Newly Diagnosed Multiple Myeloma Patients Research Articles

Quadruplet Induction, Autologous Transplantation and Minimal Residual Disease Adapted Consolidation and Treatment Cessation in Older Adults ≥70y with Newly Diagnosed Multiple Myeloma: A Subgroup Analysis of the Master Trial

Background: Half of adults with newly diagnosed multiple myeloma (NDMM) in the US are ≥70y. This age group is often considered ineligible for intensive therapy and not routinely included in prospective clinical trials. The phase II MASTER trial (NCT03224507) for NDMM did not have an upper age limit as eligibility and showed high rates of minimal residual disease- (MRD) negativity among NDMM patients receiving quadruplet induction, autologous stem cell transplantation (ASCT) and response-adapted consolidation therapy (Costa LJ et al JCO 2021). Here, we conducted a post-hoc analysis comparing the outcomes of patients age ≥70y. vs <70y. Methods: The MASTER trial enrolled patients with NDMM, with ECOG ≤2, measurable disease and creatinine clearance ≥40 ml/min as key eligibility criteria. Patients received Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRD based induction, ASCT and response adapted Dara-KRD consolidation. The primary end point was achievement of MRD-negativity (<10-5) at any point during follow-up by NGS (ClonoSEQ®). Secondary endpoints included achievement of MRD <10-6 at any point, rate of MRD negativity post-induction, rate of complete response, progression-free survival (PFS) and overall survival (OS). Those who achieved two consecutive MRD-negative assessments underwent treatment free observation and MRD surveillance (MRD-SURE). For the current analysis, we compared the achievement of primary and secondary endpoints using intent-to-treat principle between the study cohorts. Results: Of the 123 enrolled patients, 24 (19.5%) were ≥70y at the time of diagnosis (5 were ≥75y). Baseline characteristics were similar between the two age groups (Table 1). All 24 patients received planned ASCT. Compared to younger adults, older adults had similar rates of MRD negativity post induction (36% vs 41%; p= 0.66), but lower rates of overall MRD negativity (<10-5) (65% vs 84%; p=0.03) and lower rates of complete response (71% vs 93%; p= 0.002) (Table 1). Older and younger patients had similar probability of achieving MRD-SURE (61% vs. 74%, P=0.18). Median time on protocol treatment was 11.7 (IQR 7.7-15.2) months (m) for older patients and 11.6 (IQR 8.0-14.7) m for younger patients (p=0.85). Grade ³3 treatment emergent adverse events occurred in 79% of older and 69% of younger patients (p=0.31). No patients in the older group permanently discontinued protocol therapy due to toxicity. At a median follow up of 35.9 (range 1-51) m, older vs younger adults had similar PFS (3-y PFS 86.3% vs 80.3%; p= 0.74)(Fig) and OS (3y OS 95.8% vs 88.7%; p= 0.53). Three deaths occurred during the treatment period, of which one patient was ≥70y (unwitnessed sudden death 2 m after ASCT and before consolidation). Conclusion: Our study demonstrates that older adults can be candidates for quadruplet induction, ASCT, and MRD-adapted consolidation therapy and can derive similar benefits as younger NDMM pts. While toxicity may be higher among older adults, it does not appear to compromise treatment continuation, PFS or OS. Chronologic age, by itself, should not be an eligibility criterion from trials utilizing higher intensity therapies. Future studies should focus on how to identify older adults who can benefit from intensive frontline MRD adapted therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Investigation of the frequency of bortezomib neuropathy in patients with multiple myeloma diagnosis with normal and abnormal genetic characteristics.

Bortezomib-induced peripheral neuropathy in patients with multiple myeloma is an undesirable and sometimes severe side effect. Our study aimed to examine whether there was a difference in bortezomib-induced peripheral neuropathy between multiple myeloma patients with normal and abnormal genetic characteristics. This retrospective analysis is based on the assessment of bortezomib-induced peripheral neuropathy frequency in newly-diagnosed multiple myeloma patients with normal (n = 68) and abnormal (n = 45) genetic profiles. A total of 113 patients diagnosed with multiple myeloma according to the International Myeloma Working Group criteria, between 2016 and 2021, were included in this study. Neuropathy was detected in 42 (37.1%) patients. The most common genetic anomalies were 13q del (in 28.9%), t(4.14) (in 22.2%), and trisomy 7 (in 20.0%). When patients with and without bortezomib-induced peripheral neuropathy were compared, the only significant differences were observed for age (p = 0.032) and genetic grouping (p = 0.001); whereas other characteristics that could be associated with bortezomib-induced peripheral neuropathy were similarly distributed in both groups. Bortezomib-induced peripheral neuropathy was significantly more frequent in multiple myeloma patients with normal genetic characteristics (p = 0.001). As a result of our study, it was observed that the frequency of bortezomib neuropathy was significantly higher in patients with normal genetic features compared to those with abnormal genetic features. This result suggested that factors other than genetic factors should be investigated to clarify the etiology of bortezomib-associated neuropathy in patients with multiple myeloma.

Unexpected Heterogeneity of Newly Diagnosed Multiple Myeloma Patients with Plasmacytomas.

In multiple myeloma (MM), malignant plasma cells infiltrate the bone marrow. In some cases, plasma cells migrate out of the bone marrow creating either para-skeletal plasmacytomas (PS) or infiltrating soft tissues as extramedullary plasmacytomas (EMD). The aim of this study was to define risk groups in newly diagnosed MM (NDMM) patients with PS and EMD plasmacytomas. In total, 523 NDMM patients with PS plasmacytomas and 196 NDMM patients with EMD plasmacytomas were diagnosed in the Czech Republic between 2004 and 2021 using modern imaging methods. Patients’ data were analyzed from the Registry of Monoclonal Gammopathies of the Czech Myeloma Group. In NDMM patients with PS plasmacytomas, we found a subgroup with <5% of bone-marrow plasma cells to have the best prognosis (mPFS: 58.3 months (95% CI: 33.0–NA); mOS: not reached). The subgroup with >5% of bone-marrow plasma cells and ≥3 plasmacytomas had the worst prognosis (mPFS: 19.3 months (95% CI: 13.4–28.8), p < 0.001; mOS: 27.9 months (95% CI: 19.3–67.8), p < 0.001). Our results show association between tumor burden and prognosis of NDMM patients with plasmacytomas. In the case of PS plasmacytomas, NDMM patients with low BM PC infiltration have an excellent prognosis.

Response and Dynamics of Renal Function in Transplantation-Eligible Multiple Myeloma Patients Treated with a Novel Agent: The CAREMM-2201 Study

Newly diagnosed multiple myeloma (NDMM) frequently results in renal impairment (RI), and its natural course has not been fully elucidated in the era of novel agents. We aimed to identify the dynamics of renal function after autologous stem cell transplantation (ASCT) following induction treatment using a novel agent in transplantation-eligible NDMM patients with RI (estimated glomerular filtration rate [eGFR] ≤50 mL/min/1.73 m2) at diagnosis. The factors associated with achieving a renal response based on the term renal benefit regardless of baseline eGFR were investigated as well. In a multicenter registry database including 1795 patients with plasma cell disorder, 140 transplantation-eligible NDMM patients who developed RI at the time of initiation of treatment for NDMM were identified. They received protocol-based treatment (PBT) consisting of induction treatment using proteasome inhibitors and/or immunomodulatory drugs followed by ASCT. MM and renal responses were evaluated using the International Myeloma Working Group response criteria. To evaluate the standardized improvement of renal function irrespective of baseline eGFR, renal benefit was defined as a sustained (for at least 3 months) increase in eGFR >15 mL/min/1.73 m2. The mean patient age was 54.7 ± 7.4 years. With a mean baseline eGFR of 24.8 ± 13.9, the renal complete response (renalCR) and renal benefit rates were 49.3% and 67.9%, respectively. In a multivariable analysis, the 3 factors significantly associated with reduced likelihood of achieving both renalCR and renal benefit were age ≥55 years, light chain type NDMM, and failure to improve eGFR by 5 mL/min/1.73 m2 with supportive care when measured 3 days prior to induction therapy and at the initiation of chemotherapy. Hypertension and advanced eGFR also were associated with poor renalCR achievement. The mean eGFR improved until the time of ASCT and then decreased gradually over time. The mean eGFR improved significantly until 4 months post-PBT compared with each eGFR at previous time points, but this significant improvement disappeared by 5 months post-PBT. In a subgroup of patients who developed RI after undergoing ASCT (n=55), the eGFR increased temporarily at 1 month post-ASCT; however, this improvement reverted to baseline at 2 months post-ASCT. Among another subgroup of 27 patients who were dialysis-dependent at the time of initial treatment, 18 (66.7%) were no longer dialysis-dependent after a median of 60 days. The best renal response was acquired early during the PBT period, and ASCT did not have a robust impact on the renal outcome. Patients who failed to achieve a renal benefit should be provided with the best supportive care for chronic kidney disease, and this simplified criterion for evaluating the renal response needs to be validated in larger studies before it can be recommended. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

MM-359 Real-World Treatment Characteristics and Clinical Outcomes in Medicare Beneficiaries With Newly Diagnosed Multiple Myeloma (NDMM) Treated With Bortezomib in Combination With Lenalidomide and Dexamethasone (VRd)

VRd is a standard induction regimen for NDMM, with clinical trials reporting improvement in progression-free survival (PFS) and overall survival (OS), but real-world data on treatment characteristics and outcomes in NDMM patients receiving VRd is lacking. We assessed patient and treatment characteristics, PFS, and OS in NDMM patients receiving first-line (1L) VRd, stratified by stem cell transplant (SCT) status. This retrospective cohort study included adult patients (≥18 years) with MM diagnosis with continuous Part A, B, and D Medicare coverage who initiated 1L MM treatment between 2012 and 2018, using Medicare Research Identifiable Files. A total of 4,266 patients treated with VRd (14.5% with SCT; 85.5% without SCT; 37.2% still on 1L) were identified on 1L amongst 13,573 MM patients (overall sample). The proportion of patients receiving VRd without SCT increased from 18.5% to 26.1% between 2016 and 2018. Irrespective of SCT status, patients receiving VRd were younger, had a better comorbidity profile (anemia [30.1% vs. 32.9%; with SCT (25.1% vs. 30.3%); without SCT (30.9% vs. 33.2%)], and renal impairment (31.2% vs. 41.1%; 24.3% vs. 34.9%; 32.3% vs. 41.8%), and lower mean Charlson Comorbidity Index (2.4 vs. 3.0; 2.2 vs. 2.8; 2.5 vs. 3.0) vs. the overall MM sample. Longer mean duration of therapy and time to next treatment (by 2 and 4 months) were reported for patients receiving VRd vs. the overall MM sample in 1L. Median PFS and OS were longer (23.7 vs. 16.4 months; 61.7 vs. 46.8 months) for patients receiving VRd vs. the overall MM sample in 1L; these findings were consistent regardless of SCT status (with SCT: by 8.1 and 11.6 months; without SCT: by 6.7 and 13.8 months). In a real-world setting, NDMM Medicare beneficiaries receiving VRd had lower comorbidity burden and better clinical outcomes than the overall MM sample in 1L, irrespective of SCT status. Median PFS and OS were shorter than clinical trials evaluating VRd as a standard front-line treatment among NDMM patients with no intent to transplant/no transplant (SWOGS0777; VRd superior to Rd) and in transplant-eligible patients (IFM2009; VRd+SCT superior to VRd).

MM-233 Evaluation of the Comparative Effectiveness of In-Class Transition (iCT) to All-Oral Ixazomib-Lenalidomide-Dexamethasone (IRd) After Bortezomib (V)-Based Induction Therapy vs Patients Who Continued to Receive Parenteral V-Based Therapy in Newly Diagnosed Multiple Myeloma (NDMM)

Increasing the duration of proteasome inhibitor-based treatment could improve outcomes in NDMM patients. To evaluate the comparative effectiveness of in-class transition (iCT) to IRd following V-based induction vs continued V-based therapy. A secondary analysis of patients from US MM-6, (NCT03173092; Manda CLML 2020; phase IV, single-arm study) which is evaluating iCT from parenteral V to all-oral IRd ('IRd' cohort), and a comparator ('V-based') cohort of patients from INSIGHT MM (Costello Future Onc 2019; prospective, observational study) who continued to receive V-based therapy. Routine community clinical practice in the US. Non-transplant-eligible NDMM patients with ≥stable disease after 3 cycles of V-based induction and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 from US MM-6 (IRd cohort, n=100) and INSIGHT MM (V-based cohort, n=111). First-line duration of treatment (DOT), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and reasons for treatment discontinuation. Kaplan-Meier methodology was used for time-to-event outcomes. To reduce imbalances between cohorts, inverse probability of treatment weighting (IPTW) was used. Results are presented as IRd vs V-based cohorts. After IPTW, median age was 75.0 vs 74.8 years; 56.7 vs 51.3% of patients were male, 37.4 vs 29.1% had ECOG PS of 2, and 48.8 vs 41.4% were International Staging System stage III at diagnosis. Initial induction therapy was VRd/V-cyclophosphamide (C)-d/VRCd in 79.5/17.7/2.8 vs 77.3/19.5/3.1% of patients. ORRs were 73.2 (95% confidence interval [CI]: 65.0-81.3) vs 57.5% (95% CI: 47.9-67.1; p<0.0001). Median DOT was 10.8 (95% CI: 6.5-24.4) vs 5.3 months (95% CI: 4.3-7.0; p<0.0001; median follow-up, 20.3 vs 15.8 months). Median PFS and OS were not estimable in either cohort. 24-month PFS rates were 85.7 (95% CI: 68.1-94.0) vs 76.5% (95% CI: 62.6-85.8). 24-month OS rates were 94.0 (95% CI: 77.7-98.5) vs 84.9% (95% CI: 70.6-92.6). Overall, 17.6% discontinued IRd and 24.4% discontinued V due to an adverse event. In NDMM patients treated at US community oncology clinics, those who transitioned to IRd following 3 cycles of V-based induction had significantly higher ORR and longer DOT than those who continued to receive V-based therapy.

Risk Assessment for Newly Diagnosed Fit Young Patients with Multiple Myeloma in the Era of Novel Treatment Modalities: Should There Be Additional Factors Taken into Consideration??

IntroductionThe optimal treatment for young patients with high-risk newly diagnosed multiple myeloma (NDMM) remains a challenge.MethodsWe retrospectively evaluated 58 NDMM patients younger than 55 years treated in our center from 2010 to 2021 with the current recommended protocols.ResultsAfter a median follow-up of 48 months, median overall survival (OS) was not reached; however, approximately 25% of them died within 4 years after diagnosis. Advanced disease stage, presence of extramedullary disease, elevated LDH, and less than very good remission before autologous hematopoietic stem-cell transplantation adversely affected patient survival. Based on these factors, we created a risk-assessment scoring system that sufficiently discriminated young NDMM patients at risk of poor outcome. The 4-year OS was superior for patients with zero to two factors to those with three to five factors (86% vs 44%, p<0.001).ConclusionThe proposed scoring system could be reliably used at diagnosis and at interim disease evaluation in aiming for personalized treatment for young NDMM patients.

MM-253 Efficacy, Safety, and Quality of Life (QoL) in Patients With Newly Diagnosed Multiple Myeloma (NDMM) After In-Class Transition (iCT) From Parenteral Bortezomib-Based Induction Therapy to All-Oral Ixazomib-Lenalidomide-Dexamethasone (IRd): Data From the Phase 4, Community-Based US MM-6 Study (Fully Accrued Cohort)

Achieving prolonged therapy with parenteral proteasome inhibitors (PIs) in clinical practice can be challenging. To increase the duration of PI-based therapy, improve outcomes, and maintain QoL. Prospective study (NCT03173092) evaluating iCT from parenteral bortezomib-based induction to all-oral IRd. IRd was received for up to 39 cycles or until progression/toxicity (Manda CLML 2020). Interim data (N=101) were previously reported (Rifkin ASH 2021). We report results from the fully accrued study cohort (enrollment completed, May 2021; N=141). US community sites. Transplant-ineligible/delayed-transplant (≥24 months) NDMM patients with ≥stable disease after 3 cycles of bortezomib-based induction. Primary endpoint: 2-year progression-free survival (PFS) rate. Other endpoints included: key secondary, overall response rate (ORR; partial response [PR]+very good PR [VPGR]+complete response [CR]) and duration of treatment (DOT); secondary, overall survival (OS), safety, and QoL. At Feb-28-2022, 140 patients (median age, 72.5 years [range, 48-90]; 79% ≥65 years; 42% ≥75 years) had received IRd; 94% had ≥1 comorbidity at IRd initiation. Median follow-up was 20.0 months. 2-year PFS was 69% (95% confidence interval [CI]: 59-77%). ORR was 62% (CR, 8%; VGPR, 24%; PR, 30%) after bortezomib-based induction, increasing to 78% (CR, 33%; VGPR, 27%; PR, 18%) after iCT. At data cut-off, 28 patients (20%) were ongoing on IRd, median DOT with IRd was 10.0 months, and median duration of all PI-based treatment was 12.7 months. 2-year OS was 85% (95% CI: 76-90%). 66% of patients had grade ≥3 treatment-emergent adverse events (TEAEs) (treatment-related, 36%), 44% had serious TEAEs (treatment-related, 14%), and 6 on-study deaths had occurred. Most common TEAEs (any-grade/grade ≥3) were diarrhea (48%/9%), peripheral neuropathies not elsewhere classified (39%/4%), and fatigue (34%/4%). Modification/discontinuation of ixazomib, lenalidomide, or dexamethasone due to TEAEs occurred in 59%/15% of patients. Patient-reported QoL (EORTC QLQ-C30 Global Health Status/QoL score) and treatment satisfaction (TSQM-9 Global Satisfaction, Effectiveness, and Convenience scores) were maintained on IRd. Improved responses and promising PFS and OS were seen following iCT to IRd in these mostly elderly, community-treated patients with NDMM and comorbidities, with no adverse impact on QoL/treatment satisfaction. Safety results were consistent with previous reports.

Prognostic significance of immunoparesis in newly diagnosed multiple myeloma patients who achieved deep response

Objective: To evaluate the effect of immune status on disease progression in patients with newly diagnosed multiple myeloma (NDMM) achieving deep response. Methods: Clinical data of 125 NDMM patients at Beijing Chaoyang Hospital from August 2015 to February 2020 were retrospectively analyzed who achieved very good partial response (VGPR) or better after front-line treatment. The immune status and its influence on progression-free survival (PFS) were analyzed. Results: (1) All patients received novel drug regimens, and 50.4% (63/125) patients followed by autologous stem cell transplantation (ASCT). The rate of complete response (CR) as best efficacy was 89.6%, in which 66.4% achieved CR and MRD negativity tested by second generation flow cytometry. (2) Cox multivariate analysis suggested that persistent severe immunoparesis 3 months and 6 months since the best response was an independent poor prognostic factor for PFS. (3) The 3-year PFS rate in the severe immunoparesis group was significantly lower than that in the control group (41.3% vs. 64.4%, P=0.021). (4) The 3-year PFS rates in patients with persistent severe immunoparesis at 3 months or 6 months were significantly lower (30.0% vs. 63.5%, P<0.001; 16.4% vs. 63.8%, P<0.001 respectively). (5) Even in those achieving CR and negative MRD, the 3-year PFS rate when severe immunoparesis lasted 6 months was significantly lower (22.2% vs. 83.2%, P=0.005). Conclusion: The immune status in NDMM patients achieving deep response is closely related to survival. Persistent severe immunoparesis indicates early progression of the disease.

Risk assessment for newly diagnosed, fit and young patients with Multiple Myeloma, in the era of novel treatment modalities: Are there any additional factors to be under consideration?

Multiple myeloma (MM) is considered a disease of elderlies however, 35-40% of newly diagnosed MM (NDMM) patients (pts) are ≤60 years (ys) old. Although young NDMM pts succeed better outcomes with the currently used treatment protocols, a considerable number of them (25-35%) succumb to MM, within 5 ys after diagnosis. We evaluated the overall survival (OS) and the related risk factors, in NDMM pts aged ≤55 years and we designed a scoring system with predictive value on their long-term outcome. Among 116 NDMM pts treated from 2010-20 in our center, 58 were ≤55 ys and 41% had advanced disease, 24% elevated LDH, 15% extramedullary disease (EMD) and 14% high-risk cytogenetic features. Following treatment with 3 (n=48) or 2 (n=10) agents of Velcade, Cyclophosphamide, Lenalidomide and DXM, 90% underwent autologous hematopoietic stem cell transplantation (AHSCT). Female gender, advance disease, EMD presence, elevated LDH and less than very good response pre-AHSCT, adversely affected the OS. After a median follow up of 4 ys, the median OS was not reached however, approximately 25% of young NDMM patients died within 4 ys after diagnosis. Based on the aforementioned risk factors we created a risk scoring system which compared to the international staging system (ISS), sufficiently discriminated young NDMM patients who are at risk for poor outcome. The 4-year OS was superior for pts with 0-2 factors compared to those with 3-5 factors (86% vs. 44% respectively, p<0.001). Despite the current plethora of the available treatment agents, the heterogeneity in the outcomes among the NDMM pts, highlights the unmet need to establish appropriate criteria for personalized and more efficient treatment approaches, especially for the younger NDMM pts. In this study, we propose an easily applicable scoring system, which can discriminate younger NDMM pts who might need more intensive treatment aiming at prolonged survival rates.

The role of serum-free light chain ratios in the prediction of poor prognosis in multiple myeloma patients: a systematic review and meta-analysis

ABSTRACT Background The association between the serum free light chain (sFLC) ratio and the prognosis of multiple myeloma (MM) patients is controversial. Aim The purpose of this study is to explore the relationship between the sFLC ratio and the prognosis of MM patients through meta-analysis. Methods Online public databases were searched to find relevant studies. The retrieval time is limited from the establishment of the database to July 2021. The overall survival (OS) and progression-free survival (PFS) rates were compared. The results were described using hazard ratio (HR) and a 95% confidence interval (CI). Qualitative studies were also included. Results A total of 9 studies involving 2864 participants were included. A pooled analysis based on four studies including newly-diagnosed MM patients, demonstrated that an abnormal sFLC ratio was associated with poor outcomes of OS (HR = 1.82, 95% CI: 1.15–2.90) and PFS (HR = 1.87, 95% CI: 1.20–2.90). Three qualitative studies showed that an abnormal sFLC ratio was related with poor outcomes of OS (studies all included newly diagnosed MM patients) and PFS (two studies included newly-diagnosed MM patients and one study included non-newly-diagnosed MM patients). Two studies stated that the sFLC ratio is not associated with OS (both studies included non-newly-diagnosed MM patients) and one study reported that the sFLC ratio is not associated with PFS (study included non-newly-diagnosed MM patients). Conclusion sFLC ratio could be used to predict adverse outcomes in newly-diagnosed MM patients, but is not suitable for non-newly-diagnosed MM patients.

Duration of frontline therapy and impact on clinical outcomes in newly diagnosed multiple myeloma patients not receiving frontline stem cell transplant.

Extended first-line therapy (1LT) has improved clinical outcomes in newly diagnosed multiple myeloma (NDMM). This retrospective study of NDMM patients evaluated the relationship between dose-attenuation of 1LT and duration of therapy (DOT) and DOT on outcomes. Adults with NDMM not undergoing stem cell transplant (SCT) from January 1, 2012 toMarch 31, 2018 from the Integrated Oncology Network were included; 300 were randomly selected for chart review. 1LT DOT, time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis. Marginal structural models evaluated relationships between DOT and TTNT, PFS, and OS at 2 years accounting for confounders and survival bias from the time-dependent nature of DOT. Of 300 chart-reviewed patients, 93 were excluded for incomplete data or meeting exclusion criteria. Among 207 NDMM patients, median age was 74 years; 146 (70.5%) did not receive dose-attenuation during 1LT. Patients with short DOT were older, frailer, with a higher comorbidity burden, and a significantly lower proportion had an Eastern Cooperative Oncology Group PS=0. As DOT increased, more patients underwent dose-attenuation (p< 0.0001). The median 1LT DOT was 20.9 (95% confidence interval [CI]: 13.9, 26.4) versus 4.2months (95% CI: 3.2, 4.9) for patients receiving versus not receiving dose-attenuation, respectively (p< 0.0001). After accounting for survival bias, confounder-adjusted TTNT was prolonged with each additional month of 1LT (odds ratio [OR]: 0.76 [95% CI: 0.75, 0.78]); likelihoods of risks of disease progression (OR: 0.87 [95% CI: 0.86, 0.88]) and death at 2 years (OR: 0.72 [95% CI: 0.70, 0.74]) were reduced with each month of 1LT (p< 0.0001 for all outcomes). Dose-attenuated 1LT was associated with longer DOT among patients with non-SCT NDMM. Each additional month of 1LT was associated with a reduced adjusted likelihood of disease progression and death at 2 years. Dose-attenuation of 1LT can extend DOT; longer DOT may improve clinical outcomes.

Spliced X-Box binding protein 1 predicts satisfying responsiveness and survival benefit toward bortezomib-based therapy in multiple myeloma patients

ABSTRACT Objective Spliced X-Box binding protein 1 (sXBP1) modulates malignant cell activities and enhances the bortezomib sensitivity in multiple myeloma (MM) cells, while its clinical value in MM patients remains elusive. Hence, the current study aimed to explore this issue, particularly the correlation of sXBP1 with treatment outcomes of bortezomib-based therapy in MM patients. Methods Totally, 97 newly-diagnosed MM patients undergoing bortezomib-based therapy, 20 disease controls (DCs), and 20 health controls (HCs) were enrolled. Bone marrow plasma cell samples were acquired to determine sXBP1 by RT-qPCR. Results sXBP1 was lowest in MM patients, followed by DCs, and highest in HCs (P < 0.001). Beyond that, sXBP1 discriminated MM patients from DCs with area under curve (AUC) of 0.728 (95% confidence interval (CI): 0.610–0.847) and HCs with AUC of 0.855 (95% CI: 0.771–0.939). sXBP1 was negatively associated with t (4; 14) (P = 0.047), Revised International Staging System stage (P = 0.008). There was a trend that sXBP1 was negatively correlated with β2-MG, LDH, and t (14; 16) (without statistical significance). sXBP1 was higher in patients with complete response (CR) compared to those with non-CR (P = 0.017) and higher in patients with objective response rate (ORR) compared to those with non-ORR (P = 0.006). sXBP1 (high vs. low) was linked with longer progression-free survival (PFS) (P = 0.011) and overall survival (P = 0.045) in MM patients. Additionally, sXBP1 (high vs. low) (P = 0.025) independently estimated a longer PFS. Conclusion sXBP1 forecasts a favorable treatment response and survival benefit toward bortezomib-based therapy in multiple myeloma patients.

Efficacy and safety analysis of bortezomib-based triplet regimens sequential lenalidomide in newly diagnosed multiple myeloma patients

The aim of this study is to analyze the efficacy and safety of sequential therapy with bortezomib-based triplet regimens without lenalidomide (PXD, including VTD, PAD, and VCD) followed by continuous lenalidomide and dexamethasone (Rd) or bortezomib and dexamethasone (Vd) treatment. The main objective is to evaluate the advantages of PXD followed by Rd compared to the combinations of bortezomib–lenalidomide–dexamethasone (VRd) in newly diagnosed multiple myeloma (NDMM). Fifty-eight nontransplant NDMM patients who were admitted to our department from 2017 to 2019 were included in this study. Bortezomib-based triplet regimens were initially selected and followed by Rd or Vd as continuous treatment once the patients achieved partial remission (PR) or better response. The efficacy and safety of the patients were observed. The Rd continuous treatment cohort was compared with historical data from the EVOLUTION trial on continuous VRd treatment. In our cohort, the overall survival rate was 100%, and progression-free survival (PFS) was 38.5% after a median of 19 (4–36) cycles of Rd continuous therapy was applied. During the follow-up period, the best outcome assessments achieved were 53.8% complete response (CR) and 84.6% excellent partial response (VGPR). A total of 23.1% had grade 3–4 or higher drug-related adverse reactions, mainly hematological toxicity, and no patients died of adverse reactions. Compared with the Vd group, the Rd group had a better PFS and VGPR rate (2-year PFS: 92.3% vs. 56.3%, P = 0.002; 3-year PFS: 69.2% vs. 8.0%, P < 0.001; VGPR: 84.6% vs. 69.2%, P = 0.02). No significant differences were found in ORR (100% vs. 92.3%) or CR (53.8% vs. 35.7%, P = 0.082). Compared with the EVOLUTION study, patients in the Rd group had a more advanced disease stage (stage III rate of 40% vs. 19%, P = 0.039) and worse physical status (KPS 50–60 rate of 25.0% vs. 2.0%, P = 0.000). However, a higher proportion of ORR (100% vs. 73.0%, P < 0.001), VGPR or better (75.0% vs. 32.0%, P < 0.001), and PFS at 12 months (90.0% vs. 68%, P = 0.011) were achieved. Sequential administration of bortezomib-based triplet regimens without lenalidomide as an initial therapy followed by Rd as a continuous treatment may not be inferior to VRd for first-line treatment in NDMM patients.

GCRS: A hybrid graph convolutional network for risk stratification in multiple myeloma cancer patients

In this study, we present an efficient Graph Convolutional Network based Risk Stratification system (GCRS) for cancer risk-stage prediction of newly diagnosed multiple myeloma (NDMM) patients. GCRS is a hybrid graph convolutional network consisting of a fusion of multiple connectivity graphs that are used to learn the latent representation of topological structures among patients. This proposed risk stratification system integrates these connectivity graphs prepared from the clinical and laboratory characteristics of NDMM cancer patients for partitioning them into three cancer risk groups: low, intermediate, and high. Extensive experiments demonstrate that GCRS outperforms the existing state-of-the-art methods in terms of C-index and hazard ratio on two publicly available datasets of NDMM patients. We have statistically validated our results using the Cox Proportional-Hazards model, Kaplan–Meier analysis, and log-rank test on progression-free survival (PFS) and overall survival (OS). We have also evaluated the contribution of various clinical parameters as utilized by the GCRS risk stratification system using the SHapley Additive exPlanations (SHAP) analysis, an interpretability algorithm for validating AI methods. Our study reveals the utility of the deep learning approach in building a robust system for cancer risk stage prediction.

The location of the t(4;14) translocation breakpoint within the NSD2 gene identifies a subset of patients with high-risk NDMM

AbstractAlthough translocation events between chromosome 4 (NSD2 gene) and chromosome 14 (immunoglobulin heavy chain [IgH] locus) (t(4;14)) is considered high risk in newly diagnosed multiple myeloma (NDMM), only ∼30% to 40% of t(4;14) patients are clinically high risk. We generated and compared a large whole genome sequencing (WGS) and transcriptome (RNA sequencing) from 258 t(4;14) (n = 153 discovery, n = 105 replication) and 183 non-t(4;14) NDMM patients with associated clinical data. A landmark survival analysis indicated only ∼25% of t(4;14) patients had an overall survival (OS) <24 months, and a comparative analysis of the patient subgroups identified biomarkers associated with this poor outcome, including translocation breakpoints located in the NSD2 gene and expression of IgH-NSD2 fusion transcripts. Three breakpoints were identified and are designated as: “no-disruption” (upstream of NSD2), “early-disruption” (in the 5' UTR), and “late-disruption” (within the NSD2 gene). Our results show a significant difference in OS based on the location of DNA breakpoints (median OS 28.6 “late-disruption” vs 59.2 “early disruption” vs 75.1 months “no disruption”). These findings have been replicated in an independent replication dataset. Also, univariate and multivariate analysis suggest high-risk markers such as del17p, 1p independently contribute to poor outcome in t(4;14) MM patients.

Transcriptional signature of TP53 biallelic inactivation identifies a group of multiple myeloma patients without this genetic condition but with dismal outcome.

Biallelic inactivation of TP53 has been included in the definition of double-hit (DH) multiple myeloma (MM), which entails an ominous prognosis. However, this condition, or even the presence of high-risk cytogenetic abnormalities, cannot accurately capture the 15%-20% of the MM population with a median overall survival below 24 months. This prompted us to look for other MM patients who might have transcriptional characteristics similar to those with DH-TP53. In the present study, we analysed RNA-seq, whole-genome and whole-exome sequencing data from 660 newly diagnosed MM (NDMM) patients from the MMRF (Multiple Myeloma Research Foundation) CoMMpass study to characterize the transcriptional signature of TP53 double-hit (DH-TP53) MM. We found 78 genes that were exclusively deregulated in DH-TP53 patients. A score based on these genes identified a group of 50 patients who shared the same transcriptional profile (DH-TP53-like group) whose prognosis was particularly unfavourable [median overall survival (OS) < 2 years], despite not harbouring the biallelic inactivation of TP53. The prognostic value of the DH-TP53 score was externally validated using gene expression data from 850 NDMM patients analysed by microarrays. Furthermore, our DH-TP53 score refined the traditional prognostic stratification of MM patients according to the cytogenetic abnormalities and International Staging System (ISS).

Real-world patient characteristics and treatment outcomes among nontransplanted multiple myeloma patients who received Bortezomib in combination with Lenalidomide and Dexamethasone as first line of therapy in the United States

BackgroundThere is limited real-world evidence that describes patients with newly diagnosed multiple myeloma (NDMM) treated with the bortezomib, lenalidomide, and dexamethasone (VRd) triplet regimen. We evaluated patient characteristics and treatment outcomes among nontransplanted NDMM patients who received VRd as their first line of therapy (LOT) in US oncology practice settings.MethodsThis retrospective observational cohort study evaluated patients from the Flatiron MM Core Registry who received VRd as first LOT between November 1, 2015, and February 28, 2021. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method. Associations between patient demographic and clinical characteristics and PFS were evaluated using a multivariable Cox proportional hazards model.ResultsA total of 2342 eligible patients with VRd as first LOT were identified (mean age, 67.0 years). Among all identified patients, 64.3% were ≥ 65 years of age, 25.5% were elderly (≥75 years), and 47.9% were frail. Among patients with available data, 21.2% had high-risk cytogenetics, and the majority had International Staging System (ISS) stage I/II disease (71.8%), and Eastern Cooperative Oncology Group performance status (ECOG PS) score 0/1 (81.2%). Median duration of therapy was 5.5 months. With median follow-up of 21.0 months, median PFS and time-to-next-treatment were 26.5 and 16.1 months, respectively. Higher risk of disease progression or death was seen in patients categorized as elderly (hazard ratio [HR] = 1.37; 95% confidence interval [CI]: 1.13-1.66 vs patients < 65 years), having high-risk cytogenetics (HR = 1.44; 95% CI: 1.19-1.75 vs standard risk), having ISS disease stages II and III (HR = 1.31; 95% CI: 1.06-1.63 and HR = 1.37; 95% CI: 1.10-1.70 versus stage I, respectively), and having worse ECOG PS score (≥2) (HR = 1.49; 95% CI: 1.22-1.81 versus functionally active patients).ConclusionsThe majority of patients treated with VRd in this study were ≥ 65 years of age, were ISS stage I/II, had an ECOG PS score of 0/1, and had standard cytogenetic risk. Median PFS observed in real-world practice was notably shorter than that observed in the SWOG S0777 clinical trial. In nontransplanted patients treated with VRd as first LOT, a higher risk of disease progression or death was associated with older age, having high-risk cytogenetics, worse disease stage, and worse ECOG PS score.

The Effect of Improved Culturing Method on the Detection Rate of Chromosome Karyotyping in Multiple Myeloma

To investigate an improved culturing method for karyotyping analysis, and increase the detection rate of cytogenetic abnormalities in patients with multiple myeloma (MM), so as to provide more powerful information for the clinical diagnosis, prognosis stratification, and individualized treatment of MM patients. Eighty newly-diagnosed MM patients were enrolled and divided into two groups. In observation group, IL-6 (10 ng/ml) and GM-CSF (30 ng/ml) were supplemented in the culture medium, while no stimulating factor was added in control group. The samples from both groups were cultured for 72 hours under the same conditions, and their karyotypes were analyzed by G-banding. The detection rate of the cytogenetic abnormalities, as well as the corresponding characteristics were compared between the two groups. The detection rate of the chromosome aberrations was greatly increased in the observation group compared with the control group, the overall detection rate was 72.5% and 22.5%, respectively, as well as 80.0% and 19.2% in the subgroup of ≤60 years old, 68.0% and 28.6% in the subgroup of > 60 years old, which showed significant statistical differences (P<0.05). The modification of the culturing method with the addition of IL-6 (10 ng/ml) and GM-CSF (30 ng/ml) dual stimulating factors followed by incubation for 72 hours can effectively increase the detection rate of abnormal karyotypes in MM patients.

Impact of Comorbidities on Health-related Quality of Life in Nontransplant Eligible Patients With Newly Diagnosed Multiple Myeloma.

Impact of Comorbidities on Health-related Quality of Life in Nontransplant Eligible Patients With Newly Diagnosed Multiple Myeloma.