The Role of Low Dose Whole Body CT in the Detection of Progression of Patients with Smoldering Multiple Myeloma

Introduction: Multiple myeloma (MM) is the second most common haematological malignancy and is characterized by bone marrow infiltration of monoclonal plasma cells and end-organ involvement. Smoldering MM (SMM) is an intermediate clinical entity between MGUS and MM, with a risk of progression to symptomatic disease at 10% per year. Bone disease is the most frequent related symptom of MM, with approximately 90% of patients developing bone lesions throughout their disease course. Therefore, imaging plays a crucial role in diagnosis and management of these patients. Conventional radiography was traditionally considered as the standard of care, however the limited sensitivity in detecting osteolytic bone lesions has led to more advanced imaging modalities. Imaging also is of high importance to discriminate MM from smoldering disease, since the presence of bone lesions establishes the diagnosis of active disease and requires treatment initiation. Computed tomography (CT) was found to be the most sensitive modality in detecting small osteolytic bone lesions less than 5 mm. Ionizing radiation exposure was one of the main limitations of this technique. Technological advances have made possible low dose assessment of the entire skeleton with effective radiation doses comparable to those of a whole-body plain radiographic skeletal survey. Furthermore, the low dose CT is widely available and has a very short scan time. Therefore, whole-body low dose CT (WBLDCT) has been incorporated in the latest diagnostic criteria of the IMWG. The purpose of this study was to evaluate the role of WBLDCT in the early identification of patients with asymptomatic MM who progress with bone disease only and who require immediate antimyeloma treatment. Patients and Methods: Our study was approved by the local IRB and all patients provided informed consent. All patients diagnosed with SMM based on the 2003 International Myeloma Working Group (IMWG) definition of SMM were serially assessed with WBLDCT from July 2013 until March 2020 as part of our institutional workup. The assessments were performed at baseline, 1-year post diagnosis and every 1 year thereafter. The patients enrolled in the study were those who had at least 2 consecutive CT assessments at the above described time points. All WBLDCT exams were performed with a 16-detector CT scanner. The CTs were evaluated by two experienced radiologists, blinded to the clinical and laboratory data. RESULTS We prospectively evaluated 100 patients with SMM (median age at diagnosis 61 years, range 40-86 years, 52 female /48 male) who underwent WBLDCT at the above described time points. Median number of WBLDCTs exams performed was 2.5 (range 2-5). Totally, 31 patients progressed (either with CRAB criteria and/or at least one myeloma defining event). During a median follow up of 57 months 31 patients have progressed (with either CRAB criteria and/or at least one myeloma defininf event). Importantly, 10 of 31 patients progressed only with bone lesions that were identified on the scheduled WBLDCT as per protocol. Median time to progression from asymptomatic to symptomatic disease for all patients has not been reached, while median time for those who actually progressed was 22 months (95% CI:15,6-28,4). For the subgroup of patients who progressed with bone lesions only the median time was also 22 months (95%CI:3,4-40,6). Median time to progression was not statistically different between the two progressor subgroups. All patients were initiated with antimyeloma treatment immediately post evolution to symptomatic disease. PFS for all 31 patients at first line treatment was 52 months (95%CI:34,5-69,5) and median PFS for bone progressors has not yet been reached. Among the patients who progressed 29 were alive at the time of the analysis. The 2 deaths that occurred were one related (progressive disease) and one unrelated to multiple myeloma (cardiovascular event). Neither had progressed with isolated bone involvement. Conclusion: In conclusion, our strategy allowed early detection of bone lesions in 10% of our patients and these patients were immediately initiated with antimyeloma treatment to avoid further myeloma-related complications. Consecutive low-dose WBLDCT studies can identify early myeloma evolution to symptomatic disease and optimize the disease monitoring along with our therapeutic strategy. Disclosures Gavriatopoulou: Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Janssen: Consultancy, Honoraria, Other: Travel/accommodations/expenses, Research Funding; Pfizer: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel/accommodations/expenses. Terpos:Janssen: Honoraria, Other: travel expenses , Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Medison: Honoraria; Amgen: Honoraria, Research Funding; Genesis: Honoraria, Other: travel expenses , Research Funding. Dimopoulos:Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria; Amgen: Honoraria; Takeda: Honoraria.

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The Role of Low Dose Whole Body CT in the Detection of Progression of Patients with Smoldering Multiple Myeloma

Blood Cancer Journal ◽

10.1038/s41408-020-00360-9 ◽

2020 ◽

Vol 10 (9) ◽

Author(s):

Maria Gavriatopoulou ◽

Andriani Βoultadaki ◽

Vassilis Koutoulidis ◽

Ioannis Ntanasis-Stathopoulos ◽

Charis Bourgioti ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Low Dose ◽

Imaging Modality ◽

Whole Body ◽

Bone Lesions ◽

Symptomatic Disease ◽

Whole Body Ct ◽

Asymptomatic Patients

Abstract Multiple myeloma (MM) is the second most common hematological malignancy, characterized by plasma cell bone marrow infiltration and end-organ involvement. Smoldering MM (SMM) is an intermediate clinical entity between MGUS and MM, with a risk of progression to symptomatic disease 10% per year. Bone disease is the most frequent symptom of MM, with ~90% of patients developing bone lesions throughout their disease course. Therefore, imaging plays a crucial role in diagnosis and management. Whole-body low-dose CT (WBLDCT) is widely available and has been incorporated in the latest diagnostic criteria of the IMWG. The purpose of this study was to evaluate the role of WBLDCT in the early identification of lesions in patients with SMM who progress solely with bone disease. In total, 100 asymptomatic patients were consecutively assessed with WBLDCT from July 2013 until March 2020 at baseline, 1-year after diagnosis and every 1 year thereafter. Ten percent of patients were identified as progressors with this single imaging modality. This is the first study to evaluate prospectively patients with SMM at different time points to identify early bone lesions related to MM evolution. Serial WBLDCT studies can identify early myeloma evolution and optimize disease monitoring and therapeutic strategies.

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A Phase I/II Trial of Bortezomib, Low Dose Intravenous Melphalan and Dexamethasone for Patients with Relapsed Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3542.3542 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3542-3542 ◽

Cited By ~ 6

Author(s):

Rakesh Popat ◽

Catherine Williams ◽

Mark Cook ◽

Charles Craddock ◽

Supratik Basu ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Median Time ◽

Low Dose ◽

Overall Response Rate ◽

Response Rate ◽

Chemotherapeutic Agents ◽

Time To Progression ◽

Overall Response ◽

Grade 3

Abstract Background: Bortezomib is an effective treatment for patients with relapsed multiple myeloma with an overall response rate (MR+PR+CR) of 46% and time to progression of 6.2 months (APEX study). We and others have previously demonstrated potent in-vitro synergy with chemotherapeutic agents such as melphalan and it is likely that this will translate into improved responses in the clinical setting. Methods: This was a multi-centre, non-randomised Phase I/II clinical trial for patients with relapsed multiple myeloma. Bortezomib 1.3mg/m2 was given on Days 1,4,8 and 11 of a 28 day cycle, and intravenous melphalan on Day 2 for a maximum of 8 cycles. In the Phase I component melphalan was given at 2.5, 5,7.5 and 10mg/m2 in a dose escalation scheme and the maximum tolerated dose (MTD) of 7.5mg/m2 was taken forward to an expanded Phase II component. Dexamethasone 20mg on the day of and the day after each dose of bortezomib was permitted for progressive or stable disease after 2 or 4 cycles respectively. Responses were classified by EBMT criteria. Results: To date 39 patients have been enrolled (median age 61years [range 40–77]) with a median of 3 lines of prior therapy [range 1–5] of which 26 (67%) have had one previous autologous stem cell procedure and 4 (10%) have had two. 23 (59%) have had prior exposure to thalidomide and 4 (10%) to bortezomib. 36 have now completed at least 1 cycle and are therefore evaluable for response. The overall response rate (CR+PR+MR) across all treatment levels was 75% rising to 81% (CR 11%; nCR 3%; VGPR 8%; PR 39%; MR 19%) with the addition of dexamethasone in 13 cases for suboptimal response. Rapid responses were seen with the median time to response being 1 month [range 1–6]. The median time to progression is 10.1 months and the median overall survival has not yet been reached at a median follow-up of 7.4 months. Of the patients that have had disease progression 7 (35%) had responses of longer duration than their previous therapy. The MTD was defined by unacceptable delays in administering treatment due to myelosuppresion. The toxicities have been acceptable with 13 SAEs reported of which 8 were hospitalisation due to infection. The most common grade 3–4 adverse events were: thrombocytopenia (53%), infections (25%), neutropenia (17%) and neuropathy (17%). Three grade 3 cardiac events were seen (myocardial infarction, atrial fibrillation and cardiac failure) and GCSF was administered to 13 patients as treatment and prophylaxis of grade 4 neutropenia. 13 patients were withdrawn from the study due to toxicity of which 7 were for neuropathy and 3 for delayed haematological recovery. Of note, 11 patients (28%) had pre-existing grade 1 neuropathy prior to starting therapy. Summary: The combination of bortezomib, low dose intravenous melphalan and dexamethasone appears to be highly effective in patients with relapsed multiple myeloma where a response rate of 81% is seen with 14% achieving nCR/CR. The toxicity profile associated is predictable, manageable and predominantly haematological. Recruitment is ongoing to a total of 53 patients.

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Bortezomib, Low Dose Intravenous Melphalan and Dexamethasone for Patients with Relapsed Multiple Myeloma: Final Results of a Phase I/II Clinical Trial.

Blood ◽

10.1182/blood.v110.11.2713.2713 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2713-2713

Author(s):

Rakesh Popat ◽

Catherine Williams ◽

Mark Cook ◽

Charles Craddock ◽

Supratik Basu ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Phase I ◽

Median Time ◽

Low Dose ◽

Overall Response Rate ◽

Response Rate ◽

Time To Progression ◽

Overall Response ◽

Grade 3

Abstract Background: Bortezomib is an effective treatment for patients with relapsed multiple myeloma with an overall response rate (≥PR) of 43% and time to progression of 6.2 months (APEX study). We and others have previously demonstrated potent in-vitro synergy with chemotherapeutic agents such as melphalan and it is likely that this will translate into improved responses in the clinical setting. Methods: This was a multi-centre, non-randomised Phase I/II clinical trial for patients with relapsed multiple myeloma. Bortezomib 1.3mg/m2 was given on Days 1,4,8 and 11 of a 28 day cycle, and intravenous melphalan on Day 2 for a maximum of 8 cycles. In the Phase I component melphalan was given at 2.5, 5,7.5 and 10mg/m2 in a dose escalation scheme and the maximum tolerated dose (MTD) of 7.5mg/m2 was taken forward to an expanded Phase II component. Dexamethasone 20mg on the day of and the day after each dose of bortezomib was permitted for progressive or stable disease after 2 or 4 cycles respectively. Responses were defined by EBMT criteria. Results: 53 patients were enrolled (median age 61years [range 40–77]) with a median of 3 lines of prior therapy [range 1–5] of which 26 (67%) have had one previous autologous stem cell procedure and 4 (10%) have had two. 23 (59%) have had prior exposure to thalidomide and 4 (10%) to bortezomib. The overall response rate (≥PR) across all treatment levels (n=52) was 65% rising to 69% (CR 19%; nCR 4%; VGPR 6%; PR 40%; MR 15%) with the addition of dexamethasone in 27 cases for suboptimal response. Of the 32 patients treated at the MTD the overall response rate (≥PR) was 78% (CR 28%; nCR 6%; VGPR 6%; PR 38%; MR 9%). Rapid responses were seen with the median time to response being 1 month [range 1–6]. The median time to progression was 10 months and the median overall survival has not yet been reached at a median follow-up of 17 months. Of the patients that have had disease progression 7 (35%) had responses of longer duration than their previous therapy. The MTD was defined by unacceptable delays in administering treatment due to myelosuppresion. The toxicities have been acceptable with 13 SAEs reported of which 8 were hospitalisation due to infection. The most common grade 3–4 adverse events were: thrombocytopenia (53%), infections (25%), neutropenia (17%) and neuropathy (17%). Three grade 3 cardiac events were seen (myocardial infarction, atrial fibrillation and cardiac failure) and GCSF was administered to 13 patients as treatment and prophylaxis of grade 4 neutropenia. 19 patients were withdrawn from the study due to toxicity of which 7 were for neuropathy and 3 for delayed haematological recovery. Of note, 11 patients (28%) had pre-existing grade 1 neuropathy prior to starting therapy. Summary: The combination of bortezomib, low dose intravenous melphalan and dexamethasone appears to be highly effective in patients with relapsed multiple myeloma with a response rate (≥PR) at the MTD of 78% including 34% nCR/CR. The toxicity profile is predominantly haematological.

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The Role of Serum Immunoglobulin Free Light Chain In Response and Progression In Waldenstrom Macroglobulinemia

Blood ◽

10.1182/blood.v116.21.3095.3095 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3095-3095

Author(s):

Xavier Leleu ◽

Wanling Xie ◽

Meghan Rourke ◽

Ranjit Banwait ◽

Renee Leduc ◽

...

Keyword(s):

Median Time ◽

Research Funding ◽

Response Rate ◽

Early Response ◽

Response To Therapy ◽

Time To Progression ◽

Therapy Initiation ◽

M Spike

Abstract Abstract 3095 Introduction: Waldenstrom macroglobulinemia (WM) is a low grade B cell lymphoma characterized by the secretion of IgM protein in the serum. The IgM level lacks sensitivity due to its prolonged half-life. The serum free light chain (sFLC) assay has shown significant clinical application in plasma cell dyscrasias, specifically in multiple myeloma, and is used to monitor response to therapy. In this study, we sought to examine the role of sFLC in the response and progression of patients with WM. Methods: This study was performed using serum collected from a homogeneous cohort of patients diagnosed with WM and uniformly treated on a phase 2 trial using the combination of bortezomib with rituximab, previously untreated (N=26) or relapsed and or refractory to prior therapy (N=37). Patients eligible for this analysis must have measurable sFLC levels at baseline. A total of 48 patients were included. FLC response is defined as achievement of normal iFLC value or 50% decrease from baseline in the iFLC level during therapy and follow-up. Concordance between FLC and IgM response rate was evaluated using Kappa statistics. Correlation was evaluated using Spearman correlation coefficient. Time to progression was estimated using Kaplan-Meier methodology. We also did landmark analysis to compare overall response rate and time to progression by FLC or IgM response status at 2 months after therapy initiation; Fisher Exact test or Log-rank test were used. Results: The median iFLC value was 103.50mg/L (range 22.5–3540), the median kappa over lambda ratio was 13.45 (0.01-665), and the median serum IgM value by nephlometry was 3995 mg/dL (537-10,800). Overall, as per M spike response criteria, 29 (60%, 90% CI: 48%, 72%) patients responded, e.g. had partial response or better, and 19 patients failed to obtain response. Using serum IgM protein measurement by nephlometry during therapy and follow up post-therapy, 35 (73%, 90% CI: 60%, 83%) patients responded with a PR or better (>50% decrease), with 3 (6%) having normalization of their serum IgM. In comparison, iFLC response during treatment and follow up occurred in 38 (79%, 90% CI: 67%, 88%): with 2(4%) having normalization of value, 21(44%) having 50% reduction and 15(31%) having both. The time to iFLC response and IgM response among patients who achieved response by both criteria was calculated (N=33). The median time to iFLC response was 2.1 months (range 0.9–28.7months), while the median time to IgM response was 3.0 months (0.9-14.7) (p=0.07). The median time to progression per the protocol was 18.9 months (95% CI:10.5-NR). The Kappa concordance between iFLC 25% increase and M spike progression was 0.63 (95% CI: 0.41–0.84). This showed a better concordance compared to using the iFLC >50% definition (kappa=0.58, 95% CI: 0.35, 0.81), indicating that progression using iFLC>25% would be a better definition for patients with WM. The median time to progression by iFLC>25% increase was 13.7 months (95% CI:10.9-19.4) and the median time to IgM >25% increase was 14.6 months (95% CI: 9.5–19.1), showing a more rapid detection of progression by iFLC compared to M spike and IgM measurements. We next examined whether attaining a response using iFLC can be a predictor of overall response to therapy. Seventeen patients (35%) achieved an iFLC response at 2 months after therapy initiation. Patients with early iFLC response were more likely to have intermediate/high ISS-WM stage, elevated B2M or low Hemoglobin<11.5 gm/dL (p<0.05). Early iFLC response was related to overall IgM response during therapy and follow up (p=0.02). In multivariable models when adjusting for ISS stage, B2M or Hgb, there was no significant association between FLC early response and TTP either by protocol, FLC or IgM criteria. However, there was trend that early response was related to prolonged TTP especially when adjusting for hgb risk factors (HRs ranges from 0.63∼0.80, p>0.3 for various TTP endpoints. Conclusion: iFLC may be a useful marker of tumor measurement that correlates well with IgM and M spike measurements. The time to iFLC response was shorter by 1 month compared to IgM or M spike measurement. The median time to progression by iFLC was shorter by 1 month compared to IgM. There was a trend that early response was related to prolonged TTP when adjusting for other risk factors. Disclosures: Leleu: Celgene: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Chugai: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; LeoPharma: Consultancy, Honoraria.

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Knockdown Of Matrix Metalloproteinase 13 (MMP13) In 5TGM1 Multiple Myeloma Cells Inhibits Development Of Lytic Bone Lesions In Vivo

Blood ◽

10.1182/blood.v122.21.879.879 ◽

2013 ◽

Vol 122 (21) ◽

pp. 879-879

Author(s):

Jing Fu ◽

Shirong Li ◽

Huihui Ma ◽

G. David Roodman ◽

Markus Y. Mapara ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Growth ◽

Trabecular Bone ◽

Research Funding ◽

Bone Lesions ◽

Mineral Density ◽

Lytic Bone Lesions

Abstract Background Multiple myeloma (MM) cells secrete osteoclastogenic factors that activate osteoclasts (OCL) and contribute to development of pure lytic bone lesions in MM patients. We have recently shown that i) MMP13 is highly expressed by MM cells and ii) exogenous MMP13 increases OCL fusion and bone resorption (Feng et al, 2009). Further, MMP13 mediates these effects by upregulating dendritic cell-specific transmembrane protein (DC-STAMP), which is critical for OCL fusion and activation (Fu et al, 2012). Here, we investigated the role of MMP13 in MM-related bone disease (MMBD) in vivo and the underlying osteoclastogenic mechanisms. Methods and Results The role of MMP13 in MMBD was examined in vivo by the intratibial 5TGM1-GFP mouse MMBD model. Mouse MM cell line 5TGM1-GFP cells were transduced by pLKO.1-puro empty vector (EV) or sh-MMP13 (MMP13-KD) lentivirus followed by puromycin selection for 2 weeks. MMP13 knockdown in 5TGM1-MMP13-KD cells were confirmed by quantitative RT-PCR. 1×105 5TGM1-GFP-EV and 5TGM1-GFP-MMP13-KD cells were bilaterally intratibially injected into Recombination Activating Gene 2 (Rag2) knockout mice (n=9). After 4 weeks of tumor growth, tibiae were separated for micro quantitative computed tomography (micro-QCT) followed by immunohistochemistry (IHC) analysis. Following 5TGM1-GFP-EV injection, micro-QCT analysis of the tibiae and adjacent femurs indicated severe bone erosions, especially within trabecular bone. By contrast MMP13 KD inhibited the development of MM-induced bone lesions. Bone histomorphologic analysis showed that compared to 5TGM1-GFP-EV, MMP13-KD significantly reduced the MM induced trabecular bone loss with increased relative bone volume (0.069 ± 0.018 vs 0.0499 ± 0.016%; P=0.001), connective density (54.94 ± 33.03 vs 27.33 ± 18.97mm3; P=0.002), trabecular bone numbers (3.26 ± 0.29 vs 3.06 ± 0.33mm-1; P=0.032) and bone mineral density (159.1 ± 20.7 vs 134.2 ± 18.6mg/cm3; P=6E-04); as well as decreased triangulation bone surface to volume ratio (66.12 ± 6.67 vs 73.28 ± 10.07; P=0.017) and triangulation structure model index (3.05 ± 0.36 vs 3.42 ± 0.35 mm-1; P=0.002). In accordance with our finding that MMP13 induced OCL fusion, IHC results confirmed the presence of smaller TRAP+OCLs adjacent to the tumor in mice injected with 5TGM1-GFP-MMP13-KD cells compared with 5TGM1-GFP-EV cells. Although MMP13 knockdown showed no effects on 5TGM1-GFP cell growth in vitro, in vivo tumor progression represented by fluorescence imaging and sera immunoglobin 2G level (0.96 ± 0.12 vs 1.10 ± 0.11 mg/ml) was significantly inhibited (P=0.009 and 0.03 respectively), indicating MMP13 depletion in MM cells impaired OCL activation which, in turn, failed to support MM cell growth in bone marrow microenvironment as effectively in EV control group. In vitro studies demonstrated that MMP13 directly induced ERK1/2 phosphorylation in pre-osteoclasts. Consistent with a critical role for ERK1/2 phosphorylation in regulating OCL formation, U0126 (ERK1/2 inhibitor) blocked MMP13-induced ERK1/2 phosphorylation, ERK1/2-dependent DC-STAMP upregulation and MMP13-induced OCL fusion (P<0.01). Conclusion Our results demonstrate that silencing MMP13 expression in MM cells inhibits MM cell-induced OCL fusion and development of lytic bone lesions in vivo, indicating that MMP13 is essential for MM-induced bone diseases. Further, MMP13 upregulates DC-STAMP expression and OCL fusion via the activation of ERK1/2 signaling. Our data suggest that targeting MMP13 may represent a novel therapeutic approach for the treatment of MMBD. Disclosures: Roodman: Amgen: Membership on an entity’s Board of Directors or advisory committees; Lilly: Research Funding. Lentzsch:Celgene: Research Funding.

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The benefit of whole-body low-dose unenhanced multidetector computer tomography (WBLD-MDCT) for follow up and therapy response monitoring in patients with multiple myeloma: Correlation with hematologic parameters

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7607 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7607-7607

Author(s):

M. S. Horger ◽

C. Driessen ◽

C. Brodoefel ◽

C. Faul ◽

P. Pereira ◽

...

Keyword(s):

Multiple Myeloma ◽

Computer Tomography ◽

Low Dose ◽

Laboratory Data ◽

Whole Body ◽

Acquisition Time ◽

Bone Lesions ◽

Appendicular Skeleton ◽

Multidetector Computer Tomography

7607 Background: To assessthe value of whole-body low-dose multidetector computer tomography (WBLD-MDCT) as diagnostic and survey modality in multiple myeloma (MM), and as a one-stop alternative (Horger et al. EJR 2005;54:289–297) to established imaging techniques (e.g. x-ray and MRI). Methods: Between 7/2001 and 2/2005, WBLD-MDCT scans were obtained in 90 consecutive patients with histologically proven stage II-III MM, all patients having 2 or more scans (mean = 3,8; range = 2–6). CT-scans were performed using a standardized low-dose protocol and the number, size and density of focal or diffuse medullary (in the appendicular skeleton and pelvis) and extra-medullary lesions as well as osteolysis were analysed for each examination and at follow up. Results were correlated with current standard MM laboratory data and at follow up in order to assess correct temporal recognition of significant myeloma changes by both methods. Results: Detection and follow up of medullary and extra-medullary MM lesions and osteolysis by WBLD-MDCT resulted in a sensitivity of 92%, a specificity of 93%, a NPV of 95%, a PPV of 85% and a likelihood ratio for patients with CT-abnormalities to present changes in the course of their disease of 12. Results of radiologic and hematologic analysis showed high agreement at follow up (median, 3 mo). However, agreement of both techniques at the time of investigation was only moderate (κ = 0.629), with CT being correct in 60% of mismatching cases. Thus, CT enabled earlier detection of MM changes. WBLD-MDCT assessed correctly the course of disease in all 4 patients with nonsecretory MM. Evaluation of stability was optimal in all patients. Conclusions: WBLD-MD represents a reliable, widespread, quick (75s acquisition time), and cost-effective imaging technique in MM, allowing detection of bone marrow involvement, extra-medullary tumors and lytic bone lesions in different clinical settings (staging, follow up, therapy monitoring, evaluation of stability). WBLD-MDCT repeatedly allowed detection of changes in the course of the disease prior to laboratory data, especially in extramedullary MM relapse and nonsecretory MM. No significant financial relationships to disclose.

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Clinical implication of PET/CT and skeletal bone survey in evaluation of multiple myeloma and related monoclonal disorders.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18574 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18574-e18574

Author(s):

Muhammad Jawad Popalzai ◽

Homam Alkaied ◽

Maryah Mansoor ◽

Arnold Brenner ◽

Qun Dai

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Skeletal Survey ◽

Whole Body ◽

Bone Lesions ◽

Positive Finding ◽

Pet Ct ◽

Plasma Cell Disorders ◽

Smoldering Myeloma

e18574 Background: Whole body skeletal x-ray is considered a gold standard for detecting bone lesions in patients with plasma cell disorders. PET/CT has been increasingly used but its role is yet to be defined. We conducted this study to compare the role of these two imaging modalities in evaluation of plasma cell disorders. Methods: This is single institution, retrospective study to evaluate the role of skeletal survey and PET/CT in patients with multiple myeloma, smoldering myeloma and MGUS. Patients’ records, imaging reports and subsequent management plan were reviewed and compared. Results: A total of 16 patients were reviewed. Among them, 11 patients had multiple myeloma, 2 had smoldering myeloma, and 3 had MGUS. 7/11 patients with multiple myeloma had concordant findings on skeletal survey and PET. 3 of these patients had negative skeletal surveys but had positive finding on PET/CT. PET/CT also identified plasmacytomas in 2 patients. In 2 patients with smoldering myeloma, both skeletal survey and PET/CT were negative. 2/3 patients with MGUS had lytic lesions on skeletal surveys which were not revealed by subsequent PET/CT’s. Both patients were observed without treatment and at 2 years follow up did not show disease progression. Conclusions: Our retrospective analysis showed that skeletal survey is still important for base-line evaluation of bone lesions in multiple myeloma and related monoclonal disorders. PET/CT is more sensitive for detection of bone lesions and can also detect extraosseous lesions such as plasmacytomas. Using tumor metabolic activity, PET/CT may improve diagnostic accuracy and is complementary to conventional skeletal survey. [Table: see text]

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Skeletal Survey in Multiple Myeloma: Role of Imaging

Current Medical Imaging Formerly Current Medical Imaging Reviews ◽

10.2174/1573405617666210126155129 ◽

2021 ◽

Vol 17 ◽

Author(s):

Paolo Spinnato ◽

Giacomo Filonzi ◽

Alberto Conficoni ◽

Giancarlo Facchini ◽

Federico Ponti ◽

...

Keyword(s):

Multiple Myeloma ◽

Low Dose ◽

Imaging Modality ◽

Bone Marrow Involvement ◽

Conventional Radiography ◽

Response To Therapy ◽

Whole Body ◽

Initial Assessment ◽

Bone Lesions ◽

Pet Ct

: Bone disease is the hallmark of multiple myeloma. Skeletal lesions are evaluated to establish the diagnosis, to choose the therapies and also to assess the response to treatments. Due to this, imaging procedures play a key-role in the management of multiple myeloma. For decades, conventional radiography has been the standard imaging modality. Subsequently, advances in the treatment of multiple myeloma have increased the need for accurate evaluation of skeletal disease. The introduction of new high performant imaging tools, such as whole-body low dose computed tomography, different types of magnetic resonance imaging studies, and 18F-fluorodeoxyglucose positron emission tomography, replaced conventional radiography. In this review we analyze the diagnostic potentials, indications of use, and applications of the imaging tools nowadays available. Whole body low-dose CT should be considered as the imaging modality of choice for the initial assessment of multiple myeloma lytic bone lesions. MRI is the gold-standard for detection of bone marrow involvement, while PET/CT is the preferred technique in assessment of response to therapy. Both MRI and PET/CT are able to provide prognostic information.

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Results of a Prospective Study Comparing Whole-Body Diffusion-Weighted Magnetic Resonance Imaging with Skeletal X-Ray and Magnetic Resonance of the Spine for Assessing Bone Disease in Multiple Myeloma.

Blood ◽

10.1182/blood.v120.21.2913.2913 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2913-2913

Author(s):

Francesco Spina ◽

Paolo Potepan ◽

Giovanna Trecate ◽

Eros Montin ◽

Vittorio Montefusco ◽

...

Keyword(s):

Multiple Myeloma ◽

Magnetic Resonance ◽

Prospective Study ◽

Bone Disease ◽

Whole Body ◽

Bone Lesions ◽

Disease Response ◽

X Ray ◽

Time Points ◽

A Prospective Study

Abstract Abstract 2913 Introduction: Standard assessment of bone disease in multiple myeloma (MM) is based on skeletal X-ray (XR) and magnetic resonance (MR) of the spine (MRS). Diffusion-weighted MR (DW-MR) is a novel functional MR that detects changes of water diffusion through cells in tissues. To assess the value of DW-MR to detect bone lesions in MM, we designed a prospective study comparing whole-body DW-MR with XR and MRS. The study included symptomatic patients (pts) at diagnosis or at relapse before the start of the treatment; they performed XR, MRS, conventional whole-body MR (WB-MR), and whole-body DW-MR at enrolment (time point 1, T1), after treatment (T2), and after 6 months of follow-up (T3). Clinical and hematologic, including bone marrow (BM), disease evaluations were done at the same time points. The study was approved by the Institutional Review Board in 2008 (protocol 44/08). Methods: The primary objective was to assess whether DW-MR could detect more focal lesions (FL) than XR and MRS. Secondary objectives were to correlate the changes of FL detected by DW-RM with response, to assess the prognostic value of DW-RM, and to compare DW-MR with WB-MR. MRS, WB-MR and DW-MR were done in a single 45-minute session on a standard 1.5 Tesla MR scanner. DW-MR consisted of multiple stacked axial Echo Planar Imaging sequences at 4 b-values, evaluated by PET-like Maximum Intensity Projection and Multi-Planar reconstructions at the highest b-value (1000). Each exam was independently read by 3 radiologists experienced in MM. 53 bone segments per exam were evaluated in whole-body imaging (XR, WB-MR and DW-MR); 25 segments were evaluated in spine imaging (MRS and DW-MR). All the patterns (focal, diffuse, mixed, and salt-and-pepper) of bone lesions were recorded. Matching FL detected by >=2 radiologists were counted for the present analysis. Statistics were carried out with the Wilcoxon signed rank test for methods comparisons and the Kruskal-Wallis test to assess intra-patient changes through the time points. Survival and relapse were analyzed by Kaplan-Meier and Cumulative Incidence method with log-rank and Gray's tests. All tests were 2-sided. Results: Between 2008 and 2010, 36 symptomatic pts were enrolled: 43% were at diagnosis, 57% at relapse; 71% of pts had ISS stage 1 MM. The most frequent isotype was IgG (57%), median BM infiltration was 30%. FISH on selected CD138+ plasma cells detected t(4;14) and del(17) in 9 and 6% of pts. At T1, the DW-MR detected more FL than standard XR (306 vs 117 FL, p<0.01), WB-MR (306 vs 225 FL, p=0.02), and MRS (165 vs 116 FL, trend, p=0.08). At T2, a similar number of FL was detected by DW-MR and XR (97 vs 104 FL, p=0.99) and MRS (20 vs 20 FL, p=1.00); DW-MR detected more FL than WB-MR (97 vs 60 FL, p=0.01). At T3, the DW-MR detected more FL than WB-MR (88 vs 45 FL, p<0.01) and MRS (24 vs 11 FL, p=0.05), and similar FL compared to XR (88 vs 62 FL, p=0.27). Considering all the time points, the DW-MR detected more FL than XR (p=0.01), WB-MR (p<0.01) and MRS (p=0.02). Between T1 and T2, all pts were treated with IMIDS or bortezomib–based regimens, 33% underwent a stem cell transplant. Overall response rate (ORR) was 73%. DW-MR detected significant changes of FL according to disease response at T2 (from 79 to 15 FL in >=VGPR, from 69 to 27 in PR, and from 34 to 55 FL in SD or PD, p=0.04 [whole body]; p=0.02 [spine]). Also MRS consistently detected response (p=0.04), whereas WB-MR showed only a weak correlation (p=0.13); XR did not detect response (p=0.55). Between T2 and T3, pts had minor changes of disease status (72% ORR), and, accordingly, all the radiological exams did not show significant changes in FL. One-, 2- and 3-year progression-free survival (PFS) was 80, 62 and 37% (median, 30 months), OS was 88, 79 and 76% (median not reached), and relapse incidence was 15, 32, and 54% (median, 21 months). Since the median number of FL detected by DW-MR at T1 was 4 (range, 0–49 FL), we compared PFS, relapse, and OS by the presence of <=4 FL or >4 FL before treatment. Patients with <=4 FL at DW-MR had better PFS (72 vs 50% at 2 years, p=0.02) and less relapse incidence (17 vs 50%, p<0.01) than those with >4 FL, whereas OS was not different (84 vs 75%, p=0.76). Conclusions: DW-MR is superior to XR, MRS, and WB-MR in detecting FL in MM. The number of FL detected by DW-MR before treatment predicts PFS and relapse incidence. DW-MR is a functional imaging that effectively detects the bone disease changes according to treatment response and can be used to monitor disease response. Disclosures: No relevant conflicts of interest to declare.

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Lenalidomide and Dexamethasone Alone Is Equivalent To Lenalidomide and Dexamethasone With Autologous Stem Cell Transplant In Newly Diagnosed Multiple Myeloma: Interim Study Results Of a Randomized Trial

Blood ◽

10.1182/blood.v122.21.3180.3180 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3180-3180 ◽

Cited By ~ 1

Author(s):

Jordan M. Schecter ◽

Kristen Kipps ◽

Amy O'Sullivan ◽

Kent A. Griffith ◽

Daniel Normolle ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Interim Analysis ◽

Research Funding ◽

Low Dose ◽

Secondary Malignancy ◽

Similar Response ◽

Newly Diagnosed

Abstract The current standard of care for patients with newly diagnosed multiple myeloma (MM) aged less than 65 years is high-dose chemotherapy combined with autologous stem cell transplantation (ASCT) based on improved progression free survival (PFS) and overall survival (OS) compared with conventional chemotherapy. The introduction of novel agents, for example lenalidomide and bortezomib over the last decade, has substantially improved MM outcomes providing similar response rates to ASCT. As a consequence, the role of upfront ASCT has become more controversial. Therefore, this randomized clinical trial aims to determine the role of upfront ASCT in patients with newly diagnosed MM patients receiving lenalidomide and low-dose dexamethasone as induction therapy. Patients enrolled into the study were aged ≥18 years with newly diagnosed MM, transplant eligible, and meeting CRAB criteria. Patients were randomized to receive 4 cycles of lenalidomide (25 mg days 1–21) plus low-dose dexamethasone (40 mg days 1, 8, 15, 22) followed by ASCT conditioned with 200 mg/m2 melphalan (Arm A; LD+ASCT) or 8 cycles of lenalidomide plus low-dose dexamethasone (Arm B; LD alone). Both groups received lenalidomide maintenance therapy 10-15 mg for up to 2 years. Patients in both treatment arms received stem cell collection after 4 cycles of lenalidomide plus dexamethasone if at least a partial response was achieved. Patients with stable disease or progressive disease (PD) went off study. The primary objective was to compare the best response between patients treated with lenalidomide plus dexamethasone followed by ASCT and patients treated with lenalidomide plus dexamethasone alone. Secondary objectives were to compare the duration of response (DOR), PFS, and OS between the two treatment arms and to evaluate the secondary malignancies in both arms. Fifty patients with newly diagnosed MM were randomized between February 2008 and May 2013, and 47 patients were eligible for evaluation in this interim analysis; 25 patients randomized to Arm A (LD+ASCT) and 22 patients randomized to Arm B (LD alone). Overall, patients had a median age of 61.6 years (range 48–75), 60% were male, 34% ISS Stage I, 49% ISS Stage II, 17% ISS Stage III. The data were analyzed according to the IMWG response criteria (Blood. 2011 May 5;117(18):4691-5). In an intention-to-treat analysis, there was a trend towards improved overall response rate (ORR) in patients receiving LD+ASCT (96%) compared with patients receiving LD alone (77%; p=0.08) (Table 1). After a median follow-up of 36.8 months (range 1.1–62.7), the median DOR was 13.9 months (95% confidence interval [CI] 4.0–34.1) in the LD+ASCT group compared with 21.2 months (95% CI 11.0–22.9) in the LD group. Overall, 18 patients have PD (10 patients in the LD+ASCT arm and 8 patients in LD arm), and 8 patients have died (4 patents in the LD+ASCT arm and 4 patients in the LD arm). Median PFS for LD+ASCT versus LD was 17.0 months (95% CI 15.5–not estimable) versus 25.2 months (95% CI 9.0–not estimable; p=0.94). Median OS for LD+ASCT versus LD was 57.6 months (95% CI 48.0–not estimable) versus not reached (p=0.94). Two patients in the LD alone arm developed a secondary malignancy, including 1 patient with myelodysplastic syndrome (MDS) 13 months after the start of therapy. This interim analysis of an ongoing randomized clinical study comparing lenalidomide plus low-dose dexamethasone induction with and without upfront ASCT in patients with newly diagnosed MM suggests that addition of ASCT resulted in a trend towards improved ORR. This did not result in a significant difference in terms of PFS or OS between the two treatment arms. In contrast there was a trend of better DOR in the LD alone arm. The data show that LD alone can achieve similar results as LD+ASCT, however careful interpretation is required due to the low patient number and relatively short follow-up. The incidence of secondary malignancy was low, including the development of 1 MDS. Disclosures: Schecter: Celgene: Honoraria, Speakers Bureau. Mapara:Celgene: Research Funding, RO1 Other. Lentzsch:Celgene: Research Funding.

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