Charalampous, Charalampos

Abstract In this study, we first analyzed data from 147 patients with solitary plasmacytomas treated at the Mayo Clinic between 2005 and 2022 and then expanded our investigation through a systematic review and meta-analysis of 62 studies, encompassing 3487 patients from the years 1960 to 2022. Our findings reveal that patients with up to 10% clonal plasma cells in their bone marrow (BM), denoted as plasmacytoma +, had a significantly reduced median disease-free survival (DFS) of 15.7 months vs 79 months, P < .05, observed in patients with true solitary plasmacytomas, with no clonal cells in the BM. Risk factors identified for shorter DFS included the presence of clonal plasma cells in the marrow and a difference between involved and uninvolved free light chains of >5 mg/dL. The meta-analysis portion of our study highlighted a male predominance among patients, with a median age of 58 years, and confirmed radiation therapy as the predominant treatment modality. We also found that DFS rates at 3, 5, and 10 years were 66.9%, 55%, and 42.1%, respectively, and noted a significant difference in outcomes between patients with bone and extramedullary plasmacytomas, with the latter group exhibiting better survival rates. This dual-faceted approach provides a thorough overview of survival rates and critical risk factors for patients with plasmacytoma, underscoring the vital role of accurate disease staging at diagnosis and the impact of tumor location on patient prognosis.

BACKGROUND Several studies have highlighted the poor outcomes observed among patients with relapsed/refractory multiple myeloma (MM), particularly those with triple-class refractory (TCR; refractory to at least one PI, one IMiD, and one anti-CD38 mAb) disease. The aim of this study was to describe the longitudinal changes in quality of life (QOL) and other patient-reported outcomes (PROs) among TCR MM patients in real-world clinical practice who initiate a new line-of-therapy. METHODS A prospective, multi-site observational study of patients with TCR MM was conducted through the Mayo Clinic system. Patients initiating a new post-TCR therapy (defined as the index date) were followed for a 12-month observation period during which PRO surveys were administered for the first 6 months. For patients initiating a CAR-T therapy, a survey assessment was conducted at apheresis, lymphodepletion chemotherapy, and every month after T-cell infusion until Month 6. All other patients received a survey assessment before index and then every month thereafter until Month 6. PRO measures included the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30; including the Global Health Score [GHS]), the EORTC Multiple Myeloma Questionnaire (QLQ-MY20; including the Disease Symptoms [DS] domain score), the EORTC QLQ for Chemotherapy-Induced Peripheral Neuropathy (CIPN20), the EuroQoL-5 Dimensions (EQ-5D), the Patient Global Impression of Severity (PGIS), and the Patient Global Impression of Change (PGIC). Patient surveys were supplemented with retrospective chart reviews conducted 3 months and 12 months following the index date to obtain clinical information. Descriptive data were reported at each timepoint separately for patients who received CAR-T and non-CAR-T index therapies. The study is ongoing and this abstract reflects all patient visit data as of April 2023. RESULTS N=55 patients (60% male, 96% White, mean age 66 years) were included in this interim analysis. The median time interval between becoming TCR and the index date was 3.9 months (interquartile range [IQR]: 1.7, 15.5). Most patients had an ECOG score of 0 or 1 (53% and 38%, respectively) and were R-ISS I or II (36% and 54%, respectively); 53% of patients had high-risk cytogenetics and 20% had extramedullary disease. The median (IQR) number of prior treatment lines was 4 (4.0, 5.5). N=24 patients initiated a CAR-T therapy as their index therapy (equally split between ide-cel and cilta-cel); the remaining N=31 patients predominantly initiated a treatment regimen containing an IMiD (52%), a PI (55%), an anti-CD38 antibody (13%), or an alkylating agent (36%). Among CAR-T patients, QOL and disease-related symptoms worsened from baseline through Month 2-3 (eg, mean GHS was 65.9 at apheresis, 64.9 at lymphodepletion, and 53.3 at Month 2 [higher scores indicate better QOL]; mean DS domain score from the QLQ-MY20 was 24.1 at apheresis, 23.4 at lymphodepletion, and 33.7 at Month 2 [higher scores indicate more symptoms]; see Table 1). These decrements were followed by improvement back to baseline levels and, in some cases, improvement above baseline levels (eg, GHS was 67.9 and 65.0 at Months 4 and 5, respectively; DS was 18.3 and 17.8 at Months 4 and 5), though few patients had sufficient follow up to analyze QOL at later timepoints. Based on the PGIC, 77.8% of patients reported being “a little better” or “much better” as early as Month 1, though this number declined over time. Among non-CAR-T patients, QOL largely plateaued (GHS was 62.2 at baseline and 58.3 at Month 6), though disease symptoms improved over time (DS was 28.6 at baseline and 24.5 at Month 6; pain was 42.3 at baseline and 29.2 at Month 6). Based on the PGIC, 34.7% of patients reported being “a little better” or “much better” at Month 1, which improved to 50% by Month 6. CONCLUSIONS In this interim analysis of an ongoing prospective observational study, QOL and symptom measures generally worsened over the first few months for CAR-T patients in the real-world though improved to baseline levels and beyond at later time points. Patients did, however, directly report improvement in their disease state as early as Month 1 based on the PGIC. Non-CART patients generally showed a QOL plateau with some modest improvement in disease symptoms which was also reflected in their self-reported assessment of disease state improvement based on the PGIC.

OBJECTIVE Vertebral artery injury (VAI), a complication of blunt trauma, may cause posterior circulation stroke. An association of disease severity, classified in Denver grades, with stroke risk has not been shown. Using a literature-based analysis, the authors estimated the incidence of VAI following blunt trauma with the aim to investigate the impact of Denver grade and bilateral VAI on stroke occurrence. METHODS A systematic review of the literature on VAI following blunt trauma was conducted, and data on its incidence, the severity per Denver grade, and stroke occurrence were collected. The incidence of VAI and stroke occurrence were analyzed cumulatively and between Denver grades. A meta-analysis with random-effects models was performed. RESULTS Fifty-six studies including 2563 patients were identified. The overall incidence of VAI was 0.49% among blunt trauma cases and 14.5% among patients screened via any type of angiography. The incidence rates of bilateral VAI and concurrent carotid injury among all VAIs were 12.3% and 19.2%, respectively. VAI severity by Denver grade was as follows: grade I, 23.4%; grade II, 28.2%; grade III, 5.8%; grade IV, 42.1%; and grade V, 0.5%. The overall stroke risk was 5.32%, differing significantly among lesions of different Denver grades (p = 0.02). Grade III and IV lesions had the highest stroke prevalence (9.8% and 10.9% respectively), while strokes occurred significantly less frequently in patients with grade I and II lesions (1.9% and 3.0%, respectively). Denver grade V cases were too rare for meaningful analysis. Bilateral VAI was associated with a 33.2% stroke prevalence. The association between Denver grade and stroke occurrence persisted in a sensitivity subanalysis including only unilateral cases (p = 0.03). CONCLUSIONS VAI complicates a small yet nontrivial fraction of blunt trauma cases, with Denver grade IV lesions being the most common. This is the first study to document a significantly higher stroke prevalence among grade III and IV VAIs compared with grade I and II VAIs independently from bilaterality. Bilateral VAIs carry a significantly higher stroke rate.

Abstract Patients with multiple myeloma (MM) who do not respond to initial therapy have worse outcomes than primary responders, and effective treatments are lacking in this population. However, the outcomes of primary refractory disease in the modern treatment era have not yet been studied. We reviewed patients with MM treated with triplet/quadruplet therapy at our institution to assess the incidence of primary refractory disease and the impact of salvage therapies in this population. We identified 1127 patients, of whom 1086 were evaluated for hematologic responses after 4 to 6 cycles. Of these, 93.3% (1013) had evidence of response, whereas 6.7% (73) had primary refractory disease. With a median overall survival (OS) of 51.3 months, patients with primary refractory disease had an increased risk of shorter survival in univariable and multivariable analyses (hazard ratio [HR], 3.5 [95% confidence interval (CI), 2.5-4.9]; HR, 4.3 [95% CI, 2.6-6.9], respectively). In the subgroup analysis of patients with primary refractory disease, those who received second-line autologous stem cell transplantation (ASCT) had increased second progression-free survival (20.9 vs 8.1 months; P < .01) and second OS (74.7 vs 31.3 months; P = .02) compared with patients who did not. We conclude that early progression remains a significant factor for shorter OS in the current era, and salvage ASCT could be the most beneficial option for this population.

e20032 Background: The introduction of anti-CD38 antibodies (daratumumab) in the treatment landscape of multiple myeloma (MM) has increased the progression-free survival (PFS) in recent years. Still, the ideal combination (Dara-IMiD vs. Dara-PI) of these drugs in patients with relapsed MM is unclear. Methods: We reviewed MM patients treated with daratumumab as second-line therapy at our institution from 2016 to 2022 to assess the outcomes with the different combination therapies. We used the Kaplan-Meier method to estimate PFS from the first relapse. Results: We identified 329 patients with a median age of 63.6 years (range: 27.1 – 90.4). Most of the patients received triplet induction therapy (95%) and upfront transplant (67%) as primary therapy. At the time of Dara initiation, 41% were refractory to IMiDs, 22% to PIs, 18% to both, and 18% to neither drug. Patients treated with Dara-IMiD had significantly better PFS than Dara-PI (28.7 months vs. 18.5 months, p < 0.01, respectively). In a subgroup analysis based on the FISH results, high-risk patients had similar PFS outcomes (24.3 vs. 10.2 months, p = NS, respectively), while standard-risk patients benefited significantly from the Dara-IMiD regimen (48.3 vs. 19.2 months, p < 0.01, respectively). Among patients treated with Dara-IMiD, those already refractory to IMiDs from the first line had significantly shorter PFS than those without IMiD resistance (14.9 vs. 43.3 months, p < 0.01, respectively). In addition, the lenalidomide-based combination resulted in significantly better PFS compared to pomalidomide in our cohort (40.5 vs. 19.2 months, p < 0.01, respectively). However, no difference was found in the IMiD refractory population (12.3 vs. 15.1 months, respectively). Finally, no significant differences were seen between Dara-IMiD and Dara-PI in patients only refractory to IMiDs (16.1 vs. 12.8 months, p = NS, respectively). Conclusions: While further studies are required to adjudicate the best combination, we conclude that Dara-IMiD might be more effective in patients with relapsed MM, especially for patients not refractory to IMiD at first line. [Table: see text]

e20011 Background: Drug refractoriness is an important factor determining choice of next therapy and prognosis in multiple myeloma (MM). It is debatable whether refractoriness to a drug varies among patients (pts) with MM progressing on different administration schedules of the drug. Outcomes of MM pts refractory to different doses of lenalidomide have been previously described, but similar data about proteasome inhibitors (PIs) are limited. In this study, we assessed the impact of refractoriness to different schedules of bortezomib (V) on outcomes with subsequent therapies in MM pts. Methods: We retrospectively reviewed MM pts at our center diagnosed between January 2004 and December 2018, who progressed on/ after receiving first line therapy with V containing regimens. At first relapse, we divided pts into 3 groups- MM progressing on or within 60 days of receiving (1) 1-1.3 mg/m2 V once weekly or more frequently (Standard Dose Refractory), (2) 1-1.3 mg/m2 V once every 2 weeks or less frequently (Low Dose Refractory), and (3) MM progressing at least 60 days after stopping V (Not Refractory). In addition to V, we classified pts as being refractory to cyclophosphamide and immunomodulatory drugs (IMiDs) at first relapse. We classified salvage regimens into daratumumab (Dara), PI, IMiD, PI+IMiD, and VDTPACE like regimens. We then assessed progression free survival (PFS) and overall survival (OS) for next line therapy, and for next V containing therapy using Kaplan Meier and Cox models. Results: A total of 302 pts were included. Median age at diagnosis was 62 years and 60% pts were male. Overall, 23%, 31%, and 27% were International Staging System (ISS) stage I, II, and III respectively; 40% had high risk FISH as per mSMART. Of the 302 pts, 134 (44%) pts received another V containing regimen after the first line therapy at any time during the disease course. Using a multivariable Cox model to adjust for ISS, high risk FISH, refractoriness to other drugs, duration of first line therapy, and treatment received at relapse, the Not Refractory Group had a better PFS for both 2nd line therapy and the next V containing line of therapy, while no significant differences were seen between the Standard Dose Refractory and Low Dose Refractory groups. OS differences followed the same trend but were not statistically significant (Table). Conclusions: On multivariable analysis, the PFS did not differ among standard dose vs low dose refractory pts, and both were significantly inferior to pts not refractory to V. These data suggest that refractoriness to V might not be a dose dependent phenomenon. [Table: see text]

8051 Background: Patients with multiple myeloma (MM) that do not respond to initial therapy have worse outcomes compared to primary responders, and effective treatments are lacking in this population. However, the outcomes of primary refractory disease in the modern treatment era have not been studied. Methods: From 2007-2019, we reviewed MM patients treated with triplet/quadruplet therapy in our institution to assess the incidence of primary refractory disease and the impact of salvage therapies in this population. Primary refractory disease was defined as either progressive disease or stable disease at 4-6 cycles. The Kaplan-Meier estimates were used for survival probabilities. PFS and OS were calculated from MM diagnosis to progression, escalation/change of treatment, or death, respectively. For the primary refractory group, the second PFS and second OS were measured from the start of second-line therapy. The Cox regression model was used for multivariable analysis with the following variables (age, ISS, induction therapy, FISH, and bone marrow plasma cells at diagnosis). Results: We identified 1127 patients, of which 1086 were evaluated for hematologic response after 4-6 cycles. Of these, 93.3% (1013) had evidence of response, while 6.7% (73) had primary refractory disease. With a median OS of 50.7 months, patients with primary refractory disease had an increased risk for shorter survival in univariable and multivariable analysis (HR: 3.6, 95% CI = 2.61 – 4.96, HR = 3.89, 95% CI = 2.68 – 5.65, respectively). In subgroup analysis of primary refractory patients, the median second PFS and second OS from the first relapse were 11.9 months (95% CI: 8.7 – 17.3 months) and 43.4 (95% CI: 31.4– 75.9 months), respectively. Patients that received 2nd line ASCT had increased second PFS (20.9 vs. 8.1 months, respectively, p < 0.01) and second OS (74.7 vs. 31.3 months, respectively, p = 0.02) compared to patients that did not. Patients that took daratumumab as the second line did not have any significant survival differences compared to those who did not, p = NS. Conclusions: We conclude that early progression remains a significant factor for shorter OS in the current era, and salvage ASCT could be the most beneficial option for this population. [Table: see text]

Abstract Lenalidomide‐containing (R) triplet and quadruplet regimens are the standard of care for multiple myeloma (MM) and have been shown to increase the risk of thrombosis. The association between thromboembolism (TE) and survival in the novel multidrug era is not yet delineated. In this study, we evaluated the incidence of TE during the first year of MM diagnosis, its association with the type of induction regimen, and its impact on overall survival. We studied 672 newly diagnosed MM (NDMM) patients who received a triplet or quadruplet lenalidomide‐based induction at the Mayo Clinic, Rochester. TE was diagnosed in 83 patients (12.4%). Of these, 56 (8.3%) had a deep venous thrombosis (DVT), 23 (3.4%) had a pulmonary embolism (PE) with or without the DVT, and 4 (0.6%) patients had a stroke. Carfilzomib‐Rd (KRd) had the highest risk of TE (21.1%, 18/85), followed by quadruplets (11.1%, 5/45), bortezomib‐Rd (9.6%, 51/531), and 0/11 (0%), treated with other lenalidomide‐containing regimens. The difference in TE risk between KRd and the other regimens was statistically significant (OR = 2.6, p < .01). Nine patients developed a TE before being exposed to any treatment. Survival was significantly lower among patients that developed a TE (66 vs. 133 months, p < .01). The association of TE with reduced survival demonstrated in univariate analysis (HR = 2.2, 95% CI = 1.6–3.3) was maintained in the multivariable analysis adjusted for high‐risk interphase fluorescence in situ hybridization (FISH), sex, age, receipt of an upfront transplant, the response at induction, and the International Staging System (ISS) (HR = 2.61, CI = 1.74–3.9). We conclude that TE is an important aspect of MM management, and effective management is especially relevant in the novel treatment era.