt-and-pepper » pattern of myeloma involvement.

Reviewer 2 Report

Comments and Suggestions for Authors

refer attachment

Comments for author File: Comments.pdf

Comments on the Quality of English Language

needs improvement

Author Response

We thank the Reviewer for the positive assessment of our work and for these constructive suggestions, which we have addressed as detailed below.

Comment 1: The manuscript emphasized both conventional response and MRD assessment. However, it does not clearly distinguish between early metabolic response (e.g., after induction), post-ASCT response, and maintenance-phase response. These time points carry different prognostic weights and clinical decisions. The authors should explicitly separate these phases in the results.

Response 1: We thank the Reviewer for this helpful suggestion. We have added an introductory sentence at the beginning of the prognostic section (Section 3.1.2) that explicitly distinguishes the different phases at which FDG PET/CT is assessed — early/after induction, after ASCT, and during maintenance — and notes that each carries distinct prognostic and clinical implications.

 

Comment 2: The Deauville, IMPeTUs, IMWG, and EANM criteria are all presented, which is comprehensive. The text repeatedly described similar Deauville score definitions across sections without clear differentiation or practical comparison. A single comparative table or decision flowchart would reduce repetition and clarify which criteria should be used in which scenario. 

Response 2: We thank the Reviewer for this helpful suggestion. We added a table with a concise summary of characteristics of each set of criteria.

 

Comment 3: Many studies are cited showing PET negativity correlates with improved PFS and OS. However, no pooled HRs or effect sizes are provided. Given 165 reviewed studies, the authors should present a summary of consistent prognostic estimates (e.g., range of HRs for PET negativity) rather than listing individual study results.

Response 3: We thank the Reviewer for this helpful suggestion. We have added a synthesizing statement at the end of Section 3.1.2 noting that, across the prospective and large retrospective cohorts reviewed, post-therapy PET negativity or complete metabolic response was consistently associated with improved PFS, with reported hazard ratios broadly in the range of approximately 0.2–0.5 for the PET-negative group. As this is a narrative (not systematic) review without formal meta-analysis, we present this as an indicative range rather than a formally pooled estimate.

 

Comment 4: The manuscript stated that PET/CT and bone marrow techniques (flow cytometry, NGS) are complementary. It does not specify how to clinically move forward when results disagree (e.g., PET-positive but marrow-negative, or vice versa). A practical evidence-based recommendation for discordant cases would substantially improve clinical utility.

Response 4: We thank the Reviewer for this helpful suggestion. We have addressed discordant cases explicitly in Section 4, acknowledging that the management of PET-positive but marrow-MRD-negative patients currently remains undefined and that the two approaches are complementary rather than interchangeable. We have deliberately refrained from issuing a prescriptive algorithm because, to our knowledge, no prospective evidence yet supports a specific management pathway for these discordant cases; we identify this as a priority for future investigation.

 

Comment 5: EMD detection is highlighted as an advantage of PET/CT. There is no separate analysis or summary of EMD’s impact on treatment response assessment or prognosis. Given that EMD changes management, the manuscript should include a dedicated subsection with prevalence, response patterns, and outcome data for EMD patients.

Response 5: We thank the Reviewer for this helpful suggestion. We have added a dedicated passage on extramedullary disease to Section 3.1.2, noting its prevalence (approximately 5% at diagnosis, more frequent at relapse), the unique whole-body detection advantage of FDG-PET/CT for extramedullary and paramedullary sites, the independent association of baseline EMD/PMD with shorter PFS after adjustment for ISS stage and high-risk cytogenetics, and the high-risk significance of persistent post-therapy extramedullary uptake, with a recommendation that EMD status be explicitly reported at staging and response assessment.

 

Comment 6: Emerging tracers (CXCR4, CD38-immunoPET, acetate, methionine) are introduced. The authors do not critically compare these tracers against FDG in terms of sensitivity, specificity, or impact on response assessment in specific clinical contexts (e.g., FDG- negative disease, daratumumab-treated patients). A strengths/limitations summary for each tracer would be good.

Response 6: We thank the Reviewer for this comment. In Section 3.3, each emerging tracer is in fact compared with [¹⁸F]FDG: [¹¹C]choline and [¹⁸F]fluorocholine are described as offering improved detection of focal bone lesions, [¹¹C]methionine as showing higher sensitivity for a greater number of lesions, [¹⁸F]fluorothymidine as showing lower sensitivity, [¹¹C]acetate as performing better in detecting diffuse and focal disease (with preliminary data on MRD assessment after daratumumab-based induction), and CD38-targeted immunoPET as showing greater sensitivity and resolution than FDG, particularly in the bone marrow. We have also added a concluding statement clarifying that all these tracers remain investigational, with evidence limited to small or early-phase studies, and are not yet available for routine clinical use. We therefore believe the section now provides a balanced, comparative appraisal of each tracer relative to FDG, while appropriately reflecting the preliminary nature of the available data.

 

Comment 7: Daratumumab, carfilzomib, and other novel agents are well described in the introduction. However, the authors do not address whether these treatments alter FDG avidity, cause false- positive immune-related changes, or affect specificity of response criteria (e.g., daratumumab-related bone marrow changes). This is a major gap for modern clinical practice.

Response 7: We thank the Reviewer for raising this point. We reviewed the available literature and found no robust evidence that daratumumab, carfilzomib, or other novel agents alter FDG avidity or generate treatment-specific false-positive findings on PET/CT in multiple myeloma. We have added a clarifying statement. Importantly, the well-documented interference of anti-CD38 monoclonal antibodies concerns bone marrow–based techniques — flow cytometry and serum immunofixation — rather than PET/CT, which is not subject to this interference; we now make this point explicit and support it with the relevant reference (Oberle et al., Haematologica 2017). We have also noted that inflammatory and post-procedural uptake remains a general, non-specific pitfall of FDG PET/CT.

 

Comment 8: Comparisons with whole-body MRI and DWI-MRI are included. Whereas, no comparison with emerging PET/MRI or other functional techniques (e.g., sodium fluoride PET for bone turnover) is provided.

Response 8: We thank the Reviewer for this suggestion. We have added a description of hybrid PET/MRI in Section 3.1.1, presenting it as an emerging modality that combines the metabolic information of PET with the soft-tissue and marrow sensitivity of MRI, and citing the recent experience in newly diagnosed disease (Jamet et al., 2023). Regarding [¹⁸F]sodium fluoride PET, this tracer reflects osteoblastic bone turnover and has a limited role in multiple myeloma, whose bone involvement is predominantly lytic and frequently lacks the osteoblastic reaction required for sodium fluoride uptake; for this reason it is not used for response assessment in this setting, and we have therefore not discussed it in detail. We believe the addition of PET/MRI appropriately addresses the comparison with emerging hybrid functional imaging.

 

Comment 9: The conclusions do not prioritize specific research needs, such as prospective validation of Deauville thresholds in novel therapy settings, standardization of PET timing, or trials comparing tracer-guided vs conventional response-adapted strategies.

Response 9: We thank the Reviewer for this suggestion. We have expanded the Conclusions to explicitly prioritize the main directions for future research. The revised text now states that future research should prioritize the prospective validation of Deauville score thresholds in the setting of novel therapy regimens, the standardization of PET/CT acquisition and timing, and trials comparing imaging- or tracer-guided response-adapted strategies with conventional approaches, alongside the development of quantitative and radiomic imaging biomarkers. We believe this addition gives the reader a clear sense of the research priorities that remain to be addressed.

 

Remark : The authors should consider revising the manuscript accordingly. Figures should be of better quality.

Response : We thank the Reviewer for this suggestion, we chose to replace the cases we initially included with ones having improved quality.

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript reviews the role of [¹⁸F]FDG PET/CT in assessing treatment response and minimal residual disease (MRD) in multiple myeloma, covering diagnostic accuracy, prognostic value, standardized interpretation criteria (Deauville, IMPeTUs, IMWG, EANM Focus 4), and emerging non-FDG radiotracers. The topic is timely and clinically relevant, the coverage of the pivotal prognostic and PET/MRD literature is broad, and the headline trial statistics are accurate; the figures and the IMWG/IMPeTUs summary tables are useful. However, the review is presented as systematic without meeting systematic-review standards, contains at least one chronologically impossible reference attribution, lacks any limitations or evidence-characterization section, and does not differentiate itself from several recent competing reviews. These issues require major revision before the manuscript can be considered for publication.

1. The review is described as systematic but does not meet systematic-review standards. The Simple Summary states the work "systematically analyzes published evidence from 165 studies," and the Methods report 274 records reduced to 165 after duplicate removal, yet there is no PRISMA 2020 flow diagram, no registered protocol, no risk-of-bias or quality assessment, and no full search string. Please either provide the full PRISMA 2020 apparatus (flow diagram, eligibility criteria, search strategy, quality assessment) or revise the language throughout to accurately describe a narrative review and remove "systematically."
2. Reference 45 is attributed to a study it cannot describe. The text (Section 3.2.2) credits a 47-patient IMPeTUs application cohort to "Fonti et al.," but reference 45 is Fonti et al., J Nucl Med 2012, a metabolic-tumor-volume prognostic study that predates the IMPeTUs criteria (Nanni et al., 2016) by four years and therefore cannot have applied them. The actual 47-patient IMPeTUs cohort is Sachpekidis et al. (reference 46); please correct the attribution and verify that the described findings match the intended source.
3. The manuscript has no limitations section and does not characterize the strength of the evidence it presents. Findings from small single-center series (e.g., the 31-patient Derlin cohort, the 47-patient IMPeTUs cohorts) are presented alongside large prospective analyses without distinguishing established from emerging or preliminary evidence, and the novel-tracer data are described in promising terms without consistently flagging their pilot/first-in-human status. Please add a dedicated limitations section addressing the heterogeneity of the included studies and add evidence characterization (established vs. emerging vs. investigational) to the relevant tables.
4. The manuscript does not differentiate itself from recently published reviews on the same topic. Several overlapping reviews and meta-analyses appeared in 2021–2024, including Ishibashi et al. (Life 2023, cited as reference 68), Bezzi/Ambrosini/Nanni (Semin Nucl Med 2023), the Rama et al. WB-MRI-versus-FDG-PET/CT treatment-response meta-analysis (AJR 2022), and the 2024 EANM FDG PET/CT guideline for plasma cell disorders. Please add an explicit paragraph stating what this review adds beyond these works; without a concrete differentiation, the contribution is incremental.
5. The combined citation of references 22 and 23 for the 31-patient comparative statistics is imprecise. The sensitivity (50.0%), specificity (85.7%), PPV, NPV, and accuracy values in Section 3.1.1 derive specifically from the Derlin et al. Eur Radiol 2013 comparative study, whereas the co-cited Derlin et al. EJNMMI 2012 paper is a separate study with different performance figures. Please attribute these values to the single correct source.
6. Several quantitative claims should be reworded to match the primary data precisely. The CASSIOPEIA figure (Section 1.1) is the rate of complete response or better assessed at day 100 post-ASCT, not a simple "post-ASCT CR rate"; the Rasche et al. 64% figure (Section 3.1) refers to residual disease detectable by the combination of flow cytometry and imaging, not imaging alone; and the POLLUX 93% response rate should be checked against the primary NEJM denominator. Please align the wording in each case with the source.
7. The statement that targeted therapies and immunotherapy arrived "in 2010" (Section 1.1) is imprecise and corresponds to no specific landmark. Bortezomib (2003) and lenalidomide (2006) preceded this date, while the monoclonal antibodies and carfilzomib were approved between 2012 and 2015. Please revise to reflect the actual approval timeline.
8. The conclusions overreach relative to the evidence reviewed and to the absent limitations section. The abstract describes PET/CT as a "decisive imaging tool," yet the reviewed comparative data (including the Rama et al. meta-analysis showing higher treatment-response sensitivity for WB-MRI) and the manuscript's own acknowledgment that PET/CT may be less sensitive than MRI for marrow involvement at staging temper this claim. Please soften the framing and ensure the conclusions are supported by the balance of evidence presented.

Minor comments:

• The ">95% of MM patients express SLAMF7 and CD38" claim (Section 1.1) sits at the upper bound of the literature and should be cited to a primary source (e.g., Hsi et al. 2008 for SLAMF7) with the reported range noted.
• Table 1 contains spelling/translation artifacts: "lombar" (lumbar) and "Retropitoneal" (retroperitoneal).
• "still persistent disease" is rendered "sill persistent disease" in Section 3.2.2.
• The Figure 2 legend uses "femour" for femur (twice).
• The non-standard element names "Cuprum-64" (copper-64/⁶⁴Cu) recur in Section 3.3 and should be replaced with standard nomenclature.
• The novel-tracer nomenclature is inconsistent between the Conclusions (e.g., "11C-choline," "18F-FLT") and the body text ([¹¹C]choline, [¹⁸F]fluorothymidine); please standardize.
• Several abbreviations (e.g., RVd vs. VRd) are used inconsistently; please verify all are defined at first use and applied consistently, including in the abstract.
• The review relies heavily on the Italian (Zamagni/Nanni) IMPeTUs framework; while appropriate, the authors should ensure competing standardization efforts are given proportionate coverage.

 

Author Response

We thank the Reviewer for the positive assessment of our work and for these constructive suggestions, which we have addressed as detailed below.

Comment 1: The review is described as systematic but does not meet systematic-review standards. The Simple Summary states the work "systematically analyzes published evidence from 165 studies," and the Methods report 274 records reduced to 165 after duplicate removal, yet there is no PRISMA 2020 flow diagram, no registered protocol, no risk-of-bias or quality assessment, and no full search string. Please either provide the full PRISMA 2020 apparatus (flow diagram, eligibility criteria, search strategy, quality assessment) or revise the language throughout to accurately describe a narrative review and remove "systematically."

Response 1: We thank the Reviewer for this important observation. This manuscript was intended as a narrative review. To avoid any ambiguity, we have removed the term "systematically" from the Simple Summary and revised the Materials and Methods section to describe our literature search as a narrative, author-selected process rather than a systematic one. The record count and duplicate-removal language have been removed, and the eligibility description has been rephrased in narrative terms. We believe the revised text now accurately reflects the nature of the work.

 

Comment 2: Reference 45 is attributed to a study it cannot describe. The text (Section 3.2.2) credits a 47 patient IMPeTUs application cohort to "Fonti et al.," but reference 45 is Fonti et al., J Nucl Med 2012, a metabolic-tumor-volume prognostic study that predates the IMPeTUs criteria (Nanni et al., 2016) by four years and therefore cannot have applied them. The actual 47-patient IMPeTUs cohort is Sachpekidis et al. (reference 46); please correct the attribution and verify that the described findings match the intended source.

Response 2: We thank the Reviewer. The attribution has been corrected: the 47-patient IMPeTUs cohort is now correctly credited to Sachpekidis et al., and the Fonti et al. reference has been relocated to the metabolic tumour volume discussion.

 

Comment 3: The manuscript has no limitations section and does not characterize the strength of the evidence it presents. Findings from small single-center series (e.g., the 31-patient Derlin cohort, the 47-patient IMPeTUs cohorts) are presented alongside large prospective analyses without distinguishing established from emerging or preliminary evidence, and the novel-tracer data are described in promising terms without consistently flagging their pilot/first-in-human status. Please add a dedicated limitations section addressing the heterogeneity of the included studies and add evidence characterization (established vs. emerging vs.investigational) to the relevant tables.

Response 3: We thank the Reviewer for this important comment. We have addressed it in several ways. First, a dedicated Limitations section has been added. Second, throughout the text we have reframed findings from small single-centre series so that they are no longer presented as established facts. Third, the novel tracer data have been reframed to consistently reflect their investigational, mostly early-phase status. Finally, we have added an evidence characterization section with a table for clarity. We believe these changes give the reader a clearer sense of the strength of the evidence presented.

 

Comment 4: The manuscript does not differentiate itself from recently published reviews on the same topic. Several overlapping reviews and meta-analyses appeared in 2021–2024, including Ishibashi et al. (Life 2023, cited as reference 68), Bezzi/Ambrosini/Nanni (Semin Nucl Med 2023), the Rama et al. WB-MRI-versus-FDG-PET/CT treatment-response meta-analysis (AJR 2022), and the 2024 EANM FDG PET/CT guideline for plasma cell disorders. Please add an explicit paragraph stating what this review adds beyond these works; without a concrete differentiation, the contribution is incremental.

Response 4: We thank the Reviewer for this comment. We have added an explicit statement at the end of the Introduction clarifying the specific contribution of this review. Unlike previous overlapping works, our review focuses specifically on therapy assessment and minimal residual disease in multiple myeloma, integrating the prognostic value of FDG PET/CT, the standardized interpretation criteria, and the most recent developments in non-FDG radiotracers, thereby providing an updated synthesis of a field that has evolved considerably since earlier publications.

 

Comment 5: The combined citation of references 22 and 23 for the 31-patient comparative statistics is imprecise. The sensitivity (50.0%), specificity (85.7%), PPV, NPV, and accuracy values in Section 3.1.1 derive specifically from the Derlin et al. Eur Radiol 2013 comparative study, whereas the co-cited Derlin et al. EJNMMI 2012 paper is a separate study with different performance figures. Please attribute these values to the single correct source.

Response 5: We thank the Reviewer. The reported values (sensitivity 50.0%, specificity 85.7%, PPV 62.5%, NPV 78.3%, accuracy 74.2%) derive specifically from Derlin et al. (Eur Radiol 2013). We have corrected the citation to attribute these values to this single source and removed the co-cited Derlin et al. (EJNMMI 2012) study. We have verified that the reported values match the intended source.

 

Comment 6: Several quantitative claims should be reworded to match the primary data precisely. The CASSIOPEIA figure (Section 1.1) is the rate of complete response or better assessed at day 100 post-ASCT, not a simple "post-ASCT CR rate"; the Rasche et al. 64% figure (Section 3.1) refers to residual disease detectable by the combination of flow cytometry and imaging, not imaging alone; and the POLLUX 93% response rate should be checked against the primary NEJM denominator. Please align the wording in each case with the source.

Response 6: We thank the Reviewer for this careful reading. We have reworded the relevant claims to align precisely with the primary sources. In Section 1.1, the CASSIOPEIA figure has been corrected to specify that the 39% versus 26% rate refers to complete response or better assessed at day 100 post-ASCT, rather than a simple post-ASCT CR rate. The POLLUX figures have been reworded to specify that the 93% refers to the overall response rate in the daratumumab arm, with 43% achieving a complete response or better. Regarding the Rasche et al. study, the 64% figure was already attributed in the text to the combination of flow cytometry and imaging rather than to imaging alone; we have nonetheless rephrased the sentence to make this explicit.

 

Comment 7: The statement that targeted therapies and immunotherapy arrived "in 2010" (Section 1.1) is imprecise and corresponds to no specific landmark. Bortezomib (2003) and lenalidomide (2006) preceded this date, while the monoclonal antibodies and carfilzomib were approved between 2012 and 2015. Please revise to reflect the actual approval timeline.

Response 7: We thank the Reviewer for this observation. We have removed the imprecise reference to "2010" and ensured that the text reflects the actual approval timeline.

 

Comment 8: The conclusions overreach relative to the evidence reviewed and to the absent limitations section. The abstract describes PET/CT as a "decisive imaging tool," yet the reviewed comparative data (including the Rama et al. meta-analysis showing higher treatment- response sensitivity for WB-MRI) and the manuscript's own acknowledgment that PET/CT may be less sensitive than MRI for marrow involvement at staging temper this claim. Please soften the framing and ensure the conclusions are supported by the balance of evidence presented.

 

Response 8: We thank the Reviewer for this important observation. We conducted a reframing of the conclusion section, taking into account FGT-PET/CT as "one component of a multimodal assessment rather than a stand-alone determinant » and the abstract section.

 

Minor comments: • The ">95% of MM patients express SLAMF7 and CD38" claim (Section 1.1) sits at the upper bound of the literature and should be cited to a primary source (e.g., Hsi et al. 2008 for SLAMF7) with the reported range noted.

• Table 1 contains spelling/translation artifacts: "lombar" (lumbar) and "Retropitoneal" (retroperitoneal).
• "still persistent disease" is rendered "sill persistent disease" in Section 3.2.2.
• The Figure 2 legend uses "femour" for femur (twice).
• The non-standard element names "Cuprum-64" (copper-64/⁶⁴Cu) recur in Section 3.3 and

should be replaced with standard nomenclature.

• The novel-tracer nomenclature is inconsistent between the Conclusions (e.g., "11C-choline," "18F-FLT") and the body text ([¹¹C]choline, [¹⁸F]fluorothymidine); please standardize.
• Several abbreviations (e.g., RVd vs. VRd) are used inconsistently; please verify all are defined at first use and applied consistently, including in the abstract.
• The review relies heavily on the Italian (Zamagni/Nanni) IMPeTUs framework; while appropriate, the authors should ensure competing standardization efforts are given proportionate coverage.

Response: We thank the Reviewer for these detailed observations. We have addressed all the minor points; the spelling artifacts in Table 1 have been corrected; the typographical error has been corrected; the non-standard nomenclature has been replaced with the standard form; the novel-tracer nomenclature has been standardized throughout the manuscript to match the body text format; and the abbreviations have been verified for consistency and definition at first use. We would like to note that competing standardization efforts are in fact given dedicated coverage in the manuscript: in addition to the IMPeTUs framework (Section 3.2.2), the Deauville criteria (Section 3.2.1), the IMWG response criteria (Section 3.2.3, with a summary figure), and the EANM Focus 4 consensus recommendations (Section 3.2.4, with a dedicated summary table) are each presented in separate subsections. To further ensure a balanced presentation, we have added an introductory sentence at the beginning of Section 3.2 that presents the available standardization systems together and on equal footing, and we have removed the framing that previously introduced them within the IMPeTUs subsection.

Reviewer 4 Report

Comments and Suggestions for Authors

This review comprehensively summarizes the evolving role of FDG PET/CT in assessing treatment response and minimal residual disease (MRD) in multiple myeloma. By synthesizing evidence from 165 studies, the authors highlight that FDG PET/CT provides valuable whole-body assessment of disease burden, extramedullary involvement, and treatment response, while PET negativity and complete metabolic response are consistently associated with improved progression-free and overall survival. The review further discusses standardized interpretation systems (Deauville, IMPeTUs, and IMWG criteria), the integration of PET imaging with bone marrow-based MRD assessment, and the potential of emerging PET tracers such as CXCR4- and CD38-targeted agents to enhance future disease monitoring and risk stratification.

I have following major comments：1) The manuscript frequently presents favorable findings regarding FDG PET/CT but provides limited discussion of its known limitations, including false-negative results in low-FDG-avid disease, variability in acquisition protocols, inter-reader variability, and the impact of treatment-related inflammatory changes. 2) Several conclusions appear stronger than the available evidence supports, particularly regarding the role of PET-guided treatment adaptation and MRD-driven management strategies, which remain areas of active investigation rather than established standards in many clinical settings. 3) The review does not sufficiently compare FDG PET/CT with modern whole-body MRI and diffusion-weighted imaging, despite increasing evidence supporting these modalities in treatment response assessment and MRD evaluation. 4) The section discussing novel radiotracers is informative but largely descriptive; a more critical appraisal of their current evidence level, limitations, availability, regulatory status, and barriers to clinical implementation would improve clinical relevance. 5) In the introduction or discussion section, following related references should be added to improve the clarity and completeness of the paper:PMID: 38952398; PMID: 38952399. 6) Several sections are excessively narrative and repetitive, particularly regarding the prognostic significance of PET negativity and complete metabolic response, resulting in redundancy and reduced readability. 7) The review would benefit from a dedicated section addressing unresolved controversies, including optimal PET timing, standardized response thresholds, discordant PET/MRD findings, and management of PET-positive but bone marrow MRD-negative patients. 8) The clinical implications for treatment decision-making remain somewhat generalized, and the authors should better clarify how PET findings should influence management in routine practice versus clinical trial settings. 9) Future directions involving artificial intelligence, radiomics, and quantitative PET biomarkers are largely absent despite growing interest in these fields and their potential impact on response assessment. 10) The manuscript would benefit from a clearer distinction between evidence-supported recommendations and expert opinion, ensuring that readers can appropriately interpret the strength of the conclusions presented.

Author Response

We thank the Reviewer for the positive assessment of our work and for these constructive suggestions, which we have addressed as detailed below.

 

Comment 1 : The manuscript frequently presents favorable findings regarding FDG PET/CT but provides limited discussion of its known limitations, including false-negative results in low-FDG-avid disease, variability in acquisition protocols, inter-reader variability, and the impact of treatment-related inflammatory changes.

 

Response 1: We thank the Reviewer for this observation. We have addressed each of these. False negatives in low-avidity disease are now discussed in Section 3.1.1 (hexokinase-2; salt-and-pepper pattern). Treatment-related inflammatory uptake is addressed in Section 3.1.2 as a non-specific pitfall. We have added a sentence to the Limitations (Section 3.5) explicitly addressing technical and interpretative variability: differences in acquisition protocols (uptake time, reconstruction, scanner calibration) and reader experience can affect SUV-based and visual assessment, which standardized frameworks such as IMPeTUs and the EANM recommendations aim to mitigate.

 

Comment 2: Several conclusions appear stronger than the available evidence supports, particularly regarding the role of PET-guided treatment adaptation and MRD-driven management strategies, which remain areas of active investigation rather than established standards in many clinical settings.

Response 2: We thank the Reviewer for this observation. We have softened the language in the Conclusions and Abstract to ensure that statements regarding the clinical role of PET/CT, including PET-guided treatment adaptation and MRD-driven management, are presented as areas of ongoing investigation rather than established standards.

 

Comment 3: The review does not sufficiently compare FDG PET/CT with modern whole-body MRI and diffusion-weighted imaging, despite increasing evidence supporting these modalities in treatment response assessment and MRD evaluation.

Response 3: We thank the Reviewer for this comment. We have expanded the comparison between FDG PET/CT and modern MR. A new summarizing paragraph now synthesizes the comparative evidence, clarifying that the two modalities are complementary: WB-MRI, particularly with DWI, tends to be more sensitive for diffuse marrow infiltration, whereas FDG PET/CT offers greater specificity and earlier whole-body response assessment. We have incorporated the systematic review and meta-analysis by Rama et al. comparing the two modalities for treatment-response assessment, and we have added a description of hybrid PET/MRI as an emerging modality combining the strengths of both techniques. The corresponding references have been added.

 

Comment 4: The section discussing novel radiotracers is informative but largely descriptive; a more critical appraisal of their current evidence level, limitations, availability, regulatory status, and barriers to clinical implementation would improve clinical relevance.

Response 4: We thank the Reviewer for this helpful suggestion. We have revised the closing of Section 3.3 to provide a more critical appraisal of the novel radiotracers. We now state explicitly that all these tracers remain at an investigational stage and are not yet available for routine clinical use, with the available evidence largely limited to small or early-phase studies. We believe these changes give the reader a clearer sense of the current evidence level and of the practical barriers that still limit the clinical implementation of these agents.

 

Comment 5: In the introduction or discussion section, following related references should be added to improve the clarity and completeness of the paper:PMID: 38952398; PMID: 38952399.

Response 5: We thank the Reviewer for these suggestions. We have added both references where they are most relevant to the scope of our review.

 

Comment 6: Several sections are excessively narrative and repetitive, particularly regarding the prognostic significance of PET negativity and complete metabolic response, resulting in redundancy and reduced readability.

Response 6: We thank the Reviewer for this observation. We have revised the prognostic section (Section 3.1.2) to reduce redundancy, removing repetitive linking phrases and a duplicated statement on PET normalization as a therapeutic goal, while preserving the individual study data. These edits improve readability without altering the evidence presented.

 

Comment 7: The review would benefit from a dedicated section addressing unresolved controversies, including optimal PET timing, standardized response thresholds, discordant PET/MRD findings, and management of PET-positive but bone marrow MRD-negative patients.

Response 7: We thank the Reviewer for this valuable suggestion. We have added a dedicated paragraph on controversies and open questions in the Discussion. We believe this addition gives the reader a clearer view of the issues that remain unresolved in this field.

 

Comment 8: The clinical implications for treatment decision-making remain somewhat generalized, and the authors should better clarify how PET findings should influence management in routine practice versus clinical trial settings.

Response 8: We thank the Reviewer for this comment. In the same paragraph, we now clarify that the established clinical role of PET/CT relates mainly to staging and response assessment, whereas the use of PET findings to actively guide treatment decisions — such as PET-guided intensification or MRD-driven consolidation — derives largely from clinical trials and should currently be regarded as investigational rather than standard of care in routine practice.

 

Comment 9: Future directions involving artificial intelligence, radiomics, and quantitative PET biomarkers are largely absent despite growing interest in these fields and their potential impact on response assessment.

Response 9: We thank the Reviewer for highlighting this point. We have added a paragraph in the future directions section describing the emerging role of artificial intelligence and radiomics.

 

Comment 10: The manuscript would benefit from a clearer distinction between evidence-supported recommendations and expert opinion, ensuring that readers can appropriately interpret the strength of the conclusions presented.

Response 10: We have introduced a dedicated “Evaluation of strength of evidence” section (3.4) and an accompanying Table 3 that grade the principal applications as established, emerging, or investigational, allowing readers to gauge the strength of the evidence behind each statement.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

revision is satisfactory

Author Response

Comment : Revision is satisfactory
Response : We sincerely thank the Reviewer for the positive assessment of our revised manuscript and for the constructive comments provided during the previous round, which helped us substantially improve the quality and accuracy of the work.

Reviewer 3 Report

Comments and Suggestions for Authors

I've read the revised manuscript alongside the point-by-point response, and I want to start by saying the authors have done real work here. The earlier draft leaned on systematic-review language it couldn't back up; that's gone now, and the new Methods and the candid Limitations section (3.5) describe the work honestly for what it is — a narrative synthesis, with no protocol, no PRISMA diagram, no quality grading, and the authors say so plainly. The reference problems I raised before are fixed: the 47-patient IMPeTUs cohort is now correctly Sachpekidis [42], Fonti [41] has been moved to where it belongs in the metabolic-tumor-volume discussion, and the Derlin numbers are tied to the single right paper [29]. The new evidence-tiering section and Table 4 are a genuine improvement, and the conclusions read far more soberly than they did. I also went back through the full reference list this round, paying particular attention to everything that was added in revision. It holds up well — nothing fabricated, nothing retracted, no impossible dates. One citation still says something its source doesn't, and a few smaller things are worth tightening, but the manuscript is close.

1. The one thing I'd insist on before this goes further is reference 25. The text uses Rodríguez-Laval et al. to argue that a micronodular "salt-and-pepper" pattern with foci under 5 mm sits below PET's resolution and drives false negatives — but that isn't what the paper says. There, the sub-5 mm salt-and-pepper description belongs to the MRI patterns, the PET resolution limit is given separately and at a coarser threshold (10–15 mm), and the false-negative causes the authors actually name are low hexokinase-2 and diffuse marrow infiltration. So two separate statements have been welded into one claim the source doesn't make. The cleanest fix is to keep the salt-and-pepper description in its MRI context, hand the biological false-negative point to reference 26 (Rasche, which is exactly right for it), and if you want to keep a resolution argument, cite it to the PET-physics literature with the correct size cutoff.
2. The narrative reframing is mostly thorough, but a bit of the old language survived. Both the Abstract and the opening of Section 2 still call this "a comprehensive literature search," which reads as systematic-review phrasing and undercuts the honesty of the rest. I'd just soften it — "we surveyed the literature," or "a structured but non-systematic search."
3. The CAR-T sentence built on reference 18 (Singh et al.) claims a little more than the source gives. That review spans hematological malignancies broadly, and its quantitative PET response data are really lymphoma evidence; as written it implies more myeloma-specific support than exists. Worth a light edit so the claim matches what the paper actually shows.
4. The Abstract still calls PET/CT "superior in sensitivity and specificity" versus conventional imaging, which doesn't quite square with the body text or the Rama meta-analysis [35] on response sensitivity; "for metabolically active disease" would thread that needle.

 

Author Response

We sincerely thank the Reviewer for the careful and thorough re-evaluation of our manuscript, and for the time taken to go through the full reference list. We greatly appreciate the positive assessment of the changes made in the previous round. We have now addressed the remaining points raised, as detailed below.

Comment 1: The one thing I'd insist on before this goes further is reference 25. The text uses Rodríguez-Laval et al. to argue that a micronodular "salt-and-pepper" pattern with foci under 5 mm sits below PET's resolution and drives false negatives — but that isn't what the paper says. There, the sub-5 mm salt-and-pepper description belongs to the MRI patterns, the PET resolution limit is given separately and at a coarser threshold (10–15 mm), and the false-negative causes the authors actually name are low hexokinase-2 and diffuse marrow infiltration. So two separate statements have been welded into one claim the source doesn't make. The cleanest fix is to keep the salt-and-pepper description in its MRI context, hand the biological false-negative point to reference 26 (Rasche, which is exactly right for it), and if you want to keep a resolution argument, cite it to the PET-physics literature with the correct size cutoff.

Response 1: We thank the Reviewer for this precise observation, and we fully agree. On re-reading Rodríguez-Laval et al., we confirmed that the micronodular "salt-and-pepper" pattern (<5 mm) is described there as an MRI pattern of marrow infiltration, that the reduced PET sensitivity is reported separately for lesions below approximately 10–15 mm, and that the false-negative causes identified are low hexokinase-2 expression and diffuse marrow infiltration. We had inadvertently combined two distinct statements into a single claim not supported by the source. We have rewritten the passage accordingly: the salt-and-pepper pattern is now presented in its MRI context, the PET spatial-resolution limit is stated separately with the correct threshold (~10–15 mm), and the biological cause of false negativity (reduced hexokinase-2 expression, together with diffuse marrow infiltration) is attributed to Rasche et al.

 

Comment 2 : The narrative reframing is mostly thorough, but a bit of the old language survived. Both the Abstract and the opening of Section 2 still call this "a comprehensive literature search," which reads as systematic-review phrasing and undercuts the honesty of the rest. I'd just soften it — "we surveyed the literature," or "a structured but non-systematic search."

Response 2 : We thank the Reviewer for catching this. We have replaced "comprehensive literature search" in both the Abstract and the opening of Section 2 with more appropriate wording that reflects the narrative nature of the review: the Methods now describe "a structured but non-systematic literature search," and the Abstract has been reworded accordingly. We agree this phrasing is more consistent with the rest of the manuscript.

 

Comment 3 : The CAR-T sentence built on reference Singh et al. claims a little more than the source gives. That review spans hematological malignancies broadly, and its quantitative PET response data are really lymphoma evidence; as written it implies more myeloma-specific support than exists. Worth a light edit so the claim matches what the paper actually shows.

Response 3 : We thank the Reviewer for this accurate observation. On re-examining Singh et al., we confirmed that the quantitative PET response data in that review derive predominantly from lymphoma, whereas the myeloma-specific evidence is limited to a preliminary association between a negative FDG PET/CT after BCMA-directed CAR-T therapy and a favourable prognosis. We have revised the sentence to make this distinction explicit and to present the myeloma data as preliminary, so that the claim now matches what the source actually shows. 

 

Comment 4 : The Abstract still calls PET/CT "superior in sensitivity and specificity" versus conventional imaging, which doesn't quite square with the body text or the Rama meta-analysis on response sensitivity; "for metabolically active disease" would thread that needle.

Response 4 : We thank the Reviewer for this observation, which is correct. As the body of the manuscript and the meta-analysis by Rama et al. indicate, WB-MRI tends to be more sensitive for diffuse marrow infiltration, whereas FDG PET/CT provides greater specificity for metabolically active disease. We have therefore revised the Abstract to remove the claim of overall superiority and to specify that the sensitivity and specificity of FDG PET/CT refer to the detection of metabolically active disease.

Reviewer 4 Report

Comments and Suggestions for Authors

The authors have meticulously addressed all the points and revisions raised during the peer-review process. Based on the comprehensive revisions made, the manuscript has undergone significant structural refinement and enhancements. The study presents a novel and well-designed investigation, supported by solid methodology and meaningful discussion of its contributions to the field. 

Author Response

Comment : The authors have meticulously addressed all the points and revisions raised during the peer-review process. Based on the comprehensive revisions made, the manuscript has undergone significant structural refinement and enhancements. The study presents a novel and well-designed investigation, supported by solid methodology and meaningful discussion of its contributions to the field. 
Response : We sincerely thank the Reviewer for the very positive evaluation of our revised manuscript and for the encouraging comments. We are grateful for the time and effort dedicated to reviewing our work throughout the process.