Characteristics and Outcomes of Patients With Relapsed/Refractory Multiple Myeloma After Exposure to Lenalidomide in First Line of Therapy: A Single Center Database Review in Greece.

BACKGROUND: The increasing use of lenalidomide (Len) in first-line (1L) therapy of multiple myeloma (MM) has led to a significant proportion of patients becoming Len-refractory following 1L treatment. However, there are limited real-world data on treatment strategies and outcomes of patients who become Len-refractory following 1L therapy. PATIENTS AND METHODS: This real-world retrospective cohort study analyzed Len-refractory and non-Len-refractory patients who received 1L Len and initiated second-line (2L) therapy at a Greek MM center. The Len-exposed cohort (n = 249) included 55.4% Len-refractory patients after 1L. RESULTS: Compared to non-Len-refractory patients, Len-refractory patients more frequently had high-risk cytogenetics and Revised-International Staging System-3 disease stage at diagnosis, and had shorter progression-free survival (PFS) following 1L therapy. Len-refractory versus non-Len-refractory patients more frequently received triplets (59% vs. 40%), anti-CD38 agents (20% vs. 9%) and pomalidomide (22% vs. 13%). The overall response rate was 53% for Len-refractory patients and 64% for non-Len-refractory patients in 2L therapy; median PFS was 10.7 vs. 18.3 months, respectively. Median overall survival (OS) was shorter for Len-refractory patients vs non-Len-refractory patients (23.8 vs. 53.6 months). Len refractoriness was an independent prognostic factor for both PFS and OS in Len-exposed patients. CONCLUSION: In this real-world Len-exposed cohort, Len-refractory patients receiving 1L Len experienced poorer survival outcomes than non-Len-refractory patients, highlighting the unmet need in this patient population which has driven the development of novel therapies.

Thrombotic and bleeding complications in patients with AL amyloidosis.

Haemostatic abnormalities and deregulated coagulation are common complications in AL amyloidosis. The relevant risks of thromboembolic and haemorrhagic events have not been thoroughly evaluated. To describe clinically significant thrombotic/haemorrhagic events in 450 consecutive patients with AL amyloidosis. Venous thromboembolic events (VTEs) were reported in 6% and arterial embolic events (AEEs) in 5% of patients, respectively, during a 55-month median follow-up. Lower albumin, lower eGFR, higher BM infiltration, soft tissue involvement, IMiD-based therapy and prior thrombosis were associated with VTE risk. Prior thrombosis was the only independent prognostic variable (HR 9.3, p = 0.001). Coronary arterial disease, prior AEE, 24-h proteinuria and higher platelet counts were associated with AEE risk. Significant bleeding events were reported in 9%, and associated mortality was 19%. Liver involvement, higher serum creatinine and higher baseline VWF:Ag levels were linked to bleeding risk. Using competing risk analysis, the cumulative probability of thrombosis/bleeding was higher during the first year following diagnosis, but a stable lower risk for both events remained for the duration of follow-up. In AL amyloidosis patients, the risk of thrombotic/arterial embolic events is significant, but the bleeding risk is also high. A multiparametric assessment is required to initiate anti-thrombotic or anti-platelet therapy appropriately.

Tixagevimab/Cilgavimab as Pre-Exposure Prophylaxis against COVID-19 for Multiple Myeloma Patients: A Prospective Study in the Omicron Era.

Background: tixagevimab/cilgavimab, distributed under the name "Evusheld", was the first available pre-exposure prophylaxis for COVID-19 other than vaccination. It received an EUA from the FDA after sufficient trial data showed efficacy in preventing SARS-CoV-2 infections and subsequent severe disease. Its potential benefits for high-risk immunocompromised patients generated a lot of interest. Individuals with multiple myeloma fall into this category, as they are characterized by attenuated immune responses and, in some cases, vaccines have limited efficacy. Methods: this single-center, prospective study included consecutive patients with multiple myeloma. All individuals were considered high-risk for COVID-19 due to their underlying disease. Baseline demographic and clinical characteristics, as well as data regarding COVID-19 infection and antibodies, were collected. Patients were administered two intramuscular 150 mg doses of Evusheld and were monitored during the follow-up period. Results: one hundred and eleven multiple myeloma patients were included in this analysis, with a median age of 64 years (range 58-69) and fifty-three were females (47.7%). Fourteen patients (12.6%) had a prior history of COVID-19 and all patients were vaccinated with either three or four doses of mRNA-based vaccines. An increase was observed in the median neutralizing-antibody levels before and after tixagevimab/cilgavimab administration, from 92.6% to 97.3%. The high levels were sustainable, with a median neutralizing-antibody level of 95.4% at 3 months post Evusheld administration. Overall, nine patients (8.1%) were diagnosed with COVID-19 during the follow-up period, at a median of 31 days. There were no SARS-CoV-2- infection-related hospitalizations or deaths. The monoclonal antibody combination was well tolerated, with no infusion-related reactions or major adverse events, and pain at the injection site only was reported by 33 patients (30%). Conclusions: tixagevimab/cilgavimab (Evusheld) seemed beneficial for patients with multiple myeloma, who presented high neutralizing-antibody levels and a low incidence of COVID-19 during the initial Omicron wave. No new safety concerns emerged. However, novel combinations of monoclonal antibodies against the new circulating variants of SARS-CoV-2 are deemed necessary in view of the emergence of immune tolerance.

Outcomes of patients with light chain (AL) amyloidosis after failure of daratumumab-based therapy.

As daratumumab use in AL amyloidosis increases, more patients will either relapse after or become refractory to daratumumab. We present the outcome of 33 patients with AL who failed on daratumumab (due to haematological relapse in 21 [64%] patients and inadequate haematological response in 12 [36%]) and received further treatment. Overall response rate in the post-daratumumab failure treatment was 55% (CR/VGPR: 14 [42%] and PR: 3 [9%] patients). Patients retreated with daratumumab and patients harbouring +1q21 had lower rates of response. Treatment of patients with AL who fail daratumumab therapy is feasible when non-cross-resistant drugs or other targeted therapies are available.

Real-World Effectiveness and Safety of Belantamab Mafodotin Monotherapy in Triple-Class Refractory Multiple Myeloma.

B-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM). The aim of this study was to assess the effectiveness and tolerability of monotherapy with the conjugated anti-BCMA monoclonal antibody belantamab mafodotin in triple-class refractory patients with MM in real-world practice. Patients refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 monoclonal antibody received belantamab mafodotin at 2.5 mg/kg intravenously every 3 weeks. Overall, 27 patients with a median age of 65 years (range 41-81) were included. Of these, 52% were male and the median number of prior lines of treatment was 5 (4-10). The overall response rate (partial response or better) was 52%, whereas the disease control rate (stable disease or better) was 70%. The median progression-free survival (PFS) was 2 months (95%CI: 0-7), whereas the median PFS among the responders was 12 months (95%CI: 6-18). Regarding the toxicity profile, the most common toxicity was eye toxicity, in 44% of the patients. Keratopathy grade 2-3 was reported in 33.3% of the patients. In conclusion, belantamab mafodotin showed a safety and efficacy profile consistent with the results of the registrational study. Importantly, heavily pretreated patients who responded to treatment derived a substantial survival benefit.

Comparing Different Grasping Visualizations for Object Manipulation in VR using Controllers.

Virtual grasping is one of the most common and important interactions performed in a Virtual Environment (VE). Even though there has been substantial research using hand tracking methods exploring different ways of visualizing grasping, there are only a few studies that focus on handheld controllers. This gap in research is particularly crucial, since controllers remain the most used input modality in commercial Virtual Reality (VR). Extending existing research, we designed an experiment comparing three different grasping visualizations when users are interacting with virtual objects in immersive VR using controllers. We examine the following visualizations: the Auto-Pose (AP), where the hand is automatically adjusted to the object upon grasping; the Simple-Pose (SP), where the hand closes fully when selecting the object; and the Disappearing-Hand (DH), where the hand becomes invisible after selecting an object, and turns visible again after positioning it on the target. We recruited 38 participants in order to measure if and how their performance, sense of embodiment, and preference are affected. Our results show that while in terms of performance there is almost no significant difference in any of the visualizations, the perceived sense of embodiment is stronger with the AP, and is generally preferred by the users. Thus, this study incentivizes the inclusion of similar visualizations in relevant future research and VR experiences.

Use of Oral Antivirals Ritonavir-Nirmatrelvir and Molnupiravir in Patients with Multiple Myeloma Is Associated with Low Rates of Severe COVID-19: A Single-Center, Prospective Study.

In patients with multiple myeloma (MM), SARS-CoV-2 infection has been associated with a severe clinical course and high mortality rates due to the concomitant disease- and treatment-related immunosuppression. Specific antiviral treatment involves viral replication control with monoclonal antibodies and antivirals, including molnupiravir and the ritonavir-boosted nirmatrelvir. This prospective study investigated the effect of these two agents on SARS-CoV-2 infection severity and mortality in patients with MM. Patients received either ritonavir-nirmatrelvir or molnupiravir. Baseline demographic and clinical characteristics, as well as levels of neutralizing antibodies (NAbs), were compared. A total of 139 patients was treated with ritonavir-nirmatrelvir while the remaining 30 patients were treated with molnupiravir. In total, 149 patients (88.2%) had a mild infection, 15 (8.9%) had a moderate infection, and five (3%) had severe COVID-19. No differences in the severity of COVID-19-related outcomes were observed between the two antivirals. Patients with severe disease had lower neutralizing antibody levels before the COVID-19 infection compared to patients with mild disease (p = 0.04). Regarding treatment, it was observed that patients receiving belantamab mafodotin had a higher risk of severe COVID-19 (p < 0.001) in the univariate analysis. In conclusion, ritonavir-nirmatrelvir and molnupiravirmay prevent severe disease in MM patients with SARS-CoV-2 infection. This prospective study indicated the comparable effects of the two treatment options, providing an insight for further research in preventing severe COVID-19 in patients with hematologic malignancies.

Second Booster BNT162b2 Restores SARS-CoV-2 Humoral Response in Patients With Multiple Myeloma, Excluding Those Under Anti-BCMA Therapy.

COVID-19 vaccination leads to a less intense humoral response in patients with multiple myeloma (MM) compared with healthy individuals, whereas the SARS-CoV-2-specific immunity fades over time. The purpose of this study was to explore the kinetics of SARS-CoV-2 neutralizing antibodies (NAbs) in patients with MM after vaccination with the BNT162b2 mRNA vaccine, focusing on their response before (B4D) and at 1 month after the fourth vaccination (M1P4D). Overall, 201 patients with a median age of 67 years were included, whereas 114 (56.7%) were men. The median NAbs levels B4D were 80.0% (±3.5%) and at M1P4D they increased to a median value of 96.1% (±3.7%). The NAb values at M1P4D were similar to those at 1 month post the third dose and superior to all previous timepoints. At M1P4D, the NAbs levels of all the treatment groups increased, apart from the anti-BCMA group. A significant increase in median NAbs values was observed for those receiving CD38-based treatment (n = 43, from 71.0% B4D to 96.0% at M1P4D) and those who did not receive CD38- or BCMA-targeted therapy (n = 137, from 89.6% B4D to 96.3% at M1P4D). Regarding the patients under BCMA-based therapy (n = 21), there was no remarkable increase in NAbs values following the second booster shot (from 3.0% B4D to 4.0% at M1P4D). In conclusion, booster vaccination with the BNT162b2 results in a substantially improved humoral response against SARS-CoV-2 in patients with MM. Anti-BCMA treatment remains an adverse predictive factor for NAbs response; thus, tailored prevention measures should be considered for this patient subgroup.

Newly Diagnosed Multiple Myeloma Patients with Skeletal-Related Events and Abnormal MRI Pattern Have Poor Survival Outcomes: A Prospective Study on 370 Patients.

Contemporary information is sparse on the frequency of skeletal-related events (SREs) in multiple myeloma (MM) patients at a population-based level in the era of novel agents. In this context, we conducted this single-center, prospective, observational study to determine the incidence of SREs among newly diagnosed MMs (NDMM) and to explore the possible correlations with disease characteristics, imaging finding, and patient prognosis. A total of 370 patients with available baseline MRIs were included. Among them, 208 (56%) presented with at least one SRE at diagnosis. Fractures were the most common reported SREs (48%). The incidence of SREs at diagnosis was higher in patients with osteolytic lesions, abnormal MRI pattern, hypercalcemia, and at least 60% bone marrow infiltration by plasma cells. Importantly, the patients with normal MRI pattern, who did not present with SREs at diagnosis, had statistically significant improved median OS in comparison with the patients who had abnormal MRI patterns and/or the presence of SREs at diagnosis (9.3 vs. 6.6 years, p = 0.048). Our data, which represent one of a few systematic reports on the incidence and characteristics of SREs in the era of novel agents, was indicative of a high incidence of SREs at the time of MM diagnosis. Early detection of myeloma bone disease and tailored patient management are essential to optimize patient outcomes.

Chromosome 1q21 aberrations identify ultra high-risk myeloma with prognostic and clinical implications.

Numerical abnormalities of chromosome 1q (+1q21) are common in patients with newly diagnosed multiple myeloma (MM) but their prognostic impact remains a matter of debate. In addition, the impact of the number of copies of 1q21 is not known. We analyzed 912 consecutive patients with symptomatic MM to evaluate the prognostic implications of +1q21 and of their copy number variations, as assessed by FISH. At the time of initial diagnosis, 249 (27.3%) patients had +1q21, of which 150 (16.4%) had 3 copies and 99 (10.9%) had 4 or more copies. Presence of +1q21 was associated with advanced ISS stage (p = .003), concurrent presence of other cytogenetics aberrations and advanced R-ISS stage (p < .001). Patients with +1q21 had inferior PFS (median 34 vs. 20 months, p < .001) and OS (median 75 vs. 44 months, p < .001) but the copy number of 1q21 had no additional prognostic impact. In multivariate analysis, adjusting for R-ISS, age, treatment and HDM, +1q21 remained an independent prognostic factor both for PFS (p < .001) and OS (p = .008). The detrimental prognostic effect of +1q21 was more profound in R-ISS-3 patients, identifying a subgroup with OS of just 16 months (vs. 46 for R-ISS-3 without +1q21, p < .001). We further validated our findings in an independent cohort of 272 patients. In conclusion, the presence of +1q21 is associated with more advanced disease, inferior PFS, and OS but especially patients with R-ISS-3 disease and +1q21 have a very poor outcome comprising an ultra-high-risk group.

Consolidation with a short course of daratumumab in patients with AL amyloidosis or light chain deposition disease.

Daratumumab has major and rapid activity in AL amyloidosis with favourable toxicity. We used as a consolidation a short course of daratumumab in 25 patients with AL amyloidosis or light chain deposition disease (LCDD), who had not achieved a haematologic complete response (hemCR) after standard therapy with bortezomib, cyclophosphamide and dexamethasone (VCD). We evaluated minimal residual disease (MRD) and changes in the bone marrow (BM) microenvironment before and after consolidation using next generation flow cytometry (NGF). At the time of consolidation, 21 patients were in very good partial response (VGPR) and four in partial response (PR); all had detectable MRD. One month after consolidation completion, 8 patients (32%) achieved a hemCR, of whom 5 (20%) became also MRD negative. In the BM, we observed significant changes in B-cell precursors, naïve B-cells, T-cells, CD27+ NK & NKT cells, mast cells and erythroblasts. After a median follow-up of 25 months, none of the patients in hemCR has relapsed and all have achieved an organ response; a haematologic relapse occurred in 6/17 patients that did not achieve hemCR. In conclusion, consolidation with a short course of daratumumab can improve depth of response in patients with AL amyloidosis or LCDD and significantly affects BM environment.

The neutralizing antibody response post COVID-19 vaccination in patients with myeloma is highly dependent on the type of anti-myeloma treatment.

Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies. Neutralizing antibodies (NAbs) against SARS-CoV-2 were evaluated in 276 patients with plasma cell neoplasms after vaccination with either the BNT162b2 or the AZD1222 vaccine, on days 1 (before the first vaccine shot), 22, and 50. Patients with MM (n = 213), SMM (n = 38), and MGUS (n = 25) and 226 healthy controls were enrolled in the study (NCT04743388). Vaccination with either two doses of the BNT162b2 or one dose of the AZD1222 vaccine leads to lower production of NAbs in patients with MM compared with controls both on day 22 and on day 50 (p < 0.001 for all comparisons). Furthermore, MM patients showed an inferior NAb response compared with MGUS on day 22 (p = 0.009) and on day 50 (p = 0.003). Importantly, active treatment with either anti-CD38 monoclonal antibodies (Mabs) or belantamab mafodotin and lymphopenia at the time of vaccination were independent prognostic factors for suboptimal antibody response following vaccination. In conclusion, MM patients have low humoral response following SARS-CoV-2 vaccination, especially under treatment with anti-CD38 or belamaf. This underlines the need for timely vaccination, possibly during a treatment-free period, and for continuous vigilance on infection control measures in non-responders.

Carfilzomib-induced endothelial dysfunction, recovery of proteasome activity, and prediction of cardiovascular complications: a prospective study.

Carfilzomib (CFZ) improves survival in relapsed/refractory multiple myeloma but is associated with cardiovascular adverse events (CVAEs). We prospectively investigated the effect of CFZ on endothelial function and associations with CVAEs. Forty-eight patients treated with Kd (CFZ 20/56 mg/m2 and dexamethasone) underwent serial endothelial function evaluation, using brachial artery flow-mediated dilatation (FMD) and 26S proteasome activity (PrA) measurement in PBMCs; patients were followed until disease progression or cycle 6 for a median of 10 months. FMD and PrA decreased acutely after the first dose (p < 0.01) and FMD decreased at cycles 3 and 6 compared to baseline (p ≤ 0.05). FMD changes were associated with CFZ-induced PrA changes (p < 0.05) and lower PrA recovery during first cycle was associated with more prominent FMD decrease (p = 0.034 for group interaction). During treatment, 25 patients developed Grade ≥3 CVAEs. Low baseline FMD (HR 2.57 lowest vs. higher tertiles, 95% CI 1.081-6.1) was an independent predictor of CVAEs. During treatment, an acute FMD decrease >40% at the end of first cycle was also independently associated with CVAEs (HR = 3.91, 95% CI 1.29-11.83). Kd treatment impairs endothelial function which is associated with PrA inhibition and recovery. Both pre- and posttreatment FMD predicted CFZ-related CVAEs supporting its role as a possible cardiovascular toxicity biomarker.

Next generation flow cytometry for MRD detection in patients with AL amyloidosis.

The treatment of AL amyloidosis aims to eradicate the plasma cell clone and eliminate toxic free light chain production. Only in a minority of patients the plasma cell clone is completely eradicated; residual light chain production may still exist while clonal relapse may occur. We used sensitive next-generation flow cytometry (NGF) to detect minimal residual disease (MRD) in AL amyloidosis patients at complete haematologic response. MRD evaluation was feasible in 51 of 52 (98%) tested patients and at a median sensitivity of 2.3 × 10-6 MRD was undetectable in 23 (45%). An organ response occurred in 86% of MRDneg vs 77% in MRDpos; renal response in 15/17(88%) of MRDneg vs in 14/16(87.5%) of MRDpos and cardiac response in 10/10(100%) of MRDneg vs 11/15(73%) of MRDpos patients. After a median follow-up of 24 months post MRD testing, no MRDneg patient had a haematologic relapse vs 6/28(21%) MRDpos (p = .029). Pooling haematologic and organ progressions, 9 (32%) MRDpos patients had disease progression vs only 1 (4%) MRDneg patient (p = .026). In conclusion, MRD detection using NGF has profound clinical implications, so that AL patients with undetectable MRD have a very high probability of organ response and a very low probability of haematologic relapse.

Timing and impact of a deep response in the outcome of patients with systemic light chain (AL) amyloidosis.

A rapid and deep haematologic response is fundamental in order to improve outcomes of patients with AL amyloidosis. We evaluated the impact of timing and depth of haematologic response at early time points (at 1 and 3 months from the start of therapy) in 227 consecutive previously untreated AL patients, who received bortezomib-based primary therapy. After 1 month of therapy, 30.5% had ≥VGPR, 28% PR and 36% no response (NR), with 11% having iFLC <20 mg/L and 15% dFLC <10 mg/L. Deep haematologic response at 1 month (either ≥VGPR or iFLC <20 mg/L or dFLC <10 mg/L), was associated with a high organ response rate. The survival of patients with ≥VGPR was significantly better than those with PR and NR at 1-month landmark (p < .001) but this benefit was mainly driven by those with iFLC <20 mg/L. The depth of haematologic response at 1 month was significant across all Mayo stages. At 3 months, 46% of the patients had not significantly improved the depth of their response but even patients that improved their response from an iFLC ≥20 mg/L at 1 month to iFLC <20 mg/L at 3 months still had inferior outcome to those with an early deep response. Thus, in patients with AL amyloidosis, a very rapid and deep response is crucial, especially for those at high risk, targeting very low FLC levels within the first month of therapy.

Daratumumab-based therapy for patients with monoclonal gammopathy of renal significance.

Treatment of the plasma cell clone in monoclonal gammopathy of renal significance (MGRS) is necessary in order to reduce toxic immunoglobulin load to the kidneys and salvage renal function. There are limited data on the use of daratumumab in patients with MGRS. We summarize our experience with the use of daratumumab-based therapy in 25 MGRS patients, 12 of whom were previously untreated. The median follow-up of the cohort is 14 months. The best overall haematologic response in evaluable patients was complete response (CR) in five (22%), very good partial response (VGPR) in five (22%) and partial response (PR) in seven (30%) patients for an overall response rate of 74%. Two of five patients in CR and two patients with initially detectable clones, but non-measurable immunoglobulins, had undetectable minimal residual disease (MRD) with next-generation flow cytometry (NGF) after therapy. Haematologic response rate for previously untreated patients was 83% vs. 69% for previously treated and for daratumumab combinations it was 91% vs. 64%, and with CR/VGPR 82% vs. 29%, compared to daratumumab monotherapy. At six months, 12/22 (55%) patients not on dialysis achieved a reduction of proteinuria >30%, of at least 0·5 g/24 h, without an estimated glomerular filtration rate (eGFR) reduction. The toxicity was mild and predictable. In conclusion, daratumumab-based therapy is a new option for patients with MGRS.

Carfilzomib-associated renal toxicity is common and unpredictable: a comprehensive analysis of 114 multiple myeloma patients.

Carfilzomib (CFZ) is a non-reversible proteasome inhibitor approved for the treatment of patients with relapsed and refractory myeloma (RRMM). Its use has been associated with cardiovascular toxicity but although recently a signal of clinically significant renal complications has also been identified, it is less extensively investigated. We analyzed data of 114 consecutive patients with RRMM who received CFZ-based regimens. Renal complications not related to MM progression were observed in 19 (17%) patients; thrombotic microangiopathy (TMA) was seen in 6 (5%) patients, albuminuria >1 gr/day in 7 patients (6%) and at least grade 3 acute kidney injury (AKI) which could not be otherwise explained in 6 patients (5%). A total of 15 patients discontinued CFZ and dosing was reinitiated at a lower level in one patient with AKI. Albuminuria was associated with focal segmental glomerulosclerosis in the renal biopsy (performed in a total of 6 patients). Renal complications during CFZ therapy are common, occur mostly early and are unpredictable. A potential effect of CFZ on the renal endothelium could be implicated in the pathogenesis of these complications and may also share common pathophysiology with cardiovascular effects of CFZ.