Novel Therapies For Multiple Myeloma Research Articles

Early detection of multiple myeloma: A first step towards a screening programme.

Novel therapies for multiple myeloma have substantially improved the prognosis, but before patients are able to benefit from treatment, a diagnosis must have been made. The Myeloma UK laboratory working group has developed a three-part tool box to help primary care physicians to suspect myeloma despite mostly vague symptoms, to do the right tests and to derive the proper conclusions from the results. Commentary on: Drayson etal. Laboratory practice is central to earlier myeloma diagnosis; utilising a primary care diagnostic tool and laboratory guidelines integrated into haematology services. Br J Haematol 2024;204:476-486.

Advancing Collaboration across the Multiple Myeloma Treatment Journey from Oncology Clinic to CAR T-Cell Center: A Paired Center Transformative Quality Improvement Initiative

Background Treating patients with multiple myeloma (MM) is a complex endeavor that requires effective clinical decision-making from a team of specialists and supporting clinicians. Additionally, treatment with chimeric antigen receptor (CAR) T-cell therapy presents unique challenges, requiring communication and collaboration between the oncology clinic and CAR T-cell treatment centers. To improve collaborative MM care, we conducted a quality improvement (QI) study, bringing together community and academic oncology centers to assess current practice patterns and develop strategies to overcome barriers in the treatment of patients with MM across the continuum of care. Methods This QI initiative is comprised of baseline provider surveys (Community n = 21; Academic n = 18) and pre- and post-surveys of providers (n = 31) participating in small-group, team-based audit-feedback (AF) sessions (Table 1). Survey questions were designed to assess knowledge, confidence, and experiences in keeping up with the latest clinical evidence and guideline recommendations and collaboration and communication practices between centers. Care teams from each clinic, along with a nationally renowned expert MM physician, participated in audit and feedback sessions to (a) assess system-specific practice gaps identified via the provider surveys, (b) prioritize areas for improvement, and (c) develop action plans for addressing root causes. Results Provider Surveys: When asked their top challenge encountered in managing patients with MM, community-based providers reported keeping up with clinical evidence for new and emerging therapies (48%), whereas academic-based providers reported knowing how to optimally sequence therapies (50%). Further differences between community and academic clinicians were evident in their self-reported confidence in their ability to stay up-to-date with new data on CAR T-cell therapies and other MM treatment (high/very high confidence: 84% academic; 24% community; p < .001), ability to align clinical practices with evidence-based guidelines (high/very high confidence: 72% academic; 34% community; p = .018), and ability to sequence lines of therapy and differentiate between novel therapies for MM (high/very high confidence: 72% academic; 29% community; p = .007). Despite these differences, care teams from both settings reported low percentages of eligible patients have received CAR T-cell therapy for MM, citing patient resistance, cost and difficulty gaining insurance approval as top barriers (Figure 1). When asked to rate the level of communication and collaboration between academic and community centers, 44% of academic providers and 35% of community providers rated very good/excellent. The top barrier among providers not indicating very good/excellent communication from both settings was lack of time for our clinic's staff to communicate. AF Sessions: Providers participating in the small group AF sessions reported gaining access to newer therapies (55%) as their biggest challenge regarding MM management. Clinicians indicated gains in moderate/high/very high confidence in their ability to align treatment decisions with guidelines and clinical evidence for MM (78% to 92%) and ability to sequence treatment options across multiple lines of therapy for patients with MM (80% to 100%). Care teams set goals to enhance knowledge of clinical efficacy and safety of new and emerging therapies for MM. Action plans to achieve these goals include developing a hematology disease specific tumor board to collaborate on patient care plans, further train designated staff members focused on CAR T-cell/MM, discuss relevant new data to improve the team's confidence in therapy sequencing and early referrals to CAR T-cell centers. Conclusions Through this QI initiative, clinical teams identified barriers to optimal MM care, creating and implementing specific action plans to increase knowledge of current and emerging therapies for MM to enhance individualized treatment plans. While meaningful confidence gains were demonstrated, these data underscore clinical practice gaps to address in future initiatives to support evidence-based, collaborative care plans for patients with MM. Study Sponsor Statement The study reported in this abstract was funded by educational grants from Bristol Myers Squibb. The grantors had no role in the study design, execution, analysis, or reporting.

Stem Cell Utilization in the Era of Novel Therapies for Multiple Myeloma

Introduction: Stem cell collection is recommended for patients with newly diagnosed multiple myeloma (NDMM) deemed eligible for autologous stem cell transplantation (ASCT). Standard practice at most institutions is to collect an adequate number of stem cells for at least 2 ASCTs, but the benefit of maintaining extra stem cells in storage for future use beyond an initial ASCT warrants re-evaluation in the current era of novel therapies and evolving MM clinical practice. To address this, we reviewed the utilization rates and indications for the use of stored stem cells (SSC) at our institution. Methods: We conducted a single-center, retrospective study of 1470 patients with NDMM who collected sufficient stem cells for at least 2 ASCTs and underwent at least one ASCT at Memorial Sloan Kettering Cancer Center between January 2007 and December 2022. From this cohort, we assessed rates of stem cell utilization for second, non-tandem (salvage) ASCT and/or stem cell boost over time and determined progression-free survival (PFS) and overall survival (OS) from the time of salvage ASCT using the Cox proportional hazard model. Results: The median patient age atinitial ASCT was 61 years (range 24-81), with 58% male, 25% International Staging System stage III, and 42% (542/1283) with at least one high-risk cytogenetic alteration. Granulocyte-colony stimulating factor, either with or without plerixafor, was used for stem cell mobilization in 70% (834/1193) of patients, with the remaining patients undergoing chemotherapy-based mobilization, including high-dose cyclophosphamide (15%) or other multiagent chemotherapy regimens (15%). The median total CD34 + cell collection yield was 10.3 × 10 6/kg (interquartile range, IQR, 8-13). During the entire study period, SSC were used for 14.6% (214/1470) of patients, with 11.2% (n=165) for a salvage ASCT and 2.1% (n=31) for a stem cell boost. Seven patients received both a salvage ASCT and a boost. An additional 25 patients had upfront tandem ASCT (none since 2015) and were excluded from this analysis. Notably, from 2019 to 2022, the annual utilization of salvage ASCT increased compared to pre-2019 levels (median=21, range 11-27 vs. pre-2019 median=7, range 4-12), as did stem cell boosts (median=4, range 1-6 vs. pre-2019 median=1, range 0-3), despite a decline in numbers during the COVID-19 pandemic (Figure 1). The median age at SSC use was 61 years (range 29-78). The median number of prior lines of therapy (LOT) before the use of SSC was 4 (IQR: 2-7) for salvage ASCT and 6 (IQR: 1-6.5) for boosts. The median infused stem cell dose (CD34+ cells/kg) was 4.4 × 10 6 (range 3.2-5.7) for salvage ASCT and 3.1 × 10 6 (range 2.2-3.6) for boosts. The median PFS after salvage ASCT was 16 months (95% confidence interval, CI, 12-21), and the median OS was 37 months (95% CI 29 - 53). On multivariable analyses, receipt of fewer lines of therapy was the sole favorable prognostic factor for PFS and OS. Among patients with ≤ 3 prior LOT, the median PFS after salvage ASCT was 32 months (95% CI 22-42), while those with > 3 LOT had a median PFS of 8.0 months (95% CI 5.8-12) (Figure 2). Post-treatment therapy after salvage ASCT or stem cell boost most commonly included various MM triplet regimens, chimeric antigen receptor T-cell therapy, and bispecific T-cell engagers. Conclusion: While overall rates of SSC utilization at our institution remain low, rates have increased in recent years, as both salvage ASCT and stem cell boosts provide effective platforms for treating disease and treatment-related refractory cytopenias as a bridge to next therapy for patients with advanced MM. Ultimately, institutional practices for stem cell collection and storage require optimizing the balance of clinical utility with resource allocation and costs of maintaining SSC.

Treatment sequences and drug costs from diagnosis to death in multiple myeloma.

Novel therapies for multiple myeloma (MM) have improved patient survival, but their high costs strain healthcare budgets. End-of-life phases of treatment are generally the most expensive, however, these high costs may be less justifiable in the context of a less pronounced clinical benefit. To manage drug expenses effectively, detailed information on end-of-life drug administration and costs are crucial. In this retrospective study, we analysed treatment sequences and drug costs from 96 MM patients in the Netherlands who died between January 2017 and July 2019. Patients received up to 16 lines of therapy (median overall survival: 56.5 months), with average lifetime costs of €209 871 (€3111/month; range: €3942-€776 185) for anti-MM drugs. About 85% of patients received anti-MM treatment in the last 3 months before death, incurring costs of €20 761 (range: €70-€50 122; 10% of total). Half of the patients received anti-MM treatment in the last 14 days, mainly fully oral regimens (66%). End-of-life treatment costs are substantial despite limited survival benefits. The use of expensive treatment options is expected to increase costs further. These data serve as a reference point for future cost studies, and further research is needed to identify factors predicting the efficacy and clinical benefit of continuing end-of-life therapy.

Specific targeting of Multiple Myeloma by Dual Split-signaling Chimeric Antigen Receptors T-cells directed against CD38 and CD138.

The success of BCMA-specific chimeric antigen receptor (CAR) T-cells illustrates the potential of this novel therapy for multiple myeloma (MM). Nonetheless, broadening CAR T-cell therapy beyond BCMA requires inventive strategies as there are only a few MM- or plasma cell-specific target antigens. We investigated the feasibility of achieving MM specificity by dual-split CD38/CD138 CAR targeting, whereby the stimulatory and costimulatory signals for T-cell activation are split into two separate stimulatory (sCAR) and costimulatory CARs (cCAR). Using various combinations of CD38 and CD138 sCARs and cCARs with different affinities, we generated several dual-split CAR T-cells and analyzed them for MM-specific effector functions in vitro. The best-functioning CAR T-cells were tested in vivo in a murine xenograft model. We found optimal designs of both CD38sCAR/CD138cCAR and CD138sCAR/CD38cCAR combinations, that effectively lysed MM cells, but spared single CD38 or CD138 positive healthy hematopoietic cells. While the CD38sCAR/CD138cCAR T-cells achieved MM-specific activity solely due to the low affinity of the CD38sCARs, the MM-specific cytotoxicity, cytokine release, and proliferation of CD138sCAR/CD38cCAR T‑cells were established through a true combinatorial stimulatory and costimulatory effect. The most optimal combination comprised a low affinity CD138sCAR combined with a high affinity CD38cCAR. These CD138sCAR/CD38cCAR T-cells also showed dual-antigen specific anti-MM effects in vivo. Importantly, they were also effective against MM cells from daratumumab pre-treated patients with decreased CD38 expression levels. We demonstrate the possibility to specifically target MM cells, even after CD38 targeted therapy, with carefully-designed dual-split CARs directed against CD38 and CD138.

Trends in utilization of stored cryopreserved autologous peripheral hematopoietic cells intended for a second (or beyond) autologous hematopoietic cell transplantation in patients with multiple myeloma: a single center experience

Due to the advent of effective novel therapies for multiple myeloma (MM), the use of cryopreserved autologous peripheral blood hematopoietic cells (APBHC) for a salvage autologous transplant (auto-HCT) is in decline. We evaluated utilization trends and costs associated with cryopreserved APBHC in patients with MM. We retrospectively evaluated the clinicopathologic data from 440 patients with MM who underwent APBHC mobilization and collection at Mayo Clinic Florida between 2010 and 2019. Based on institution-specific charges as of May 2021, the cost of 1 session of APBHC collection/apheresis was $4,680 and the cost of 1 year of APBHC cryopreservation was $4,790 per patient. Out of 347 patients who had APBHC in cryopreservation, 5 (1.4%) underwent a salvage auto-HCT and 61% of patients had ≥1 excess collection sessions for APBHC that ultimately went unused. The median cost of excess collection sessions was $4,680 per patient (range, $4,680-$32,760) and the median total cost for excess collection sessions plus costs for storage was $23,840 per patient (range, $4,680–$85,450). The sum of costs of excess collection sessions was $2,077,920 and the sum of costs of cryopreservation was $5,812,665. Institutional policies regarding universal APBHC collection and long-term storage should be reevaluated in the era of novel therapeutics.

A real-world data analysis of predictors of early mortality after a diagnosis of multiple myeloma.

Despite the increased availability and use of novel therapies for multiple myeloma, early mortality is a pervasive challenge with a significant impact on older adults. Reported rates and predictors of early mortality have varied in the literature, with most studies seldom focusing on community-treated patients. In this retrospective cohort analysis of a real-world electronic health record-derived deidentified database of 7512 patients newly diagnosed with multiple myeloma between January 1, 2011, and February 2, 2021, and treated primarily in US-based community oncology practices, factors associated with early mortality (defined as death within 6 months after the multiple myeloma diagnosis) were examined with the use of binary logistic regression. The median age was 70years overall. We found an overall early mortality rate of 8.3%, with 73% of early deaths occurring in those aged ≥70years. Among the early deaths, only 49 patients (8.7%) had documented disease progression before death (median time to progression, 30days [interquartile range, 7-53 days]). Baseline factors associated with higher odds of early mortality included an Eastern Cooperative Oncology Group performance status (ECOG PS)≥2, Revised International Staging System (R-ISS) stage III, an age ≥ 70 years, receipt of proteasome inhibitor-doublet therapy, a light-chain isotype, and the presence of renal dysfunction (estimated glomerular filtration rate < 30mL/min). Among those aged ≥70years, ECOG PS≥2 and R-ISS stage III remained the strongest predictors of early mortality. Early mortality disproportionately affects older adults (aged ≥70years) with multiple myeloma. Interventions to support this population are needed to reduce disparate survival outcomes. Factors associated with an increased risk of dying within 6 months (early mortality) of a new diagnosis of multiple myeloma (MM) among 7512 mostly community-treated patients with MM were evaluated. The early mortality rate was 8.3%; among those deaths, 49 patients (8.7%) had documented evidence of MM progression before death. The risk of early mortality was greatest for older patients (aged ≥70years) and those with a poor performance status, poor kidney function, a higher disease stage, and light-chain MM and those receiving two-drug MM therapies. These findings highlight the need for supportive interventions geared toward older adults with MM.

HSV1716 Prevents Myeloma Cell Regrowth When Combined with Bortezomib In Vitro and Significantly Reduces Systemic Tumor Growth in Mouse Models

Multiple myeloma remains largely incurable due to refractory disease; therefore, novel treatment strategies that are safe and well-tolerated are required. Here, we studied the modified herpes simplex virus HSV1716 (SEPREHVIR®), which only replicates in transformed cells. Myeloma cell lines and primary patient cells were infected with HSV1716 and assessed for cell death using propidium iodide (PI) and Annexin-V staining and markers of apoptosis and autophagy by qPCR. Myeloma cell death was associated with dual PI and Annexin-V positivity and increased expression of apoptotic genes, including CASP1, CASP8, CASP9, BAX, BID, and FASL. The combination of HSV1716 and bortezomib treatments prevented myeloma cell regrowth for up to 25 days compared to only transient cell growth suppression with bortezomib treatment. The viral efficacy was tested in a xenograft (JJN-3 cells in NSG mice) and syngeneic (murine 5TGM1 cells in C57BL/KaLwRijHsd mice) systemic models of myeloma. After 6 or 7 days, the post-tumor implantation mice were treated intravenously with the vehicle or HSV1716 (1 × 107 plaque forming units/1 or 2 times per week). Both murine models treated with HSV1716 had significantly lower tumor burden rates compared to the controls. In conclusion, HSV1716 has potent anti-myeloma effects and may represent a novel therapy for multiple myeloma.

Anti-BCMA novel therapies for multiple myeloma.

Recent advances in multiple myeloma therapy have increased the depth of response and ultimately survivals; however, the prognosis remains poor. The BCMA antigen is highly expressed in myeloma cells, thus representing a target for novel therapies. Several agents that target BCMA through different mechanisms, including bispecific T cell engagers drug conjugated to antibody and CAR-T cells, are now available or under development. Immunotherapies targeting BCMA have shown good results in efficacy and safety in multiple myeloma patients previously treated with several lines of therapy. This review will discuss the recent development of anti-BCMA targeted treatments in myeloma, with a special focus on currently available agents.

Bispecific antibody treatment of multiple myeloma: latest updates from the 2022 ASH annual meeting.

Effective novel therapies for multiple myeloma (MM) patients who are unresponsive to conventional treatments (triple-class refractory) are an urgent need. Bispecific antibodies (BsAbs) offer a promising new approach to stimulate T cells and induce tumor cell death by targeting molecules on the surface of malignant plasma cells and CD3 on the surface of T cells. Addressing the issue of improving the prognosis of triple-class refractory MM patients has become a significant clinical challenge. This is a brief report. This article summarizes the latest updates of BsAbs treatment of MM from the 2022 ASH annual meeting. BsAbs that target B-cell maturation antigen and G protein-coupled receptor family C group 5 memberD have demonstrated remarkable clinical activity and favorable safety profiles. Many potential targets for myeloma cells are currently undergoing phase I/II clinical trials, and these off-the-shelf bispecific molecules are likely to become a critical part of the MM treatment landscape. This article provides an overview of the latest advances in BsAbs immunotherapy for refractory and relapsed MM and highlights significant findings from the 2022 ASH annual meeting.

T-Cell Senescence and Exhaustion Are Associated with Interval Progression of Multiple Myeloma before Autologous Hematopoietic Cell Transplant

Background: The introduction of novel therapies in multiple myeloma (MM) has greatly improved patient outcomes, but the disease remains incurable. Induction therapy followed by autologous hematopoietic stem cell transplant (aHSCT) is widely adopted as the standard-of-care strategy for eligible patients. The current treatment timeline includes a gap between the end of induction and the day of aHSCT to permit correct mobilization and collection of stem cells. During this interval, some patients experience interval progression (IP) of their disease. The association between a complete response (CR) after aHSCT and outcomes has been well studied. However, the association between pre-aHSCT responses and outcomes is less clear. MM patients have abnormal immune cell markers, with increased percentages of exhausted and senescent T lymphocyte markers compared with healthy donors. We hypothesize that IP is associated with a permissive immune microenvironment, likely involving T cell dysfunction. Methods: We completed a retrospective analysis of 482 patients who underwent aHSCT at The Ohio State University between 2011 and 2016. A 20% increase in the index protein between the end of induction and the day of aHSCT was defined as IP. Of these patients, we had access to peripheral blood (PB) samples for 40 patients (n = 18 patients with IP, n = 22 non-progressors) taken from day -2 of aHSCT and 6 healthy donors. Samples were stained to evaluate the percentage and phenotype of different subsets of CD3+, CD4+ cells and CD3+, CD8+ cells, including additional markers LAG3, CD28, CD25, CD57, PD1, CD45RA, and CD62L. Samples were acquired using an AttuneNxT flow cytometry machine and analysis was performed by FlowJo software. Results: One hundred and fifty-six (32.3%) patients were defined as having IP. Of those, 44.8% changed International Myeloma Working Group response groups between induction therapy and aHSCT, with 11.9% of patients dropping more than one response group. Patients in the IP cohort experienced significantly shorter five-year progression-free survival (36.0% vs 47.1%, P = 0.003) and five-year overall survival (69.6% vs 76.8%, P = 0.029). Patients with IP had significantly greater percentages of CD3+, CD8+, CD57+, CD28- terminally differentiated-senescent-like T-cells (Median subset cell percentage (MSCP): 33% IP, 20.3% non-progressors, P = 0.05; healthy donors: 22.60%), CD3+, CD4+, LAG3+ exhausted T cells (MSCP: 4.15% IP, 0.245% non-progressors, P = 0.01; healthy donors: 0.4%), and CD3+, CD4+, PD1+ inhibitory exhausted T cells (MSCP: 17.3% IP, 6.8% non-progressors, P = 0.0006; healthy donors: 3.6%). There was no significant difference in effector memory (CD45RA-, CD62L-) or central memory (CD45RA-, CD62L+) T cell populations between the IP and the non-progressor groups, but the non-progressor group had significant increased naïve CD3+, CD4+ T cell population (CD45RA+, CD62L+), with median of 13.9% in non-progressor patients versus 5.46% in IP patients; P = 0.0449 (healthy donors: 18.40%). These findings suggest that exhausted and senescent T cells are more common in MM patients with IP, potentially leading to a less robust immune response. Conclusion: In this study, we show that patients who experience pre-aHSCT rapid disease progression have inferior long-term survival post-aHSCT. Efforts to discern identifiers that contribute to IP and hence early relapse are crucial in improving and maintaining long-term disease control. We also demonstrated that patients with IP have features of T cell dysfunction, likely causing a permissive immune microenvironment and reduced anti-tumoral responses. As immunophenotyping becomes more accessible, knowing these differences would allow planning for additional induction therapy cycles prior to proceeding with aHSCT or additional consolidation after aHSCT.

Impact of ixazomib-lenalidomide-dexamethasone therapy on overall survival in multiple myeloma patients: Analysis of the emerging-markets subgroup of the TOURMALINE-MM1 trial.

Ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) showed clinical efficacy over placebo-Rd in patients with relapsed/refractory multiple myeloma (MM) in the TOURMALINE-MM1 trial. Over a median follow-up of ∼85months, as patients showed disease progression, they received subsequent novel therapies that confounded the overall survival (OS) benefit. Here, we conducted a post hoc analysis in 148 patients from seven countries defined as emerging markets, with limited access to novel therapies for MM during the trial period, to describe the impact of these therapies on OS. Patients were randomised to ixazomib-Rd (n = 71) or placebo-Rd (n = 77). The median progression-free survival (PFS) was 18.7 versus 10.2months, with ixazomib-Rd versus placebo-Rd (hazard ratio [HR], 0.504; p = 0.008) demonstrating a statistically significant improvement as observed in the primary trial. The median OS improved by 32.6months with ixazomib-Rd over placebo-Rd (63.5 vs. 30.9months; HR, 0.794; p = 0.261); however, the statistically significant benefit seen in PFS was not observed for OS. Improvement with ixazomib-Rd over placebo-Rd was observed in overall response (81.7% vs. 64.9%; odds ratio [OR], 2.38; p = 0.019) and complete response (22.5% vs. 3.9%; OR, 7.57; p < 0.001). Patient-reported quality of life and use of subsequent therapies were similar across treatment groups. No new safety concerns were identified. Compared with the main cohort, median OS was 10months longer with ixazomib-Rd and 21months shorter with placebo-Rd in this subgroup, indicating a clinically meaningful survival benefit of ixazomib-Rd treatment in this patient population with limited access to subsequent novel therapies.

A Systematic Review of Cost-Effectiveness Analyses of Novel Agents in the Treatment of Multiple Myeloma.

Simple SummaryNew treatments in multiple myeloma are embraced by patients and physicians but are also associated with substantial higher costs. To ensure the affordability and accessibility of health care, an evaluation of the outcomes in relation to the costs is increasingly requested. However, an up-to-date summary and assessment of the cost-effectiveness evidence for multiple myeloma treatments is currently lacking. We identified the cost-effectiveness studies currently available and show that novel treatments could improve survival with almost 4 years compared to standard of care. However, additional costs compared to standard of care could increase up to USD 535,530 per patient. The ratio between outcomes and costs is above currently accepted willingness to pay thresholds. Our results show cost-effectiveness ratios should be either improved or less favorable ratios should be accepted to ensure accessibility to promising treatments.Background: Novel therapies for multiple myeloma (MM) promise to improve outcomes but are also associated with substantial increasing costs. Evidence regarding cost-effectiveness of novel treatments is necessary, but a comprehensive up-to-date overview of the cost-effectiveness evidence of novel treatments is currently lacking. Methods: We searched Embase, Medline via Ovid, Web of Science and EconLIT ProQuest to identify all cost-effectiveness evaluations of novel pharmacological treatment of MM reporting cost per quality-adjusted life year (QALY) and cost per life year (LY) gained since 2005. Quality and completeness of reporting was assessed using the Consolidated Health Economic Evaluation Reporting Standards. Results: We identified 13 economic evaluations, comprising 32 comparisons. Our results show that novel agents generate additional LYs (range: 0.311–3.85) and QALYs (range: 0.1–2.85) compared to backbone regimens and 0.02 to 1.10 LYs and 0.01 to 0.91 QALYs for comparisons between regimens containing two novel agents. Lifetime healthcare costs ranged from USD 60,413 to 1,434,937 per patient. The cost-effectiveness ratios per QALY gained ranged from dominating to USD 1,369,062 for novel agents compared with backbone therapies and from dominating to USD 618,018 for comparisons between novel agents. Conclusions: Cost-effectiveness ratios of novel agents were generally above current willingness-to-pay thresholds. To ensure access, cost-effectiveness should be improved or cost-effectiveness ratios above current thresholds should be accepted.

Demographics and Outcomes of Multiple Myeloma Patients Undergoing Modern Modality Treatments Proceeding to ASCT: A Retrospective Study

Introduction: Multiple myeloma accounts for 1% of all cancers and approximately 10% of all hematologic malignancies. With the advent of novel therapies for multiple myeloma and emerging data from randomized trials, there has been a substantial improvement and favorable outcomes in survival. Here, we report demographics and outcomes in a cohort of patients who underwent Autologous Stem Cell Transplant (ASCT) over the past year.Methods: In this retrospective, cohort study, we assessed all MM patients who received ASCT from January 1, 2020, to January 15, 2021, at Cleveland Clinic, and followed until July 31, 2021. Baseline demographics, ECOG performance status, ISS stage, cytogenetic risk category, therapy received before ASCT, maintenance therapy, time to first relapse/progression, time to next treatment (TTNT; 2nd line of treatment onwards) with treatment response (defined per IMWG response criteria) before and after ASCT were obtained by review of electronic medical records. All patients received HDCT Melphalan 140 mg/m2 or 200 mg/m2 prior to ASCT. Continuous variables were presented as median and interquartile range, while categorical variables were presented as numbers and percentages. Categorical variables were compared using the chi-square test.Results: Of 81 MM patients who underwent ASCT, 59% were males, 84% were white, with a median age of 62 (IQR: 57-67) at the time of diagnosis. 42 (52%) and 24 (30%) patients belonged to the standard and high-risk category. Amongst high-risk cytogenetic abnormalities, +1q was the most common (72%) followed by del(17p) (28%). Baseline characteristics of patients are included in Table 1.1. Lenalidomide, bortezomib, and dexamethasone (VRd) regimen was the most common (75%) first-line induction regimen used, followed by Daratumumab-based regimens (20%). 10 (12%) patients required second-line treatment, and 6 (7%) patients required more than 2 lines of treatments prior to transplant. The median time to transplant was 6.5 months. The overall response rate (ORR) prior to transplant was 99% (21% complete (CR), 40% very good partial (VGPR), and 38% partial (PR)). The ORR post-ASCT was 78% (CR 27%, VGPR 37%, PR 14%). There was no significant difference in response between risk categories after transplant (P=0.72). At 1-year follow-up, 10 (12%) patients had relapsed and 7 (9%) patients had progression of the disease. 3 (4%) patients died of progressive MM, one of which had progressed to plasma cell leukemia. Response to treatment before and after the ASCT are summarized in Table 1.2 and Figure 1. The time to second-line treatment among patients with relapse/progression was 7 months [IQR: 3.75-10.25].Conclusion: Here we report the demographics and outcomes of patients with MM undergoing modern modality treatments and ASCT, at our center over the last year. The median time to transplant was 6.5 months after induction therapy, and the ORR post-ASCT was 78%. No significant difference in response was observed between high and standard risk categories. No transplant-related mortality was observed as well. [Display omitted] DisclosuresAnwer: Allogene Therapeutics: Research Funding; Janssen pharmaceutical: Honoraria, Research Funding; BMS / Celgene: Honoraria, Research Funding; GlaxoSmithKline: Research Funding.

Functional Precision Profiling: The Way Forward for Personalized Medicine

Multiple Myeloma (MM) is a malignancy of the antibodyproducing plasma cells found in the bone marrow [1]. In recent years, we have witnessed significant improvements made in both the diagnostic criteria and novel therapies for MM, resulting in the prolonged survival of MM patients.

P-223: Bortezomib-Thalidomide-Dexamethasone (VTD) as salvage treatment in patients with Multiple Myeloma eligible for transplantation in the real world. Long-term follow-up

<h3>Background</h3> Peru is a middle-income country with limited options to access to novel therapies in multiple myeloma (MM). Bortezomib has been introduced as salvage treatment a few years ago. In this setting, bortezomib, thalidomide, dexamethasone (VTD) became the standard salvage treatment for transplant-eligible patients <h3>Objectives</h3> To determine the response to treatment to VTD in patients with relapsed/refractory multiple myeloma eligible to transplant. To determine progression-free survival (PFS) and overall survival (OS) to VTD. <h3>Methods</h3> We retrospectively assessed the clinical efficacy and toxicity of VTD as salvage treatment in patients with relapsed/refractory MM eligible to autologous stem cell transplantation treated at Instituto Nacional de Enfermedades Neoplasicas in Lima, Peru, between January 2014 and December 2016. The treatment consisted of bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8 and 11; thalidomide 100mg orally on days 1 through 21; dexamethasone 40mg orally on days 1, 2, 4, 5, 8, 9, 11, 12 for three-week cycles. Antithrombotic prophylaxis was based on acetylsalicylic acid. Prophylaxis against herpes zoster infection was with acyclovir 400mg twice a day, also trimethoprim/sulfamethoxazole was given each other day. <h3>Results</h3> Sixteen patients were found to fulfill the selection criteria. The median age was 52 (39-62), fifty-six percent (n=9) were male. International Staging System III disease was present in 75%.Ig G and IgA MM were 62.5% and 12.5% respectively. For VTd regimen the median number of treatment cycles delivered was four (range 2-5), totally 62 cycles. After a median follow-up of 19 months since patients received VTd (range 6-63), the overall response rate was 81%, stringent complete response (SCR) was 18.8% (n= 3), complete response 37.5%, very good partial response 12,5%. Seven out of 16 patients (43.8%) with VTD treatment who were candidates for transplantation finally were transplanted. Median PFS was 19 months (95% CI,12-NR), for the cohort who received SCT was the median PFS was 40 m (95% CI,16-NR), and for the cohort who did not undergo SCT was 14 m (95% CI, 6 - NR), however, this difference was statistically non-significant (p = 0.10). After a median follow-up of 41 months (range 7-141) since the diagnosis of MM, the median overall survival (OS) for the entire cohort was not reach (95% CI, 41– NR). For the cohort who received ASCT the median was not reached (95% CI, 41 - NR), and for the cohort who did not received was 49 months (95% CI, 22 - NR), however this difference was statistically non-significant (p = 0.20). 3-years OS was 86.7% (95%, CI, 56.4 –96.5), the 5-year OS was 66 m (95%, CI, 31.1 – 86.2). <h3>Conclusion</h3> VTD is an effective treatment in transplant-eligible patients with multiple myeloma who have relapsed after one previous therapy including thalidomide achieving high response rates and acceptable PFS and OS.

AUTOLOGOUS STEM-CELL TRANSPLANTATION FOR MULTIPLE MYELOMA: EXPERIENCE OF A PUBLIC CENTER IN BRAZIL

Several novel therapies have been developed in recent years improving multiple myeloma (MM) treatment, although autologous hematopoietic stem cell transplantation (HSCT) remains a fundamental strategy in eligible patients. HSCT is even more important where access to drugs such as bortezomib is not available in Brazilian public health system. To evaluate the outcomes after auto-HSCT in patients with MM treated at a public center in Brazil, identifying possible targets to improve assistance. Between Jan-2010 and Oct-2018, 233 patients who underwent the first HSCT for MM were included. This was an observational, retrospective, and single-center study with data collected through medical records after approval by the local research ethics committee. The primary outcome was Progression-Free Survival (PFS) – defined as time between HSCT and death, date of last follow-up or disease progression according to current International Myeloma Working Group (IMWG) criteria. Secondary outcomes were: Overall Survival (OS), Transplant-Related Early Mortality (TRM) and HSCT toxicities (according to the Common Terminology Criteria for Adverse Events). Univariate analysis was performed followed by multiple Cox regression with regression elimination selection method, considering the following predictive variables: International Staging System (ISS), ECOG Performance Status, Charlson index, number of treatments and pre-HSCT response, lactic dehydrogenase at diagnosis, age and time between diagnosis and HSCT. At the time of HSCT, the median patient's age was 57 years (27-70) and 30% of them were over 60. There was a predominance of advanced stages by Durie-Salmon (87% stage IIIA/IIIB), ISS II/III (58%) and ECOG ≤2 (74%). Charlson's comorbidity index was ≥4 in 50.6% of the sample and 80% had undergone only one previous treatment line. 23.8% of the patients were in complete response (CR) prior to HSCT and the procedure was able to increase this proportion to 46.7% at post-HSCT restaging. This increased depth of response was seen in all subgroups stratified by ISS. With a median follow-up after HSCT of 47.8 months, the 2-year PFS was calculated to be 52% (95%CI 45-58%). Multivariate analysis showed significant risk of reduced PFS for Charlson index ≥4 (HR 1.52 95%CI 1.10-2.09) and pre-HSCT depth of response (partial response [HR 1.52 95%CI 1.10- 2.09] and very good partial response [HR 1.52 95%CI 1.10-2.09], compared to CR). The 2-year OS was 82% (95%CI 77-87%). TRM was 4.3% and 41.8% of the patients had at least one toxicity classified as grade ≥3, the main ones being: oral mucositis, nausea and diarrhea. With a median follow-up of 4 years, this study presents results of a Brazilian public center with similar rates of PFS and OS to those reported in the international literature prior to the advent of novel therapies for MM. HSCT proved to be safe and effective, with better outcomes in patients with fewer comorbidities and with deeper pre-HSCT responses, emphasizing the importance of incorporating new drugs to achieve even better results.

The Multiple Myeloma Research Consortium (MMRC): A Model For Accelerating Development Of Novel Therapies For Multiple Myeloma

The Multiple Myeloma Research Consortium (MMRC): A Model For Accelerating Development Of Novel Therapies For Multiple Myeloma

Aplidin (Plitidepsin) Regulates Viability and Function of Myeloma Cells and Bone Cells in Combination with Other Anti-MM Drugs

In multiple myeloma (MM) the clonal expansion of malignant plasma cells within the bone marrow results in the development of lytic bone lesions due to exacerbated bone resorption. Despite recent progress in its treatment, MM remains incurable and the associated bone disease persists even after complete remission. Thus, identification of new therapeutic approaches that suppress MM cell growth and protect the bone is an unmet need. Aplidin, a novel anti-cancer compound isolated from the marine tunicate Aplidium albicans, exhibits anti-MM activity even in MM cells resistant to conventional chemotherapy and is currently in phase III clinical trials in Europe. However, the effects of Aplidin on bone cells and MM-induced bone disease are unknown. The goal of the current study was to examine the effect of Aplidin, alone or in combination with other anti-MM drugs, on myeloma cells and bone cells (osteocytes, osteoblasts, and osteoclasts) using in vitro approaches.Aplidin decreased the number of human JJN3 and murine 5TGM1 MM cells with an EC50~10nM, determined by MTT assay, due to decreased cell viability, assessed by Trypan blue exclusion, reaching a 20% increase in MM cell death after 48h. Treatment with glucocorticoids (GC) (10-5M) or Bortezomib (3nM) also decreased MM viability and enhanced the anti-MM activity of Aplidin by 1.6-fold and 2.5-fold, respectively. In addition, Aplidin at >10nM induced MLO-A5 osteocytic dead up to 15% and in combination with GC up to 50%; whereas, in contrast, Bortezomib did not affect osteocyte viability and partially prevented the increase in MLO-A5 cell death induced by Aplidin. Further, 1nM Aplidin increased OB-6 osteoblastic cell death up to 20% and decreased their matrix mineralization capacity, quantified by Alizarin red. These effects were enhanced when Aplidin was combined with GC, but partially prevented by combination of Aplidin with Bortezomib. Cells of the osteoclastic lineage exhibited higher sensitivity to Aplidin in comparison to MM cells or osteoblastic cells, and thus it was tested at lower concentrations. Specifically, 50 pM Aplidin decreased the number of hematopoietic precursors by 15-20%, as quantified by enumerating GM-CSF colonies in cultures established from murine bone marrow. Moreover, Aplidin, at concentrations as low as 0.01 pM, reduced osteoclast precursor commitment and differentiation by 10%, as quantified by enumerating the number of osteoclast precursors maintained in the presence of M-CSF for 3 days with or without Aplidin. In addition, Aplidin decreased by 40% the number of TRAP positive osteoclasts generated after 4 days in the presence of M-CSF and sRANKL; and blunted the rapid (5-15min) increased in ERK phosphorylation induced by Rankl, but did not affect RANKL-induced p38 phosphorylation, suggesting that Aplidin inhibited RANKL-induced differentiation of osteoclast precursors by preventing ERK activation. Lastly, to test the effects of Aplidin on osteoclasts function, mature osteoclasts generated in the presence of M-CSF/sRANKL were detached by trypsinization, replated on bovine dentin slides and exposed to Aplidin for 3 and 7 days. 10pM Aplidin reduced the number of mature osteoclasts by 60% and markedly decreased the number of resorption pits.In summary, Aplidin (1nM and up) decreases MM cell viability and GC or Borteozmib enhances its anti-MM activity. In addition, Aplidin (10nM and up) decreases osteocytic cell viability and this effect is exacerbated by GC but partially prevented by Bortezomib. Moreover, Aplidin (1nM and up) induces osteoblastic cell death and decreases their mineral production, and these effects are increased by GC, but partially prevented by Bortezomib. Furthermore, Aplidin (0.01pM and up) reduces osteoclast precursor commitment and differentiation, and inhibits mature osteoclast resorption activity. Taken together these findings suggest that combining Aplidin with proteosomal inhibitors may be a novel therapy for MM to enhance anti-tumor responses, decrease bone destruction by inhibiting bone resorption, and prevent potential side effects of Aplidin on cells of the osteoblastic lineage. DisclosuresDelgado-Calle:PharmaMar: Research Funding. Galmarini:PharmaMar: Employment. Roodman:PharmaMar: Research Funding. Bellido:PharmaMar: Research Funding.

Inhibition of PI3K Alpha and PI3K Delta with Copanlisib Shows Preclinical Activity As a Single Agent and in Combination in Multiple Myeloma

Background: The reversible, pan-class I PI3K inhibitor, copanlisib (BAY 80-6946), has preferred activity for the alpha and delta isoforms. This is in contrast to the delta and delta/gamma isoform-selective PI3K inhibitors developed primarily for Non-Hodgkin Lymphoma. We hypothesize that a copanlisib-based combination strategy could provide an effective, novel therapy for multiple myeloma with a pharmacodynamic biomarker to identify patients most likely to benefit from the therapy. Here we demonstrate the preclinical efficacy of copanlisib as a single agent and in combination with carfilzomib, a BET bromodomain inhibitor (BETi) and venetoclax.Methods: A panel of 20 human multiple myeloma (MM) cell lines were evaluated for the effects of copanlisib on cell proliferation after a 5-day exposure to the drug. Sensitive NCI-H929, MM.1S, L-363, and resistant AMO-1, JJN3, COLO-677 MM cell lines were selected for further analysis. All mechanism of action (MOA) studies were performed by treating the MM cells at a dose of 100 nM copanlisib. Cell cycle analysis and induction of apoptosis was performed by FACS after propidium iodide or Annexin V FITC staining respectively on cells treated for 72 hours. Reverse phase protein array (RPPA) was performed at baseline and post treatment for proteomic analysis with confirmatory western blots. Phospho-flow was performed to measure pre- and post-treatment levels of the ribosomal protein phospho-S6 (p-S6). The combination studies utilized serial dilutions of copanlisib with carfilzomib, a BETi, and venetoclax. Excess over highest single agent (EOHSA) was used to evaluate for potentiation. These findings were confirmed in vivo using a SCID mouse model.Results: Following copanlisib exposure, we observed apoptosis in the sensitive cell lines (50-80% AN-V+ cells) but not in resistant cell lines (1-5% AN-V+ cells). We saw an increased cell cycle arrest in G1 in the sensitive cell lines, but not in the resistant cell lines. RPPA performed at baseline revealed a pattern of low p-S6 at the serine positions 235/236 and 240/244 in sensitive compared to resistant cell lines. Western blot analyses validated the RPPA results. We next performed RPPA following exposure to copanlisib, which resulted in a greater decrease in p-S6 in the sensitive cell lines NCI-H929 and L363 (53-83%, 73-93% respectively) compared to resistant cell lines COLO-677 and JJN3 (5-27%, and 38-67%, respectively). The pharmacodynamic p-S6 response was maintained following 24hr and 48hr of drug exposure. These findings were further supported with western blot analysis and phospho-flow. Treatment with copanlisib in combination with carfilzomib or BETi showed potentiation by EOHSA statistics, but this was not seen in with venetoclax. In xenograft models, treatment with copanlisib 10mg/kg by tail vein injection twice daily every 7 days resulted in regression of tumor growth compared to vehicle control. In the L-363 xenograft model, single agent copanlisib resulted in greater tumor regression than single agent carfilzomib.Discussion: Copanlisib demonstrated pre-clinical anti-tumor activity as a single agent and in combination with conventional and novel agents in vitro and in vivo . The low nanomolar range IC50 values correlated with low baseline and post-treatment p-S6, which may allow for the development of a pharmacodynamic FACS based biomarker assay to select patients most likely to benefit from a copanlisib based combination therapy. DisclosuresSlamon:Pfizer: Equity Ownership, Honoraria, Research Funding; Eli Lilly: Consultancy; Bayer: Consultancy; Biomarin: Consultancy, Equity Ownership; Novartis: Honoraria, Research Funding.