Abstract: Autologous stem cell transplantation (ASCT) is feasible and effective in selected older patients with Multiple Myeloma, but specific criteria for evaluating ASCT eligibility in elderly patients are lacking. We evaluated 131 patients aged 65‐75 considered for ASCT at our center: The Charlson Comorbidity Index (CCI), Hematopoietic cell transplantation comorbidity index (HCT‐CI) and IMWG frailty score were obtained at diagnosis, but the intensity of treatment was left to physician's choice. The scores and age's impact on outcome was analyzed: 85 patients were judged transplant eligible, whereas 46 patients received a less intensive treatment (median follow up 27 months). No patients classified as frail had been considered eligible to ASCT with a worse outcome compared to fit and unfit patients (median PFS (progression free survival): 7.9 vs 32.9 and 29.6 months; P 〈  .001). PFS was superior in the ASCT group (35.6 vs 19.9 months, P .013). In the ASCT group, PFS was better in patients aged 65‐69 years than in patients ≥70 (51.5 vs 27.7 months, P .004). Indeed, in unfit patients aged ≥70 the PFS of the ASCT group was comparable to NO ASCT group (18 vs 27 months, P = .33) whereas in unfit patients aged 65‐69 PFS was superior in the ASCT group: 43.3 vs 18.4 months, P .01. ISS III and impaired functional status independently affected PFS in a multivariate analysis ( P .011 and P .006). While CCI and HCT‐CI did not predict different outcome in ASCT patients, the IMWG frailty score would be of help in identifying unfit patients aged 70‐75, whose outcome with ASCT selected by clinical judgment was no better than with less intensive treatments.

Abstract: Introduction: The role of minimal residual disease (MRD) in Multiple Myeloma (MM) as a surrogate biomarker of patients' outcome, as well as the prognostic information of functional imaging response after treatment have been established in recent years. Furthermore, the predictive relevance of sustained MRD negativity assessed by marrow and imaging techniques and its association with an excellent outcome is emerging in clinical trials. Diffusion-weighted whole-body MRI (DW-MRI) is increasingly used in the management of MM patients, but data regarding the predictive role of sustained DW-MRI response after treatment are lacking. The Myeloma Response Assessment and Diagnosis System (MY-RADS) recommendations have established criteria for Response Assessment Category (RAC) (Messiou C et al, Radiology 2019) with a 5 point scale defining the probability of complete imaging response (i.e. RAC 1) or progressive disease after treatment (i.e. RAC 5). We implemented the RAC criteria in our clinical practice and DW-MRI at 1-year in MM patients treated with autologous stem cell transplantation (ASCT) followed by maintenance therapy. Patients and methods: We retrospectively analyzed the outcome of 57 newly diagnosed MM patients (median age 61 years) diagnosed at our institution from January 2015 to December 2019 receiving maintenance therapy after ASCT. Patients underwent DW-MRI evaluation according to MY-RADS criteria at day +100 after ASCT, before maintenance, and after 1 year with the aim of monitoring imaging residual disease. Bone marrow samples were collected for MRD assessment by 8-color FCM (sensitivity 10-5) at day +100 after ASCT, before maintenance, and after 1 year. We focused on sustained 1-year DW-MRI negativity evaluated according to RAC response, and its potential predictive role at that timepoint on progression free survival (PFS) and overall survival (OS). In patients with available 1-year MRD evaluations, concordance between 1-year MRD and DW-MRI results was calculated and the level of agreement was expressed by Cohen's kappa statistics. Results: Out of 57 patients, 23 (40%) were ISS stage 3 and 14 (25%) showed high risk cytogenetics. Patients were treated with the following induction regimens: VTD 42, VRD 5, Dara-VRD 6, KRD 3, KCD 1. Single ASCT with MEL200 conditioning was performed in 33 patients (58%), whereas 24 patients (42%) received double ASCT. Subsequent maintenance was performed with lenalidomide (49 patients, 86%) or daratumumab-lenalidomide (8 patients, 14%). Response rates after ASCT were PR 9%, VGPR 23%, CR 51% and sCR 17%. According to MY-RADS, a complete imaging response (RAC1) at day +100 after ASCT was observed in 34 patients (60%). Sustained 1 year complete imaging response during maintenance therapy was observed in 43 patients (75%). Some residual disease was identified at that timepoint in 14 patients (25%) [RAC 2: 6 (11%), RAC & gt; 2: 8 (14%)]. After a median follow up of 36 months, PFS and OS were significantly longer in patients with sustained 1-year imaging negativity, compared to patients with imaging residual disease (RAC 1 vs RAC ≥2): median PFS 56 vs 24,1 months, p & lt;0,0001, HR 0,11 (95% CI: 0,030-0,382); median OS NR vs 40,5 months, p & lt; 0,0001, HR 0,05 (95% CI: 0,006-0,364). MRD at 1-year timepoint was available in 30 patients and was negative in 28 (93%) cases. Concordance between 1-year DW-MRI and MRD results was high (97%, kappa 0,783: 7% both positive, 90% both negative). Conclusion: Our real-life data analysis confirms the predictive value of imaging residual disease assessment with DW-MRI after ASCT and highlights the importance of achieving sustained imaging MRD negativity during maintenance therapy regardless of different treatment strategies. Moreover, given the high rates of CR seen in patients with MM with novel effective treatment combinations, the detection of residual disease with the combined evaluation of marrow and functional imaging techniques during maintenance therapy can help the physician to identify patients with increased risk of early relapse and particularly poor prognosis. Our preliminary data regarding the high concordance observed between DW-MRI and MRD results during maintenance therapy suggest that DW-MRI could represent a reliable non-invasive technique to monitor residual disease. Disclosures Belotti: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees. Ribolla: Janssen: Membership on an entity's Board of Directors or advisory committees. Cancelli: Amgen: Membership on an entity's Board of Directors or advisory committees. Roccaro: Amgen, Celgene, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees; AstraZeneca,: Research Funding; Associazione Italiana per la Ricerca sul Cancro (AIRC): Research Funding; European Hematology Association: Research Funding; Fondazione Regionale per la Ricerca Biomedica (FRRB), Transcan-2 ERA-NET: Research Funding. Rossi: Sanofi: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Tucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction and aim of the study: monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) have a distinct risk of evolving towards symptomatic multiple myeloma (MM) but it is widely accepted that they should not be treated until clinical evolution. The clinical presentation of symptomatic MM includes severe complications like acute renal failure, spinal cord compression by vertebral collapse, pathologic bone fractures which cannot be completely avoided even by strict follow-up of MGUS/SMM patients. The recent availability of effective and less toxic therapies has fueled renewed interest in the identification of prognostic models able to predict the risk of impending progression of MGUS/SMM patients to symptomatic MM and criteria for MM defining events have been recently broadened to allow an earlier start of treatment even in asymptomatic patients (Rajkumar SV et al, Lancet Oncol 2014). However, from a clinical perspective it would be more important to prevent the development of severe MM related complications by treating those MGUS/SMM considered at high risk of developing them. To this end, we have analyzed known risk factors for MGUS/SMM progression and other disease biomarkers in order to identify those able to consistently predict an high risk of "severe MM" development. Methods: we retrospectively analyzed 67 patients with symptomatic MM with a known previous history of MGUS/SMM, referred to our division from 1985 to December 2014 (23 males, 44 females; median age at MGUS/MM diagnosis 60 years). Focusing on the first assessment of their asymptomatic disease, we compared patients who subsequently developed severe CRAB criteria (Bladé J et al, Hematol Oncol Clin North Am. 2007), defined as having at least one of the following: hypercalcemia 〉 11.5mg/dL, creatinine 〉 4mg/dL, Hb 〈 8 mg/dL, severe bone lesions characterized by pathological fractures or causing spinal nerve compression, and called "severe MM" with patients who lacked severe CRAB symptoms at MM diagnosis, in order to identify risk factors for "severe MM" during its asymptomatic phase. Variables analyzed for comparison were: involved/uninvolved free light chains (FLC) ratio, monoclonal component (MC) quantification, presence of evolving pattern of MC (defined as an increase in the level of MC of at least 10% in 6 months), presence of immunoparesis, LDH levels, 24h-urinary protein levels, Ig isotype and bone marrow plasma cells percentage. Frequency of follow up was also considered (every 6 months or more). Time to treatment start (TTTS) from MGUS/SMM diagnosis, progression free survival (PFS) from first line treatment and overall survival (OS) were also calculated. Results: median 24-hour urine protein levels were significantly higher in MGUS/SMM patients who subsequently developed "severe MM", compared with patients without severe CRAB symptoms at MM diagnosis (140 vs 90mg/24h, p 0.022, see Figure 1), with an increased risk of severe myeloma related complications for MGUS/SMM patients with more than 200mg/24h urine proteins (Odds Ratio 2.65, p 0.037). Risk was highest in 4 MGUS/SMM patients with 24h-urinary protein levels higher than 1500mg (Odds Ratio 8.43, p 0.030) who invariably developed "severe MM". No difference were found comparing other variables. Of note, there was no difference between the two subgroups in terms of median TTTS (5.3 vs 8.3 years for MGUS patients and 1.7 vs 1.6 years for SMM, respectively), PFS ( 24.4 vs 32.2 months, respectively) and OS (nr vs 4.36), although a higher early mortality was observed in patients with "severe MM" (2 y OS 69% vs 93%). Conclusions: increased 24h-urinary protein levels ( 〉 200mg) in MGUS/SMM patients are associated with a higher risk of the occurrence of severe CRAB symptoms at MM progression. Further data with larger series of patients are needed to better define the best predictive threshold for "severe MM". However, patients with more than 1500mg/24h urinary protein loss represent a small subgroup of MGUS/SMM patients who should better start treatment while still asymptomatic. Figure 1. 24h-urinary protein (mg) levels in the asymptomatic phase Figure 1. 24h-urinary protein (mg) levels in the asymptomatic phase Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction: Autologous stem cell transplantation (ASCT) has proven effective in Multiple Myeloma (MM) patients (pts) aged 〈 65. However in several studies ASCT has proven safe and effective also in selected MM pts aged 〉 65. With the increase of treatment options, several geriatric assessment tools have been proposed to help physicians in selecting treatment of appropriate intensity. However specific criteria for evaluating ASCT eligibility in elderly MM pts have been seldom investigated.Patients and Methods: From January 2013 to December 2017 131 consecutive newly diagnosed symptomatic MM pts aged 65-75 (M/F: 66/65) were considered for ASCT at our center according to physician's clinical judgement. The variables included in Charlson Comorbidity Index (CCI), Hematopoietic cell transplantation comorbidity index (HCT-CI), and International Myeloma Working Group (IMWG) frailty score were not considered for selection but were retrieved for this study and pts were classified accordingly. Of note, ADL and IADL were referred to pts status prior the occurrence of MM related symptoms. The impact of age and the predictive role of the above mentioned scores on progression-free survival (PFS) of pts selected or not for ASCT was analyzed. Pts characteristics are shown in Table 1. Results: Of 131 pts, 85 (65%) were judged transplant eligible (ASCT ITT arm) by the clinician and received bortezomib-based induction (VTD 94%, VD 5%, VCD 1%); 72 of them (85%) actually underwent ASCT (70% single, 30% double) with melphalan conditioning 200 mg/sqm in 68% of cases. The 46 pts considered ineligible to ASCT received a less intensive first line treatment (89% VMP, 4% Daratumumab-VMP, 2% MP, 5% steroids/palliation). Complete remission (CR) after the first ASCT was higher in the ASCT (ITT) vs the NO ASCT group (43,5% vs 26%, respectively; p 0.048), whereas ORR and ³VGPR rates were comparable (83% vs 74% and 76,4% vs 61%, respectively). Transplant related mortality (TRM) was 0%. 2 year death rate was 13% in the ASCT (ITT) arm and was due to PD in 91% of cases (the latter 9% concerns a cardiac arrest secondary to aspiration pneumonia in a pt in VGPR 3 months after first ASCT). After a median follow-up of 27 months, PFS was 35,6 in the ASCT (ITT) group vs 19,9 months in NO ASCT pts, respectively; p 0,013, HR 0,42 (95% CI: 0,25-0,71). HCT-CI was ≥2 in 87% of pts overall. PFS was better in pts with HCT-CI 0-1 compared to HCT≥2 (NR vs 27,3 months; p 0,025, HR 0,45, 95% CI 0,23-0,91) and also in pts with HCT-CI ³2 undergoing ASCT (ITT) than in NO ASCT pts: median 34 vs 19,9 months, p 0,008 (HR 0,5, 95%CI 0,30-0,84). CCI was 0-3 in 78% of pts. Their outcome according was similar to pts with CCI 〉 3 but ASCT performed better than NO ASCT also in the few (median PFS 51,4 vs 16,9 months; p 0,04, HR 0,37, 95%CI 0,15-0,95). IMWG frailty score was more useful. No pts classified as FRAIL had been considered eligible to ASCT by clinical decision with a significantly worse outcome compared to FIT and UNFIT pts (median PFS: 7,9 months vs 32,9 and 29,6; FIT vs FRAIL: p 〈 0.0001, HR 0,02, 95%CI 0,004-0,008; UNFIT vs FRAIL: p 〈 0,001, HR 0,03 95%CI 0,007-0,12). Unlike HCT-CI and CCI, the distribution of patients according to IMWG score was more balanced both overall and between the ASCT (ITT) and NO ASCT groups, particularly for UNFIT pts. However on the whole no outcome differences were observed between FIT and UNFIT pts. PFS was better in FIT & UNFIT pts in the ASCT (ITT) group than in the NO ASCT group: median 35,6 months vs 25,8 months; p 0,04, HR 0,54, 95%CI 0,31-0,97. However, in the ASCT (ITT) group, the age group 65-69 years fared better than pts ³70 years (51,5 vs 27,7 months, p 0,0037; HR 0.34, 95% CI 0.17-0.7). Indeed, in IMWG UNFIT patients aged ³70, the PFS of the ASCT (ITT) group was comparable to NO ASCT group (18 vs 27 months, p 0,33) whereas in UNFIT pts aged 65-69, PFS was superior in pts treated more intensively by physician choice: 43,3 months in ASCT (ITT) arm vs 18,4 months in NO ASCT (p 0.01, HR 0.03; 95%CI 0.003-0.24). Conclusion: In an unselected series of elderly MM pts aged 65-75 and undergoing ASCT according to clinical judgement the outcome of ASCT pts was better than those of NO ASCT. CCI and HCT-CI score proved of little help for better identifying the best candidates to ASCT. Conversely the IMWG frailty score would be of help in identifying the category of UNFIT pts aged 70-75 whose outcome with ASCT selected by clinical judgement was no better than with less intensive treatments. Table 1: Disclosures Belotti: Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Cattaneo:GILEAD: Other: Advisory Board. Rossi:TEVA: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD; SANOFI: Other: ADVISORY BOARD; MUNDIPHARMA: Honoraria; ABBVIE: Other: ADVISORY BOARD; JANNSEN: Other; PFIZER: Other: ADVISORY BOARD; ROCHE: Other: Advisory Board; NOVARTIS: Honoraria; SANDOZ: Honoraria; GILEAD: Other: ADVISORY BOARD; BMS: Honoraria; JAZZ: Other: ADVISORY BOARD; AMGEN: Other: ADVISORY BOARD.

Abstract: Introduction: The role of functional imaging in Multiple Myeloma (MM) has evolved in recent years due to the increasing availability of high platform imaging and the prognostic information of imaging response after treatment, as observed in PET/CT studies. Diffusion weighted whole body MRI (DW-MRI) is a functional imaging technique with an emerging role in the management of MM patients (pts) due to its high sensitivity, but consistent data regarding its prognostic role in the detection of residual disease after treatment in MM are lacking. The Myeloma Response Assessment and Diagnosis System (MY-RADS) imaging recommendations have been recently published (Messiou C et al, Radiology 2019) in order to promote standardization in response assessment. Criteria for Response Assessment Category (RAC) have been proposed with a 5 point scale defining the probability of complete imaging response (i.e. RAC 1) or progressive disease after treatment (i.e. RAC 5), but this score still needs to be validated in clinical practice. For this purpose, we performed an external validation of RAC criteria according to MY-RADS in newly diagnosed MM pts in order to evaluate the prognostic role of this technique after autologous stem cell transplantation (ASCT). Furthermore, we tried to correlate the results of MY-RADS with those of minimal residual disease (MRD) assessment by flow cytometry (FCM). Patients and methods: We retrospectively analyzed the outcome of 60 MM pts (median age 63 years) diagnosed between January 2016 to January 2020 who underwent DW-MRI evaluation to assess the response at day +100 after ASCT, before maintenance. After anonymization, images were reviewed according to MY-RADS by Radiologists who were blinded to the results of clinical and biological data. Post ASCT Progression free survival (PFS) was calculated from the date of last ASCT (the second one in case of double ASCT) until progression or death from any cause. The predictive role of MRI RAC response on outcome was analyzed. Bone marrow samples were collected before maintenance for MRD by 8-color FCM (sensitivity 10-5). In pts with MRD evaluations, exploratory PFS analysis was performed; concordance between MRD and DW-MRI results was calculated and the level of agreement was expressed by Cohen's kappa statistics. Results: out of 60 pts, 21 (35%) were ISS stage 3 and 13 (22%) showed high risk cytogenetics. Pts were treated with the following induction regimens: VTD 51, VRD 4, Dara-VRD 3, VCD 1, KRD 1. Single ASCT with MEL200 conditioning was performed in 41 pts (68%), %), whereas 19 patients (32%) received double ASCT. Response rates were VGPR 18,3%, CR 51,6% and sCR 13,3%. MRD before maintenance was available for 44 pts and was positive in 20 (45,5%). According to MY-RADS, a complete imaging response after transplant was observed in 36 (RAC 1: 60%). Some residual MM was identified in 24 (40%) [RAC2: 20 (33%), RAC3: 3 (5%), RAC4: 1 (2%), respectively]. After a median of 28 months, post ASCT PFS was significantly longer in pts with RAC 1 vs RAC ≥2: median NR vs 26,5 months, p 0,017, HR 0,29 (95% CI: 0,10-0,80). Concordance between WB-MRI and MRD results was low (52%, kappa 0,017: 16% both positive, 36% both negative). PFS according to DW-MRI response and MRD was significantly better for pts DW-MRI RAC1 and MRD negative before maintenance, compared to pts with RAC ≥2 and MRD positive results (PFS NR vs 10,6monts; p 0.012, HR 0,11 - 95%CI: 0,02-0,62). Intermediate PFS was observed for pts with either imaging or MRD positive results (PFS NR), with a significantly different outcome of the three subgroups (p 0,021) Figure 1. In 30 pts achieving CR or sCR, residual disease was identified in 14 (47%); in 4 of them by FCM only, in 8 by DW-MRI only, including two pts in sCR, and in two by both techniques. Conclusion: given the high rates of CR seen in pts with MM with new treatment approaches, DW-MRI is a powerful tool to better evaluate the prognosis of pts treated with novel combinations and ASCT. Our external validation of RAC criteria highlights the ability of DW-MRI to stratify pts with different outcome and promotes the standardization in reporting functional imaging response after treatment. The low concordance between DW-MRI response and MRD results suggests that these two techniques may be complementary for the definition of response: their combined use could help clinicians to better refine the prognosis of MM pts achieving CR Figure 1 Disclosures Belotti: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees. Rossi:Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Novartis: Other: Advisory board; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees.