In the Phase 3 DREAMM-7 study of patients with relapsed/refractory multiple myeloma (RRMM) who received ≥ 1 prior therapy, belantamab mafodotin plus bortezomib and dexamethasone (BVd) demonstrated a progression-free survival (PFS) benefit versus daratumumab plus bortezomib and dexamethasone (DVd). This study aimed to indirectly compare the efficacy of BVd against alternative regimens in this patient population. A systematic literature review (SLR; December 2021-February 4, 2024) was performed to identify relevant efficacy data. Studies were selected based on the Population-Intervention-Comparators-Outcomes-Study design framework criteria and independently reviewed for inclusion in the network meta-analysis (NMA) if they had a connection to DREAMM-7 (approved in the US or EU, or likely to be a future DREAMM-7 comparator). Each trial had a common comparator arm, allowing for a connected network between the trials and linkage by shared treatments. The primary analysis was PFS in the intent-to-treat population from each study, and secondary analyses examined other endpoints. All endpoints were also evaluated in subgroups by lenalidomide-exposure, -refractoriness, and other patient characteristics. The SLR identified 12 comparator studies comprising 12 comparator regimens (each contained a proteasome inhibitor [bortezomib or carfilzomib] plus dexamethasone), all of which were included in the NMA with the DREAMM-7 study. BVd improved PFS versus all comparators, including daratumumab plus carfilzomib and dexamethasone, isatuximab plus carfilzomib and dexamethasone, and DVd. Overall survival was also improved by belantamab mafodotin plus bortezomib and dexamethasone over the other regimens. This study provides compelling evidence for belantamab mafodotin, plus bortezomib and dexamethasone, in early lines of treatment for RRMM.

In multiple myeloma, functional high risk (FHR) is a predictor of poor outcomes. It is defined as M protein reduction to ≤ 50% of normal, suboptimal response (SR), or progressive disease (PD) within 12 months (i.e., early PD). The clinical significance of anti-CD38 monoclonal antibody (MoAb) as second-line treatment for FHR myeloma remains unclear. We retrospectively investigated the efficacy of anti-CD38 MoAb as second-line treatment for FHR myeloma. We included 332 patients who were newly diagnosed with myeloma and received proteasome inhibitors and/or immunomodulatory drugs as first-line therapy. Their median age was 70 years, and 29.4% were FHR. At a median follow-up of 48.5 months, the overall survival (OS) in the FHR group was significantly shorter (hazard ratio [HR], 2.086; P < 0.001). However, the OS in the SR without early-PD group was comparable to that in the non-FHR group (HR, 1.659; P = 0.330). The OS in patients with FHR who received anti-CD38 MoAb as second-line treatment was similar to that in the non-FHR group (HR, 1.157; P = 0.660). Anti-CD38 MoAb as second-line treatment improved the outcome in our patients with FHR although FHR predicted a poor prognosis.

Daratumumab (Dara)-based regimens have been investigated in randomized controlled trials (RCTs) involving patients with newly diagnosed and previously untreated multiple myeloma (NDMM), but the optimal daratumumab-based regimen remains unclear. This study compares the efficacy of daratumumab-containing regimens for NDMM patients and explores optimal combinations.

Databases were searched from inception until February 29, 2024. Trials comparing regimens with and without daratumumab, as well as their mutual comparisons, were included. Random effects models for serious adverse events (SAEs) and fixed effects models for other outcomes were utilized in both network meta-analysis (NMA) and component NMA (CNMA), with pooled effects estimated. The efficacy of all possible combinations of daratumumab with other drugs was assessed.

A total of 17 trials were included, enrolling 7261 patients, of whom 2083 were treated with daratumumab. The optimal regimens for different outcomes were identified as follows: Dara-bortezomib (V)-melphalan (M)-corticosteroids (D) (Dara-VMD) showed the best results for both overall response rate (ORR) [RR = 1.97; 95% CI: 1.42 to 2.75; I2 = 0.00%; 16 trials; 7136 participants; P = 0.00] and ≥ very good partial response (≥ VGPR) [RR = 7.46; 95% CI: 4.10 to 13.46; I2 = 23.96%; 16 trials; 7118 participants; P = 0.00]; Dara-V-thalidomide (T)-D (Dara-VTD) was optimal for achieving ≥ complete response (≥ CR) [RR = 14.15; 95% CI: 3.74 to 53.52; I2 = 0.00%; 17 trials; 7261 participants; P = 0.00]. The individual effects of daratumumab were calculated as follows: [ORR: RR = 1.14; 95% CI: 1.08 to 1.21; I2 = 0.00%; 16 trials; 7136 participants; P = 0.00; ≥ VGPR: RR = 1.46; 95% CI: 1.36 to 1.58; I2 = 23.96%; 16 trials; 7118 participants; P = 0.00; ≥ CR: RR = 1.77; 95% CI: 1.55 to 1.99; I2 = 0.00; 17 trials; 7261 participants; P = 0.00; progression-free survival (PFS): hazard ratio (HR) = 0.53; 95% CI: 0.43 to 0.65; I2 = 0.00%; 13 trials; 5977 participants; P = 0.00; overall survival (OS): HR = 0.68; 95% CI: 0.58 to 0.79; I2 = 28.97%; 12 trials; 5977 participants; P = 0.00]. Additionally, the optimal regimens for PFS and OS were Dara-lenalidomide (R)-D [HR = 0.37; 95% CI: 0.23 to 0.61; I2 = 0.00%; 13 trials; 5977 participants; P = 0.00] and Dara-VRD [HR = 0.40; 95% CI: 0.19 to 0.85; I2 = 28.97%; 12 trials; 5977 participants; P = 0.02], respectively. Finally, CNMA indicated that Dara-VRD, Dara-carfilzomib (K)-RD, Dara-RD, and Dara-cyclophosphamide (C)-RD were four regimens, which could improve remission rate, and reduce death or progression during induction and prolong lifetime.

Dara-VRD, Dara-KRD, Dara-RD, and Dara-CRD are optimal daratumumab-based regimens for patients with newly diagnosed and previously untreated multiple myeloma.

Clinical management of patients with relapsed/refractory multiple myeloma (RRMM) can be challenging, whereby each relapse is associated with progressively poorer outcomes. In addition, changes in disease biology and patient characteristics hamper treatment strategies in this setting, as do toxicities accumulated across previous lines of therapy. The availability of several new treatment classes has brought about improvements in outcomes, but with median survival in the RRMM setting at only ~32 months, a review of current standard of care treatments and considerations for optimizing care in this setting is warranted. Here, we discuss our preferred approach to treating patients with RRMM, based on our collective experience across the Gulf region. We present position statements for the treatment of lenalidomide-sensitive and -refractory patients, as well as for those patients experiencing late relapse. We discuss the major impact that anti-CD38 agents daratumumab and isatuximab have had on the management of RRMM, which is reflected in our preferred use of daratumumab-based regimens across the lenalidomide-sensitive and -refractory settings. For late-relapse settings, we discuss how bispecific antibodies and chimeric antigen receptor [CAR]-T cells are among the biggest breakthroughs in recent years, achieving excellent responses in triple-class exposed patients. While the use of these agents is not yet widespread in the Gulf region, we advocate their use where available and discuss strategies to manage and minimize common toxicities and adverse events associated with their use.

Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with direct on-tumor and immunomodulatory mechanisms of action. Daratumumab-based treatment is a standard of care for multiple myeloma (MM) based on data from randomized controlled trials. Real-world studies, such as that presented here from China, provide important data to complement randomized trials.

This ongoing observational study describes real-world treatment patterns and outcomes among patients with symptomatic, newly diagnosed or relapsed/refractory MM treated with daratumumab in China. Patients must have received ≤ 3 prior lines of MM therapy. Data were collected prospectively and/or retrospectively, depending on time of treatment initiation. The primary study objective was to describe treatment patterns and clinical outcomes, and the secondary objective was to assess the safety and tolerability of daratumumab treatment.

As of the cutoff date (April 30, 2023) for this analysis, 212 patients had received ≥ 1 dose of daratumumab at 13 sites in China. Regimens included daratumumab monotherapy (n = 22) and daratumumab combined with dexamethasone only (n = 21), proteasome inhibitors (PIs) ± dexamethasone (n = 57), immunomodulatory drugs (IMiDs) ± dexamethasone (n = 72), PIs and IMiDs ± dexamethasone (n = 29), and other combinations (n = 11). Daratumumab was initiated by 16.5%, 53.3%, 16.5%, and 13.7% of patients across the first, second, third, and fourth lines of therapy, respectively. A best overall response of partial response or better was achieved by 71.8% of evaluable patients and very good partial response or better was achieved by 51.4% of patients. Estimated 6-month and 12-month progression-free survival rates were 84.3% and 75.0%, respectively. Outcomes were generally more favorable with daratumumab-based combinations than with daratumumab monotherapy. Serious treatment-emergent adverse events were reported in 13.7% of patients, with pneumonia (4.7%) the only serious event in ≥ 5 patients. The most frequently reported adverse drug reactions were leukopenia (6.6%), neutropenia (5.7%), and thrombocytopenia (5.7%).

This observational study provides real-world insights into treatment decisions for Chinese patients with MM. The effectiveness and safety results support the use of daratumumab-based treatment as a standard-of-care therapy in Chinese patients with newly diagnosed or relapsed/refractory MM. This study is ongoing, with continued collection of outcomes data during a longer follow-up.

Most transplant-ineligible patients present with multiple myeloma (MM) refractory to lenalidomide and/or anti-CD38 monoclonal antibody at first relapse and represent a difficult-to-treat population. The Intergroupe Francophone du Myélome phase 2 study iberdomide, ixazomib and dexamethasone (I2D) evaluated the oral triplet iberdomide, ixazomib and dexamethasone in MM patients aged ≥70 years at first relapse (NCT04998786). Seventy patients were enrolled to receive iberdomide (1.6 mg on day 1-21), ixazomib (3 mg on day 1, 8, 15) and dexamethasone (20 mg on day 1, 8, 15, 22 on cycle 1-2 and 10 mg on day 1, 8, 15, 22 on cycle 3-6) (28-day cycle) until disease progression. Median age was 76; 50% patients were frail according to the International Myeloma Working Group frailty score; 74% and 37% were refractory to lenalidomide and daratumumab respectively. With a median follow-up of 14 months, the overall response rate was 64%, including 36% very good partial response or better. The 12-month progression-free survival, duration of response and overall survival were 52%, 76% and 86% respectively. The most common (46%) grade 3-4 toxicity was neutropenia. Non-haematological adverse events were mostly grade 1 or 2. Overall, I2D demonstrated a favourable risk-benefit profile in elderly MM patients at first relapse, including in patients with lenalidomide and daratumumab refractory disease.

Current treatment strategies have led to unpredictable improvements in the management of multiple myeloma (MM) over time. However, resistance to therapy, particularly regarding lenalidomide refractoriness and, more recently, daratumumab and lenalidomide refractoriness, even in the first-line setting, has become an increasingly significant issue in recent years. This resistance complicates the identification of the optimal treatment algorithm for patients with relapsed/refractory MM, particularly at first relapse. In this review, we focus on current strategies for MM patients progressing on or after lenalidomide-based and daratumumab-lenalidomide-based regimens. The forthcoming availability of next-generation immunotherapies, along with a deeper understanding of resistance mechanisms, is highly anticipated. Meanwhile, based on promising results from recent studies, the approval of novel drugs to expand the current therapeutic armamentarium against MM is bringing us closer to the goal of making a potential cure for the disease much more achievable in the hopefully near future.

The multicenter, phase 3 German-Speaking Myeloma Multicenter Group (GMMG) ReLApsE trial randomized patients with relapsed and/or refractory multiple myeloma (RRMM) equally to lenalidomide/dexamethasone (LEN/DEX; 25 mg days 1-21, DEX 40 mg weekly, in 4-week cycles) reinduction, salvage high-dose chemotherapy (sHDCT; melphalan 200 mg/m2), autologous stem cell transplantation (ASCT), and LEN maintenance (10 mg/d; transplant arm, n = 139) vs continuous LEN/DEX (control arm, n = 138). Ninety-four percent of patients had received frontline HDCT/ASCT. We report an updated analysis of survival end points with a median follow-up of 99 months. Median progression-free survival (PFS) was 20.5 and 19.3 months in the transplant and control arm, respectively (hazard ratio [HR], 0.98; P = .9). Median overall survival (OS) was 67.1 and 62.7 months, respectively, (HR 0.89; P = .44). Landmark analyses from sHDCT and the contemporaneous LEN/DEX cycle 5 were performed because of 29% dropout of patients before sHDCT/ASCT in the transplant arm but did not reveal significant differences in PFS/OS. Time to progression after frontline HDCT/ASCT was a prognostic factor but did not predict benefit from sHDCT/ASCT. The GMMG ReLApsE trial does not support use of sHDCT/ASCT in RRMM after frontline HDCT/ASCT. This trial was registered at www.clinicaltrialsregister.eu as #EudraCT2009-013856-61.

Newly approved drugs and combinations treating multiple myeloma (MM) have resulted in substantial improvements in patients' survival. To deliver rapid access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to evaluate the minimal residual disease-negative complete response (MRD-CR) as an intermediate end point for progression-free survival (PFS) and overall survival (OS) in newly diagnosed (ND) transplant-eligible (NDTE) patients, ND transplant-ineligible (NDTinE) patients, and patients with relapsed/refractory (RR) MM.

Individual patient data from 20 randomized multicenter trials were collected. Eleven studies (4,773 patients) with sufficient data were analyzed to evaluate whether 9- or 12-month MRD-CR classified at a 10-5 threshold could be reasonably likely to predict the clinical benefit of new agents regarding PFS and OS. Global odds ratio (OR) was estimated using the bivariate Plackett Copula model. Supportive evaluation included correlations of the treatment effects on MRD-CR end points and PFS/OS, evaluated by both linear regression (R2weighted least squared) and Copula (R2Copula) models.

The analysis demonstrated that both 9- and 12-month MRD-CR strongly correlated with PFS at patient level in NDTE patients, NDTinE patients, and patients with RRMM. Global ORs ranged from 3.06 to 16.24, all with 95% CIs excluding 1.0. Encouraging trial-level correlations (R2, 0.61-0.70) were observed by pooling three populations and were stronger (R2, 0.67-0.78) in the ND population. Similar results were observed for OS.

Our findings provided the support for use of MRD-CR classified at a 10-5 threshold at either 9 or 12 months after starting of the treatment, as an intermediate end point to support accelerated approvals, in future trials in NDTE patients, NDTinE patients, and patients with RRMM.

Significant advancements have been made in the management of multiple myeloma (MM); however, high relapse rates continue to worsen prognosis and reduce survival for many patients. This study aims to evaluate treatment refractoriness and response rates in individuals with relapsed and/or refractory MM using real-world evidence.

A retrospective cohort study utilizing commercial registry data for 2022, included individuals with relapsed and/or refractory MM who are 18-79 years old and obtain minimum of 5 lines of therapy. Patients at least have one proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and CD38-targeting monoclonal antibody (CD38 MoAB), with their last MM-related visit before October 2022. Patients were excluded if they had concurrent primary malignancies or documented death within 28 days of last line of treatment initiation. Descriptive data, including patient demographic and clinical characteristics, were summarized using continuous and categorical variables.

We identified 283 patients after applying inclusion and exclusion criteria. 35.7 % of patients have an overall response rate with median response duration of 6.3 months. Most of patients were found to be categorized in penta-refractory class (33.6 %), followed by triple-refractory (25.4 %), dual-refractory (19.4 %), and not triple-refractory classes (13.4 %). The response rate was 49.1% in dual-class refractory, 22.2 % in triple-class refractory, 44.7 % in not triple-class refractory, and 33.7 % in penta-class refractory patients.

Findings imply that substantial proportion of patients continue to show limited treatment response and treatment refractoriness even after multiple lines of therapy.

Therapy adherence can significantly influence the outcome of cancer patients. The prospective, non-interventional CARO study (NCT02970747) investigated adherence, effectiveness, and safety of carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) in the German real-world setting. In total, 359 patients were included at 69 sites. Data on carfilzomib combination regimens were evaluated for three treatment cohorts: carfilzomib with lenalidomide and dexamethasone (KRd), with dexamethasone only (Kd) or with daratumumab and dexamethasone (KdD). Encouragingly, patients maintained levels of treatment adherence ≥95% to carfilzomib across cohorts. The effectiveness outcomes of CARO were in line with previous data. Median PFS (95% CI) was 17.5 months (14.5, 24.7 [KRd]), 13.4 months (7.0, 18.1 [Kd]), and 15.6 months (9.9, NA [KdD]), respectively. Median OS was 38.9 months (31.5, 53.9 [KRd]), 24.2 months (17.3, 36.8 [Kd]), and not reached (KdD). Overall, the CARO study impressively demonstrates efficacy and safety of KRd, Kd, and KdD regimen in real-world.

The therapeutic landscape for multiple myeloma has gradually expanded in recent decades, leading to unprecedented deep and sustained responses as well as remarkable improvements in patient survival. Nonetheless, changes in treatment algorithms have raised new demands for patients with relapsed/refractory disease, as prior exposure and refractoriness to prior therapies impact the choice of subsequent treatments. In particular, refractoriness to lenalidomide-an established backbone of treatment in both front-line and maintenance settings and a key component of many approved regimens used in relapsed disease-is associated with suboptimal clinical outcomes. Therefore, identifying the most appropriate management in lenalidomide-refractory patients, and even more so in patients who are refractory to more than one agent, is critical. At present, treatment options for this growing subgroup of patients are still limited; however, recent data from clinical research are promising. Herein, we summarized the currently available treatment options and discuss future directions based on the latest results from ongoing clinical trials.

Carfilzomib-based regimens brought a significant improvement in the treatment of relapsed/refractory multiple myeloma (RRMM). Even though efficacy and safety profiles of carfilzomib are well-established in several clinical trials, there is limited real-world data with carfilzomib-based protocols. Here we present our real-world experience with carfilzomib-based regimens for treatment of patients with RRMM in Croatia.

Data on patients with RRMM starting carfilzomib-based protocols in the period between June 2019 and February 2023 was collected by retrospective chart review from 14 Croatian centres.

A total of 119 patients with RRMM were included; median age was 66 years (range 45-83 years), 59 (49.6 %) were females, and the median number of previous lines of therapies was 2 (range 1-8). Triplet based regimen was treatment choice in 84 (70.6 %) and 35 (29.4 %) patients were treated with carfilzomib in combination with dexamethasone (Kd). Overall response rate was 61.7 %, with 20 patients (18.7 %) achieving complete response (CR). Median progression free survival (PFS) and overall survival (OS) for entire cohort were 9.4 and 13.2 months, respectively. Median PFS was 12.8 months and 4.1 months for the triplets and doublets, respectively; the corresponding median OS was 18.6 and 7.9 months, respectively. The most common adverse events were anemia and thrombocytopenia; 19 patients (16 %) experienced cardiovascular events.

This is the first study to analyze clinical outcomes of RRMM patients treated with carfilzomib-based regimens in Croatia. Carfilzomib-based regimens showed substantial efficacy and acceptable toxicity in RRMM, especially in earlier treatment lines and triplet combinations.

Daratumumab is a fully human immunoglobulin G1 monoclonal antibody employed for treating relapsed/refractory multiple myeloma and light-chain amyloidosis. Quantifying monoclonal antibodies in serum presents challenges due to interference from biological matrices. This research aimed to develop and verify an liquid chromatography tandem-mass spectrometry (LC-MS/MS) approach for quantifying serum daratumumab, employing immunoglobulin G purification without alkylation, and to assess its applicability in patients with multiple myeloma receiving intravenous daratumumab. The chromatographic peaks of the daratumumab-derived peptides and internal standard were well-delineated from the serum digests, with an overall run time of 14 min. The calibration curves for serum daratumumab were linear across over 1-1000 μg/mL. The inter- and intra-day accuracy varied between 92.4 % and 108.4 %, with a coefficient-of-variation below 10 %. In patients receiving intravenous daratumumab, serum concentrations ranged from 181.8 to 975.3 µg/mL. Bland-Altman analysis revealed no significant bias, and Passing-Bablok regression demonstrated a good agreement between the LC-MS/MS method and enzyme-linked immunosorbent assay.

Cardio-oncology is an emerging interdisciplinary field concerned with cancer treatment-related cardiovascular toxicities (CTR-CVT) and concomitant cardiovascular diseases (CVD) in patients with cancer. Inflammation and immune system dysregulation are common features of tumors and cardiovascular disease (CVD). In addition to the mutual exacerbating effect through inflammation, tumor treatments, including immunotherapy, chemotherapy, radiation therapy, and targeted therapy, may induce immune inflammatory reactions leading to cardiovascular damage. Cancer immunotherapy is currently a new method of cancer treatment. Immunotherapeutic agents, such as immune checkpoint inhibitors (ICIs), chimeric antigen receptor T cell immunotherapy (CAR-T), mRNA vaccines, etc., can induce anti-tumor effects by enhancing the host immune response to eliminate tumor cells. They have achieved remarkable therapeutic efficacy in clinical settings but lead to many immune-related adverse events (irAEs), especially CTR-CVT. Establishing specific evaluation, diagnostic, and monitoring criteria (e.g., inflammatory biomarkers) for both immunotherapy and anti-inflammatory therapy-related cardiovascular toxicity is vital to guide clinical practice. This article explores the role of immune response and inflammation in tumor cardiology, unravels the underlying mechanisms, and provides improved methods for monitoring and treating in CTR-CVT in the field of cardio-oncology.

Elotuzumab is a monoclonal antibody targeting signaling lymphocyte activation molecule F7 on plasma and natural killer cells, which enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM). The OPTIMISMM study showed improved outcomes with the combination of pomalidomide, bortezomib, and dexamethasone (PVd) in relapsed/refractory MM. Therefore, we studied adding elotuzumab to PVd (elo-PVd) in relapsed/refractory MM in a multicenter phase 2 trial. The primary objective was to determine the overall response rate (ORR). Patients with relapsed/refractory disease and ≥1 prior line of treatment (including lenalidomide and a proteasome inhibitor) were eligible. For each 28-day cycle, elotuzumab was weekly for the first 2 cycles and then every other week; pomalidomide on days 1 to 21; bortezomib on days 1, 8, and 15; and dexamethasone weekly. The trial enrolled 48 patients with a median 3 prior lines (range, 1-9). Prior therapies included pomalidomide (33%), daratumumab (25%), and isatuximab (4%). The ORR was 56.3%, and the median progression-free survival (PFS) was 10 months. In patients with 1 prior line of therapy, ORR was 73.7%; median PFS was 23.4 months. Common grade ≥3 adverse events were neutropenia (33%); infections, any (33%); lung infection (27%); hypophosphatemia (19%); and thrombocytopenia (15%). Elo-PVd is, to our knowledge, one of the first trials of a quadruplet regimen in relapsed/refractory MM incorporating a monoclonal antibody to show efficacy across diverse prior treatments, including triple-class exposed patients with prior anti-CD38 monoclonal antibody. This trial was registered at ClinicalTrials.gov as #NCT02718833.

New generation therapies such as bispecific antibodies (BsAb), chimeric antigen receptor T-cell therapy (CAR T) and antibody-drug conjugates (ADC) have revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). However, there is emerging evidence of increased infection risk associated with these treatments in clinical trials and observational settings. This infection risk may be mediated by on-target, off-tumor side effects such as cytokine release syndrome, hypogammaglobulinaemia and cytopenias, disease-related humoral impairment and the consequences of multiple previous lines of treatment. While bacterial and viral pathogens predominate, reactivation of latent infection and opportunistic infections also warrant attention. This review characterizes the epidemiology of infections associated with novel therapies for RRMM to guide prophylaxis and antimicrobial prescribing in this patient population and highlights future areas of focus to inform ongoing infection prevention strategies.

For patients (pts) with relapsed or refractory multiple myeloma (RRMM) after previous autologous hematopoietic cell transplantation (AHCT), novel agents, cellular and immunotherapies are increasingly available. Options for second-line treatment mostly include triplet regimens based on proteasome inhibitors, immunomodulatory drugs and anti-CD38 monoclonal antibodies and since recently also CAR T cells. The importance of autologous salvage transplantation (retransplantation, Re-AHCT) has significantly decreased in recent years due to the availability of many new treatment options. Therefore, we performed a retrospective analysis of 171 pts cases with RRMM who received Re-AHCT between 2002 and 2021. With a median follow-up of 74.7 months, the 5-year rates of progression-free survival (PFS) and overall survival (OS) were 18% (median 20.6 months) and 57% (median 65.0 months), respectively, the 100-day mortality rate was 4%. Multivariate analysis identified R-ISS stage and duration of previous response (DoR) as independent prognostic factors for PFS and OS. While the revealed high-risk population (R-ISS stage II/III, DoR ≤ 24 months) was associated with a significantly worse PFS (HR 2.728) and OS (HR 3.129), the low-risk group (R-ISS I, DoR > 24 months) achieved a median PFS and OS of 45.0 months and 80.2 months, respectively. Therefore, Re-AHCT could remain an option in such prognostically favorable pts with RRMM even in the era of novel therapies especially when more potent treatment modalities are not available.

Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are two chimeric antigen receptor T cell (CAR T) therapies approved for use in patients with relapsed/refractory multiple myeloma (MM). Initially approved for late line MM (>4 prior lines), these were recently approved for use in MM with 1-2 prior lines of therapy in April 2024. As their use outside of the pivotal clinical trials continues to expand, it is important to critically evaluate the safety and efficacy of these therapies. Further, it is important to identify patients that would be most likely to benefit from the use of CAR T in earlier lines of therapy. Cilta-cel was initially studied in the phase-I LEGEND-2 study, followed by CARTITUDE-1 and CARTITUDE-4 trials, demonstrating remarkable efficacy. A recent large real-world study also demonstrated similar efficacy, in a mostly pivotal trial ineligible patient population. Based on these impressive results, cilta-cel is currently being studied in trials for newly diagnosed as well as smoldering multiple myeloma. Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) are known toxicities of cilta-cel (and other CAR Ts), however movement and cognitive disorders (delayed neurotoxicity) and second primary malignancies are an evolving concern. In this article we discuss safety and efficacy data from existing cilta-cel studies. We propose that all patients with MM who have received ≥4 prior lines of therapy should be considered for CAR T. Earlier line use of CAR T should be restricted to patients with a high-risk disease phenotype (eg, functional high-risk disease). This disease phenotype has historically shown poor outcomes with standard triplet regimens and would be most likely to benefit from earlier use of CAR T: considering the availability of other safe and highly effective therapies, and potential high-risk toxicities of CAR T.

In the phase 3 CANDOR trial (NCT03158688), daratumumab added to carfilzomib and dexamethasone (KdD) significantly prolonged progression-free survival relative to carfilzomib and dexamethasone (Kd) alone in previously treated patients with relapsed/refractory multiple myeloma (RRMM).

We present a post hoc analysis of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30-item module (EORTC QLQ-C30) and EORTC QLQ Myeloma 20-item module (EORTC QLQ-MY20) patient-reported outcome (PRO) measures from the CANDOR trial.

Median (range) duration of observation for PROs was 18.4 (0.9-50.0) months (KdD) and 10.3 (0.9-48.4) months (Kd). PRO compliance rates were high and similar between arms. Mean scores on the EORTC QLQ-C30 global health status (GHS)/quality-of-life (QOL) scale were numerically higher in the KdD than in the Kd arm and were generally sustained or trended toward improvement from baseline. Other EORTC QLQ-C30, EORTC QLQ-MY20, and EQ-5D visual analog scale (VAS) scores were generally similar between treatment arms and were stable over time, with some numerical trends favoring KdD. Risks of deterioration were similar for most scales; hazard ratios suggested improvement for KdD for EORTC QLQ-C30 social functioning, EORTC QLQ-MY20 disease symptoms, and EQ-5D VAS. Results were consistent for lenalidomide-exposed and lenalidomide-refractory subgroups. EORTC QLQ-C30 GHS/QOL scores trended toward improvement at some time points, and other scores remained generally stable when daratumumab was added to carfilzomib and dexamethasone.

These results support the benefits of KdD for the RRMM population, including lenalidomide-exposed and lenalidomide-refractory patients.

NCT03158688.

Patients with relapsed/refractory multiple myeloma (RRMM) have a poor prognosis and a need remains for novel effective therapies. Belantamab mafodotin, an anti-B-cell maturation antigen antibody-drug conjugate, was granted accelerated/conditional approval for patients with RRMM who have received at least 4 prior lines of therapy, based on response rates observed in DREAMM-1/DREAMM-2. Despite the 41% response rate and durable responses observed with belantamab mafodotin in the Phase III confirmatory DREAMM-3 trial, the marketing license for belantamab mafodotin was later withdrawn from US and European markets when the trial did not meet its primary endpoint of superiority for progression-free survival compared with pomalidomide and dexamethasone. This review reflects on key lessons arising from the clinical journey of belantamab mafodotin in RRMM. It considers how incorporating longer follow-up in DREAMM-3 may have better captured the clinical benefits of belantamab mafodotin, particularly given its multimodal, immune-related mechanism of action with responses deepening over time. A non-inferiority hypothesis may have been more appropriate rather than superiority in the context of a monotherapy versus an active doublet therapy. Further, anticipation of, and planning for, non-proportional hazards arising from response heterogeneity may have mitigated loss of statistical power. With the aim of improving the efficacy of belantamab mafodotin, other Phase III trials in the RRMM development program (DREAMM-7 and DREAMM-8) proceeded to evaluate the synergistic potential of combination regimens in earlier lines of treatment. The aim was to increase the proportion of patients responding to belantamab mafodotin (and thus the likelihood of seeing a clear separation of the progression-free survival curve versus comparator regimens). Protocol amendments reflecting DREAMM-3 learnings could also be implemented prospectively on the combinations trials to optimize the follow-up duration and mitigate risk. The wider implications of the lessons learned for clinical research in RRMM and in earlier treatment settings are discussed.

Multiple myeloma (MM), a hematological malignancy, is characterized by malignant plasma cell proliferation in the bone marrow. Recent treatment advances have significantly improved patient outcomes associated with MM. In this study, we aimed to develop comprehensive, evidence-based guidelines for the diagnosis, prognosis, and treatment of MM. We identified 12 key clinical questions essential for MM management, guiding the extensive literature review and meta-analysis of the study. Our guidelines provide evidence-based recommendations by integrating patient preferences with survey data. These recommendations include current and emerging diagnostic tools, therapeutic agents, and treatment strategies. By prioritizing a patient-centered approach and rigorous data analysis, these guidelines were developed to enhance MM management, both in Korea and globally.

Hypertension (HTN) has been found to be the most common comorbidity in patients with cancer. In addition to increased prevalence of baseline HTN, patients with cancer may be at increased risk of HTN as a short-term or long-term adverse event from cancer therapy. Different classes of cancer therapies have been implicated in the development of HTN, including inhibitors of vascular endothelial growth factor (VEGF), Bruton tyrosine kinase inhibitors, proteasome inhibitors, androgen deprivation therapy, and others. While some of these drugs may lead to increases in blood pressure through on-target effects (eg, with VEGF inhibition), others may be associated with HTN from off-target mechanisms that are not always well understood.

Background: Daratumumab (DARA), lenalidomide (LEN), and dexamethasone (DEX, DRd) are one of standards of care for patients with multiple myeloma (MM); however, the clinical impact of relative dose intensity (RDI) remains unclear. In this retrospective study, the aim was to analyze the relationship between the RDI and clinical outcomes in patients with myeloma treated with DRd. Methods: The numbers of patients with newly diagnosed, relapsed, and/or refractory MM were 40 and 71, respectively. Results: The median patient age was 74 years, and the median RDIs for DARA, LEN, and DEX were 84.0%, 39.4%, and 14.6%, respectively. At a median 26.8 months follow-up interval, the 2-year time to the next treatment (TTNT) of the high RDI of DARA (cutoff, 90%) was greater than that of the low RDI of DARA (77.3% vs. 51.6%, p < 0.001), and the 2-year overall survival (OS) of the low RDI of DEX (cutoff, 15%) was longer than that of the high RDI of DEX (87.7% vs. 61.0%, p = 0.027). Multivariate analysis showed that a high RDI for DARA and low RDI for DEX were associated with longer TTNT and OS (hazard ratio, 0.503, p = 0.044; hazard ratio 0.426, p = 0.022, respectively). The high RDI of DARA and low RDI of DEX reduced the incidence of severe infections (p = 0.040 and 0.049). Conclusion: The high RDI of DARA and low RDI of DEX predicted good clinical outcomes in this study's cohort.

The introduction of proteasome inhibitors (PIs) and lenalidomide as treatment for newly diagnosed multiple myeloma (MM) has led to an increased population of lenalidomide-refractory patients. Limited data are available characterizing current treatments and outcomes in this difficult-to-treat population.

Individual patient-level data were analyzed from the treatment arms of multiple daratumumab studies, including APOLLO, CASTOR, CANDOR, EQUULEUS, ALCYONE, MAIA, GRIFFIN, POLLUX, and CASSIOPEIA. Included patients were PI exposed and lenalidomide refractory, received 1-3 prior lines of therapy (LOT), and had an Eastern Cooperative Oncology Group performance status < 2. Treatments and outcomes were analyzed by number of prior LOT in the lenalidomide-refractory population. Time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method.

Out of 4764 patients, 915 patients (prior LOT, one [n = 114]; two [n = 462]; three [n = 339]) met inclusion criteria. Median follow-up was 29·7 months (range 28·0-31·7). The overall response rate was 55·4 %. Estimated median TTNT was 9·7 months, median PFS was 10·0 months, and median OS was 27·5 months. Response rates and PFS decreased as number of prior LOT increased. Prognostic factors for response, TTNT, PFS, and OS included International Staging System stage, baseline plasmacytoma status, baseline hemoglobin, anti-CD38-refractory status, and cytogenetic risk status.

Lenalidomide-refractory patients treated with 1-3 prior LOT have poor PFS and OS, which generally worsen with each additional LOT, highlighting the need for new and effective treatments for this population.

Survival outcomes for multiple myeloma (MM) have drastically improved over the past two decades with the advent of highly effective biologic agents and integration of autologous stem cell transplant (ASCT) for select patients. Despite these advances, MM remains an incurable disease and duration of remission decreases with each relapse. Palliative radiotherapy (RT) for MM, including treatment of pain, relief of compression, and prevention of fracture, is highly effective and generally well tolerated. Though RT can be delivered concurrently with biologic agents, caution should be exercised for potential added hematologic toxicity that may disrupt systemic therapy, especially in heavily pretreated patients, who have limited bone marrow reserve. In this review, we discuss the safety of RT with biologic agents (proteasome inhibitors, immunomodulators, monoclonal antibodies), review indications for palliative RT in MM, and present a framework for how to personalize RT based on goals of treatment, classification of uncomplicated versus complicated lesions, and patient and lesion characteristics. Additionally, we discuss the emerging role of bridging RT prior to chimeric antigen receptor (CAR) T-cell therapy.

Thrombotic microangiopathy (TMA) is a potentially life-threatening complication associated with carfilzomib, a proteasome inhibitor approved for treating multiple myeloma. TMA typically presents within the initial months of treatment; however, delayed onset is rare and poses significant diagnostic challenges.

We conducted a retrospective analysis of the medical records of a 47-year-old Caucasian woman diagnosed with IgA kappa myeloma who developed signs and symptoms consistent with TMA eleven months after the initiation of carfilzomib therapy and already in ongoing very good partial remission.

The clinical presentation included an acute onset of weakness, dizziness, somnolence, diffuse bruising, oliguria, jaundice, severe thrombocytopenia, and acute kidney injury. An immediate workup raised a strong suspicion for TMA, confirmed by laboratory findings of schistocytosis and complement activation. Following the immediate discontinuation of carfilzomib, the patient underwent 18 plasmapheresis (PEX) sessions and received supportive fresh frozen plasma transfusions, which resulted in the complete remission of TMA symptoms without the need for complement inhibitory therapy.

The need for ongoing monitoring for TMA throughout carfilzomib therapy, regardless of treatment duration, is emphasized. Early diagnosis and intervention, including drug discontinuation and the timely initiation of PEX, are crucial for patient recovery.

Renal insufficiency (RI) is a key factor affecting the prognosis of multiple myeloma (MM) patients. Because the benefit of daratumumab for treating MM patients with RI remains unclear, our objective was to evaluate the efficacy of daratumumab on MM patients with RI.

We conducted a systematic search of the PubMed, EMBASE, and Cochrane Library databases as of October 24, 2023. Two independent reviewers screened the article titles, abstracts, and full text to identify the randomized controlled trials (RCTs) meeting the inclusion and exclusion criteria. Meta-analyses were performed using RevMan version 5.4. Outcomes of interest were progression-free survival (PFS), overall survival (OS), complete response or better (≥CR), and minimal residual disease (MRD) negativity, all calculated as hazard ratios (HRs) or risk ratios (RRs) with 95% confidence intervals (CIs).

A total of 10 RCTs with 5003 patients were included. Add-on daratumumab improved PFS and OS among newly diagnosed MM (NDMM) patients with RI (HR 0.48 [95% CI: 0.36, 0.64, I2 = 65%] and HR 0.63 [95% CI: 0.48, 0.82, I2 = 0%]) as well as relapsed/refractory MM (RRMM)-RI patients, compared with the control group (HR 0.46 [95% CI: 0.37, 0.58, I2 = 0%] and HR 0.68 [95% CI: 0.51, 0.92, I2 = 0%]). In terms of the renal status, the efficacy of add-on daratumumab for MMRI patients was similar to that for MM patients with normal renal function. A prolonged PFS benefit for add-on daratumumab treatment versus the control was evident across all RRMM-RI subgroups, and the benefits tended to increase with the follow-up time.

Our results indicate that MM patients with RI could benefit from a daratumumab-added regimen regardless of MM status. Additional high-quality RCTs are still warranted to confirm our findings.

Carfilzomib, a new proteasome inhibitor indicated for patients with relapsed/refractory myeloma, has been associated with cases of thrombotic microangiopathy (CFZ-TMA). The role of variants in the complement alternative pathway and therapeutic potential of complement blockade with eculizumab remain to be determined.

We report 37 cases of CFZ-TMA recorded in the French reference center for TMA with their clinical characteristics, genetic analysis and outcome according to treatments.

A trigger was identified in more than half of cases, including eight influenza and five severe acute respiratory syndrome coronavirus-2 cases. All patients presented with acute kidney injury (AKI) [KDIGO stage 3 in 31 (84%) patients] while neurological (n = 13, 36%) and cardiac (n = 7, 19%) damage were less frequent. ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats-13) and complement activity were normal (n = 28 and 18 patients tested) and no pathogenic variant in the alternative complement pathway was found in 7 patients tested. TMA resolved in most (n = 34, 94%) patients but 12 (44%) still displayed stage 3 AKI at discharge. Nineteen (51%) patients were treated with therapeutic plasma exchange, 14 (38%) patients received corticosteroids and 18 (50%) were treated with eculizumab. However, none of these treatments demonstrated a significant impact on outcomes.

This study is the largest case series of CFZ-TMA since its approval in 2012. Patients present with severe AKI and experience frequent sequelae. Complement variants and blockade therapy do not seem to play a role in the pathophysiology and prognosis of the disease.