Introduction Of Novel Agents Research Articles

The Role of Monoclonal Antibodies in the Treatment of Myeloma Kidney Disease.

Renal failure is one of the most important manifestations of multiple myeloma. It is caused by renal lesions such as cast nephropathy, immunoglobulin deposition disease, AL amyloidosis or other glomerular and/or tubular diseases, mostly due to the toxic effect of free light chains in serum. Renal failure can represent a clinical emergency and is associated with poor outcome in newly diagnosed and relapsed/refractory multiple myeloma patients. Although progression-free survival and overall survival have improved with the introduction of novel agents, renal failure remains a challenge for the treatment of patients with multiple myeloma. Monoclonal antibodies are a component of therapy for newly diagnosed and relapsed/refractory patients and, based on clinical trials and real-world experience, are also safe and effective for subjects with renal failure, even if they are on dialysis. Most of the data are on anti-CD38 and anti-SLAM7 antibodies, but new antibody-drug conjugates such as belantamab mafodotin and bispecific antibodies also appear to be effective in myeloma kidney disease. In the future, we will have to face some challenges, such as defining new criteria for renal response to treatment, defining specific trials for these difficult-to-treat patients and integrating different therapeutic options.

Impact of Novel Agents on Patient Characteristics, Treatment Patterns, and Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer.

The therapeutic landscape for metastatic castration-resistant prostate cancer (mCRPC) has changed dramatically with the introduction of several novel agents. However, limited data are available to determine whether the introduction of novel agents affected patient characteristics, treatment patterns, and outcomes compared with the period when these agents were not available. The objective of this study was to evaluate the impact of the introduction of novel mCRPC agents on patient characteristics, treatment patterns, and outcomes. Two cohorts of Japanese patients diagnosed with mCRPC between 2009 and 2014 (Epoch 1) and 2015 and 2019 (Epoch 2) were retrospectively analyzed. A total of 125 treatment-naïve mCRPC patients, consisting of 42 patients in Epoch 1 and 83 patients in Epoch 2, were evaluated. We obtained the following results: (i) a dramatic shift in the first-line treatment from docetaxel to androgen receptor axis-targeted agents (ARATs), (ii) an age range expansion for first-line treatment, and (iii) an overall survival (OS) advantage in Eopch 2 compared to Epoch 1. Multivariate analysis in the overall population showed that Epoch 2 and low prostate-specific antigen (PSA) levels at the start of first-line treatment were independent prognostic factors for OS. In real-world mCRPC practice, the introduction of novel agents has improved the prognosis of mCRPC while allowing more patients to receive mCRPC treatment across a broad age range. In addition, low PSA levels at the start of first-line treatment were associated with improved OS, indicating the importance of starting mCRPC treatment while PSA levels are low.

Inhibition of glutaminolysis alone and in combination with HDAC inhibitor has anti-myeloma therapeutic effects.

Aim: This study aimed to investigate drug candidates and their efficacy in treating refractory multiple myeloma (MM) despite significant therapeutic advances and the introduction of novel agents. Our study focused on how myeloma cells mediate the metabolic pathways essential for survival. Therefore, we examined the role of glutaminolysis in this process. Methods: We investigated the role of glutaminolysis in myeloma cell growth. In addition, we analyzed the ability of CB-839 (telaglenastat), a glutaminase (GLS) inhibitor, to suppress myeloma cell proliferation and enhance the sensitivity to histone deacetylase (HDAC) inhibitors. Results: Glutamate deprivation significantly reduced MM cell proliferation. We observed an upregulation of GLS1 expression in MM cell lines compared to that in normal controls. CB-839 inhibits MM cell proliferation in a dose-dependent manner, resulting in enhanced cytotoxicity. Additionally, intracellular α-ketoglutarate and nicotinamide adenine dinucleotide phosphate levels decreased after CB-839 administration. Combining panobinostat with CB-839 resulted in enhanced cytotoxicity and increased caspase 3/7 activity. Cells transfected with GLS shRNA exhibited reduced cell viability and elevated sub-G1 phase according to cell cycle analysis results. Compared to control cells, these cells also showed increased sensitivity to panobinostat. Conclusion: Glutaminolysis contributes to the viability of MM cells, and the GLS inhibitor CB-839 has been proven to be an effective treatment for enhancing the cytotoxic effect of HDAC inhibition. These results are clinically relevant and suggest that CB-839 is a potential therapeutic candidate for patients with MM.

Allogeneic stem cell transplantation in multiple myeloma: is there still a place?

The introduction of novel agents dramatically improved response and outcomes of multiple myeloma (MM) and led to a sharp decline in the use of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Thus, recent guidelines do not recommend anymore allo-HSCT as consolidation in the first-line treatment of newly diagnosed MM, even in high-risk patients. In a relapsed/refractory setting, allo-HSCT is not routinely recommended but should only be performed within clinical trials in young and high-risk patients. Nonetheless, allo-HSCT still represents a potential curative approach that has been used for decades in the treatment of MM and plasma cell neoplasms with favorable results and may still represent a treatment option for carefully selected patients. Despite that promising results were obtained with CAR T-cell therapies and bispecific antibodies in triple- and penta-exposed/refractory MM, these patients will inevitably relapse. To date, less is known about outcomes of allo-HSCT in patients exposed to novel immunotherapeutic drugs. Therefore, allo-HSCT could represent a reasonable treatment choice for younger and high-risk patients who have relapsed after CAR T-cell therapies and bispecific antibodies as well as an alternative for patients not eligible to these treatments and in those countries where immunotherapies are not yet available. In the choice of conditioning, reduced intensity conditioning regimens are currently recommended for the lower toxicity and mortality. Moreover, the use of alternative donors, particularly haploidentical, has progressively increased in last years with results comparable to full matched donors. Finally, post-transplantation maintenance strategies are encouraged whenever feasible.

Treatment Pattern and Outcome of Newly Diagnosed Multiple Myeloma Patients in a Resource-Limited Setting.

Multiple myeloma is the third most common hematologic malignancy in Malaysia. The introduction of novel agents over the past decades has improved patient outcome and survival substantially. However, these agents incur significant economic burden, thus leading to limited use in less developed countries. This study aims to report on the real-world treatment pattern and outcome of newly diagnosed multiple myeloma (NDMM) patients from a resource-constraint setting. This is a retrospective study on NDMM patients diagnosed between 1 January 2008 and 31 December 2022 in a single academic center. Patients' demographic and treatment details were included for analysis of progression free survival (PFS) and overall survival (OS). One hundred and thirty-six NDMM patients with a median age of 64.0 years (ranged from 38 to 87 years old) were included. Bortezomib-containing regimens were the most commonly used induction agent, followed by thalidomide. Almost half of the patients (47.1%) achieved very good partial response (VGPR) or complete remission (CR), while 31.6% achieved partial response (PR). Bortezomib containing regimen was associated with significantly deeper and more rapid response, (p=0.001 and p=0.017, respectively) when compared to other agents. Only 22.8% of these patients proceeded to upfront autologous haematopoietic stem cell transplantation. The median OS and PFS were 60.0 months and 25.0 months, respectively. Best initial response and upfront autologous stem cell transplantation (ASCT) were significantly associated with better PFS. Achieving at least a VGPR significantly associated with better outcome in NDMM patients. In a resource constrain country, we recommend incorporating bortezomib in the induction therapy followed with an upfront ASCT.

Primary Cutaneous CD30-Positive Lymphoproliferative Disorders—Current Therapeutic Approaches with a Focus on Brentuximab Vedotin

One of the most common subgroups of cutaneous T-cell lymphomas is that of primary cutaneous CD30-positive lymphoproliferative disorders. The group includes lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (pcALCL), as well as some borderline cases. Recently, significant progress has been made in understanding the genetics and treatment of these disorders. This review article summarises the clinical evidence supporting the current treatment options for these diseases. Recent years have seen the introduction of novel agents into clinical practice; most of these target CD30, such as anti-CD30 monoclonal antibodies and conjugated antibodies (brentuximab vedotin), bispecific antibodies and cellular therapies, particularly anti-CD30 CAR-T cells. This paper briefly reviews the biology of CD30 that makes it a good therapeutic target and describes the anti-CD30 therapies that have emerged to date.

Racial differences in treatment and survival among older patients with multiple myeloma.

Treatments for multiple myeloma (MM) have evolved over time and improved MM survival. While racial differences in MM treatment and prognosis between non-Hispanic African American (NHAA) and non-Hispanic White (NHW) patients are well-established, it is unclear whether they have persisted after the introduction of novel agents. Using the Surveillance, Epidemiology, and End Results-Medicare linked database, our study investigated racial difference in the receipt of treatment within 1 year following diagnosis and assessed survival outcomes among Medicare beneficiaries (≥66 years) diagnosed with MM from 2007 to 2017. We applied multivariable Cox proportional hazards models to estimate the association between race and survival and presented hazard ratios (HRs). Of 2094 NHAA and 11,983 NHW older patients with MM, 59.5% and 64.8% received treatment during the first year, respectively. Discrepancy in the proportion of patients receiving treatment between the two groups increased from 2.9% in 2007 to 2009 to 6.9% in 2014-2017. After controlling for relevant factors, patients who received treatment within the first year had lower mortality than those who did not (HR = 0.90, 95% confidence interval [CI]: 0.86-0.94). NHAA patients had a lower probability to receive treatments during the first year than NHW patients (HR = 0.91, 95% CI: 0.85-0.97) but had lower mortality (HR = 0.94, 95% CI: 0.88-1.00). The lower mortality was only observed among patients who received no treatment (HR = 0.84, 95% CI: 0.77-0.93); NHAA and NHW patients who received treatment had similar survival (p = 0.63). The increasing racial disparity in treatment utilization over time is concerning. Efforts are needed to eliminate the barriers of receiving treatment.

Diagnostic and therapeutic advances in adults with acute lymphoblastic leukemia in the era of gene analysis and targeted immunotherapy.

Acute lymphoblastic leukemia (ALL) is one of the most rapidly changing hematological malignancies with advanced understanding of the genetic landscape, detection methods of minimal residual disease (MRD), and the development of immunotherapeutic agents with good clinical outcomes. The annual incidence of adult ALL in Korea is 300-350 patients per year. The WHO classification of ALL was revised in 2022 to reflect the molecular cytogenetic features and suggest new adverse- risk subgroups, such as Ph-like ALL and ETP-ALL. We continue to use traditional adverse-risk features and cytogenetics, with MRD-directed post-remission therapy including allogeneic hematopoietic cell transplantation. However, with the introduction of novel agents, such as ponatinib, blinatumomab, and inotuzumab ozogamicin incorporated into frontline therapy, good MRD responses have been achieved, and overall survival outcomes are improving. Accordingly, some clinical trials have suggested a possible era of chemotherapy-free or transplantation-free approaches in the near future. Nevertheless, relapse of refractory ALL still occurs, and some poor ALL subtypes, such as Ph-like ALL and ETP-ALL, are unsolved problems for which novel agents and treatment strategies are needed. In this review, we summarize the currently applied diagnostic and therapeutic practices in the era of advanced genetic analysis and targeted immunotherapies in United States and Europe and introduce real-world Korean data.

Outcomes of Salvage VDT-PACE-like Regimens in Relapsed-Refractory Multiple Myeloma: 10-Year Experience of a Large Academic Institution

Introduction: Rapidly evolving therapies for multiple myeloma (MM) have drastically changed the treatment landscape over the last decade. Despite the introduction of novel agents into clinical practice, MM remains challenging to treat in the setting of aggressive relapse and/or multi-refractory disease, accompanied by high tumor burden and extramedullary sites. Intensive chemotherapy with VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide)-like regimens may be used for a limited number of cycles as a bridging regimen to quickly achieve cytoreduction. This study aimed to evaluate outcomes of patients treated with VDT-PACE-like regimens (VPRs) for relapsed-refractory MM (RRMM) at our center. Methods: We retrospectively analyzed medical records of patients with RRMM who were treated with VPRs at our institution between 1/1/2013 and 6/1/2023. Responses including complete response (CR), very good partial response (VGPR), partial response (PR) and minimal response (MR) were measured according to the International Myeloma Working Group (IMWG) criteria. Baseline characteristics were outlined by descriptive analysis. Kaplan-Meier method was used for progression free survival (PFS), and overall survival (OS) calculations. Patients were censored in PFS analysis if they started another therapy before progression. Results: A total of 93 patients with RRMM were included in this analysis. Median age was 59 (range 42-84) years, 41% were female and 82% were White. The median number of prior lines of therapy was 6 (range 1-17) and median percentage of bone marrow plasma cells prior to VPRs initiation was 70%. Of the entire cohort, 60% of patients had high risk cytogenetics and 27% had plasma cell leukemia; other baseline patient and disease characteristics are summarized in Table 1. Patients received a median of 1 cycle (range 1-4) of VPRs; 37% received >2 cycles of treatment. After completion of cycle 1, VGPR or better, PR, and MR were achieved in 25 (27%), 30 (32%) and 11 (12%) patients, respectively. The estimated median PFS was 4 months (95% Cl, 2.8 - not reached [NR]) and the estimated median OS was 7 months (95% Cl, 5-8) from VPRs initiation (Figure 1). Among the 72 patients who received further treatment post VPRs completion, 19% underwent autologous hematopoietic cell transplant (AHCT), 70% were switched to another plasma cell-directed therapy, and 11% received chimeric antigen receptor T (CAR T)-cell therapy as the next line of therapy. The remaining 21 patients were transitioned to hospice immediately following VPRs, or died prior to receiving next line of therapy due to disease progression. Thirty-eight patients (41%) were readmitted after cycle 1 due to complications; median number of readmissions was 1 (range 1-4), and median cumulative duration of inpatient hospital stay was 7.5 (range 1-42) days. Severe neutropenia (defined as neutrophilic count <500 x10 9/L) and severe thrombocytopenia (defined as platelet count <25 x10 9/L) were seen in 57 (61%) and 43 (46%) patients, respectively after cycle 1, and 28 (30%) patients developed neutropenic fever. Conclusion: VPRs are feasible salvage treatment options in RRMM patients with aggressive and multi agent-refractory disease. Most patients responded to VPRs bridge therapy and were able to transition to autologous hematopoietic cell transplant, CAR T-cell therapy or other less toxic plasma-cell directed regimens. Despite that, the median overall survival of the entire cohort was short indicating that VPRs might not be able to reverse the poor prognosis of highly aggressive RRMM disease.

New Strategies for the Treatment of Older Myeloma Patients

Multiple myeloma (MM) mostly affects older patients, who represent a highly heterogeneous population. In the last few years, the introduction of novel agents led to a significant improvement in the outcome of MM patients. Nonetheless, this positive trend is less likely to occur in all older patients due to comorbidities/disabilities and major susceptibility to toxic events. Furthermore, older patients with major comorbidities are usually excluded or underrepresented in most registrational clinical trials. In this context, physicians have called for greater caution in the management of the disease. Several scores allow for the identification of frail and unfit patients and establish the possibility of tailoring therapy, reducing toxicity. This review explores the available tools for the assessment of frailty and what has been done to improve the discriminative power of the available scores. Thereafter, it describes the main therapeutic strategies for the management of transplant-ineligible (NTE) newly diagnosed (ND) MM patients and relapsed/refractory (RR) MM patients, in order to better guide physicians in choosing treatment options and to suggest possible strategies for more frail patients.

P60 EVOLVING OUTCOMES OF EXTRAMEDULLARY DISEASE IN MULTIPLE MYELOMA: 20-YEARS SINGLE CENTER EXPERIENCE

Extramedullary disease (EMD) represents an aggressive form of multiple myeloma (MM) characterized by hematogenous spread of a clone or a subclone of disease able to thrive and grow independently form bone marrow microenvironment. This form of disease has poorer outcome and dismal prognosis. In the last two decades therapeutic armamentarium for treatment of MM is increased and there is a trend toward more prolonged therapy, leading to a better outcome of MM patients. However, the efficacy of the new treatments on patients with EMD is not clear. We retrospectively evaluated patient characteristics and treatment durations in terms of time to next treatment and outcomes in our center from January 1994 until December 2022. A total of 52 patients were evaluable and were investigated. All the patients were diagnosed with multiple myeloma and EMD and received at least one line of therapy during their life. EMD was present at diagnosis or at relapse in 27 (52%) and 25 (48%) patients respectively. Pure extramedullary plasmocytomas were present in 23 (44%), among them seven patients had bone-related plasmocytomas too. Sites involved were: central nervous system (CNS, 7 cases), lung (4 cases), skin (4), lymph nodes (1),pleura (1), eye (1 case), mediastinum (1), liver (1), gallbladder(1), abdomen (1), stomach (1), uterus (1). Bone-related plasmocytomas were present in 29 patients (55%). FISH analysis was evaluable in 33 patients: 16 standard risk, 17 high risk (51,5%). The majority of patients were treated outside controlled clinical trials (39, 75%); 25% of patients (13) have been enrolled in a clinical trial during their life (10, in trials on upfront therapy, 2, in trials on therapy at relapse, one patient in both). On the basis of the year when a patient was exposed to first line therapy, patients were divided in two groups: patients diagnosed and treated from 1994 to 2012 (group A, 11 patients, 21%), and patients diagnosed and treated from 2013 (group B, 41 patients, 79%). Less than a half of patients (24, 46%) are still alive; among them more than 95% were diagnosed and treated after 2012 (group B). 100% (52) of patients were exposed to first line therapy, 81% (42) to second, 73% (38) to third, 46% (24) to fourth, 33% (17) to more than fifth, 9% (3) to more than eight, 3 were allotransplanted (6%) (Table 1). For group A mean and median of lines of therapies were 4.7 and 4 months (range 1-9), for group B were 3.7 and 3 months (range 1-9). Time to next treatment was unfortunately lower from one line of therapy to the next one, particularly in patients belonging to group A where relapses and need of a new treatment occurred more frequently than for patients belonging to group B (introduction of novel agents, maintenance/continuous therapy. Observed cumulative median overall survival (m OS) is 65 months, range 1-202 months. These real-world data show an evolution of EMD patient outcomes in the last two decades. Data are encouraging to design prospective studies including EMD patients for optimal treatment decisions to translate in clinical practice. Table 1 - Patients characteristics 52 EMD At diagnosis 27 (52%) At relapse 25 (48%) Pure EMD 23 (44%) Bone-related plasmacytomas 29 (55%) FISH Standard risk 16 High risk 17 (51.5%) Not evaluable 19 Clinical trials Not included 39 (75%) First line 11(21%) At relapse 2 (4%) First exposition to therapy 1994-2012 11 (21%) >2013 41 (79%) Lines of therapy Median 3 (1-9) First 52 (100%) Second 42 (81%) Third 38 (73%) Fourth 24 (46%) >fifth<eighth 17 (33%) >eighth 3 (9%) Median OS 65 (range 1-202 months)

Multiple myeloma with t(11;14): impact of novel agents on outcome

Multiple myeloma (MM) patients with t(11;14) present unique biological features and their prognosis is not well established. We report a retrospective study of 591 MM patients, 17.3% of whom had t(11;14). It was designed to determine the prognostic impact of this abnormality and the effect of novel agents on the response and outcomes. Three groups were established based on their cytogenetics: (1) t(11;14); (2) high-risk chromosomal abnormalities; and (3) standard risk (SR). After 80.1 months (1.2–273.8 months) of follow-up, no differences were observed in overall survival (OS) between the t(11;14) and SR groups (75.8 vs. 87.2 months; P = 0.438). Treatment of MM t(11;14) with novel agents did not improve their overall response rate (ORR) or complete response (CR) compared with those who received conventional therapy (ORR: 87.2 vs. 79.5%, P = 0.336; CR: 23.4 vs. 12.8%, P = 0.215). This effect translated into a similar PFS (39.6 vs. 30.0 months; P = 0.450) and OS (107.6 vs. 75.7 months; P = 0.175). In summary, MM t(11;14) patients did not benefit from the introduction of novel agents as much as SR patients did, indicating that other therapies are needed to improve their outcomes.

The role of transplantation in Hodgkin lymphoma.

Despite the success of frontline anthracycline-based chemotherapy for classical Hodgkin Lymphoma (cHL), approximately 15% of patients do not achieve an adequate response and require further therapy. For transplant-eligible patients, additional treatment followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autoHCT) provides a durable response in 50% of patients. The most refractory patients, including those requiring multiple lines of therapy to achieve a response or those relapsing after an autoHCT, may achieve long-term survival with allogeneic hematopoietic stem cell transplant (alloHCT). Contemporary salvage regimens used as a bridge to transplant have expanded to include not only non-cross resistant chemotherapy, but also brentuximab vedotin (BV) and checkpoint inhibitors (CPI). As the management of relapsed/refractory (R/R) cHL evolves with the introduction of novel agents, so too does the role of transplantation. The paradigm of chemosensitivity as a predictor for autoHCT efficacy is being challenged by favorable post- autoHCT outcomes in heavily pre-treated CPI-exposed patients. Contemporary supportive care measures, validated comorbidity assessments, and an increased donor pool with haploidentical donors have broadened the application of transplantation to an increasingly older and diverse patient population. Despite the introduction of increasingly effective treatment options for R/R cHL, transplantation continues to play an important role in the management of these patients. In this review, we explore the impact of salvage therapy on autoHCT, conditioning regimens, maintenance therapy and the diminishing role of alloHCT for patients with cHL.

Post-Transplant Complications.

Hematopoietic cell transplantation (HCT) is a potentially curative therapy for patients with high-risk malignant and nonmalignant conditions. Nevertheless, various post-allogeneic HCT (allo-HCT) complications with diverse chronology, etiology, and pathophysiological background can develop, including general and organ-specific complications, such as graft dysfunction, infectious, and non-infectious etiologies, as well as non-infectious pulmonary complications (NIPCs). Post-transplant complications can also be related to conditioning intensity and drug-specific side effects. However, treatment options for these complications are suboptimal at present. Poor graft function (PGF) is a potentially life-threatening post-allo-HCT complication and is reported in 5-30% of patients. Nevertheless, consensus guidelines to define and treat PGF are not available. Most therapies are symptomatic with variable success rates. NIPCs are diverse and difficult to diagnose. The pathophysiology of NIPCs remains ill-defined, and effective treatment approaches have not been standardized, with mortality exceeding 50% for some conditions, such as idiopathic pneumonia syndrome (IPS). Modification of the conditioning regimen intensity and introduction of novel agents have been used to decrease post-allo-HCT complications, including infections, non-infectious complications, graft-versus-host disease (GvHD), as well as cardiopulmonary, neurological, hepatorenal, and other complications. Transplant-associated thrombotic microangiopathy (TA-TMA) is a lethal post-allo-HCT complication that may be associated with functional and genetic abnormalities in complement activation and related to the use of calcineurin inhibitors, such as cyclosporine and tacrolimus. The introduction of complement inhibitors has transformed TA-TMA from a lethal complication to a treatable syndrome.

Combined inhibition of Wee1 and Chk1 as a therapeutic strategy in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal clonal proliferation of malignant plasma cells. Despite the introduction of novel agents that have significantly improved clinical outcome, most patients relapse and develop drug resistance. MM is characterized by genomic instability and a high level of replicative stress. In response to replicative and DNA damage stress, MM cells activate various DNA damage signaling pathways. In this study, we reported that high CHK1 and WEE1 expression is associated with poor outcome in independent cohorts of MM patients treated with high dose melphalan chemotherapy or anti-CD38 immunotherapy. Combined targeting of Chk1 and Wee1 demonstrates synergistic toxicities on MM cells and was associated with higher DNA double-strand break induction, as evidenced by an increased percentage of γH2AX positive cells subsequently leading to apoptosis. The therapeutic interest of Chk1/Wee1 inhibitors' combination was validated on primary MM cells of patients. The toxicity was specific of MM cells since normal bone marrow cells were not significantly affected. Using deconvolution approach, MM patients with high CHK1 expression exhibited a significant lower percentage of NK cells whereas patients with high WEE1 expression displayed a significant higher percentage of regulatory T cells in the bone marrow. These data emphasize that MM cell adaptation to replicative stress through Wee1 and Chk1 upregulation may decrease the activation of the cell-intrinsic innate immune response. Our study suggests that association of Chk1 and Wee1 inhibitors may represent a promising therapeutic approach in high-risk MM patients characterized by high CHK1 and WEE1 expression.

Primena nivolumaba kod bolesnice sa mukozalnim melanomom i sistemskim lupusom - prikaz slučaja sa pregledom literature

Introduction. Systemic lupus erythematosus (SLE) represents a multisystemic disease characterized by antibody production, complement activation, and immune complexes deposition. Certain types of malignancies occur more often, and conversely, some of them occur less often in SLE patients. Mucosal melanoma of the anorectal region represents a rare form of melanoma occurring in 1.5% of all melanoma patients, predominantly female. The introduction of novel agents dramatically changed the outcome in melanoma patients and introduced different adverse events, diverse contraindications, and drug interactions. Immune checkpoint inhibitors have a role in the maintenance of immunologic homeostasis. Patients with underlying autoimmune diseases were often excluded from clinical trials, for fear of possible autoimmune disease exacerbation or high-grade immune-related adverse events. Due to that, data regarding this subgroup of patients is limited, with no clear recommendations. Given the fact that prevalence among the general population is high (5-10%), autoimmune diseases represent common comorbidity in cancer patients. Having that in mind, it is of utmost importance to personalize the approach and individualize the SLE treatment and enable the use of PD-1 antibody in the safest and most useful way while keeping the SLE in control. Case report. Herein we present a 79-year-old with primary mucosal melanoma of the anorectal region, with lung metastasis and preexisting SLE in remission. Hydroxychloroquine was the only treatment for SLE. Nivolumab treatment was initiated in the standard dosing schedule. After the first and second follow-up, no further progression of melanoma was detected, with no SLE exacerbation and immune-related adverse events. Conclusion. PD-1 treatment in a patient with an underlying autoimmune disease represents a viable choice with a necessity for a multidisciplinary approach and close monitoring.

Combining Plasma Cell Leukemia-like Status with the Second Revision of the International Staging System Improves Risk Classification

Introduction Newly diagnosed multiple myeloma (NDMM) is characterized by a highly variable clinical course, with an overall survival (OS) ranging from less than 3 years to over 10 years. While patients with standard risk disease have benefited significantly from the introduction of novel agents, it remains unclear what the best upfront treatment strategy is for those with high-risk disease. As a result, risk-adapted trial designs (e.g., the MUKnine b OPTIMUM study, NCT03188172) are becoming more common in NDMM and are driving research efforts to improve the identification of high-risk disease. High-risk NDMM can be identified with the recently published Second Revision of the International Staging System (R2-ISS), which combines several conventional risk markers including tumor burden and cytogenetic aberrations that generally reflect increased proliferation and resistance to apoptosis (D'Agostino et al. - J Clin Oncol 2022). We have recently shown that NDMM with high levels of circulating tumor cells can be identified based on a plasma cell leukemia-like (PCL-like) transcriptome that reflects aggressive disease, which is different from the high-risk biology that is recognized by conventional risk models (Hofste op Bruinink et al. - J Clin Oncol 2022). Hence, we hypothesized that combining PCL-like status with the R2-ISS classification would improve prognostic accuracy. Methods Baseline characteristics including serum β2 microglobulin, albumin, lactate dehydrogenase and high-risk cytogenetic markers including deletion of chromosome 17p, t(4;14) and gain/amplification of chromosome 1q were collected from NDMM patients enrolled in the HOVON-65/GMMG-HD4 (EudraCT 2004-000944-26), HOVON-87/NMSG-18 (EudraCT 2007-004007-34), MRC-IX (ISRCTN68454111), Total Therapy 2 (NCT00083551), Total Therapy 3 (A: NCT00081939 and B: NCT00572169) and MMRF CoMMpass studies (NCT01454297) and used to determine the R2-ISS classification. Transcriptomic profiles were generated from CD138-enriched bone marrow tumor cells and used to calculate PCL-like status. For progression-free survival (PFS), an event was defined as either progressive disease or death from any cause. For OS, an event was defined as death from any cause. Hazard ratios (HRs) for PCL-like status, the R2-ISS classification or a combination thereof were estimated using a Cox proportional hazards model stratified by study cohort and corrected for age ≤ 65 years. Two-sided P values < 0.05 were considered statistically significant. Results For a total of 976 NDMM patients of known age, both the R2-ISS classification and PCL-like status could be determined, with a median follow-up time of 53 months. 31% of patients were classified as R2-ISS low (R2-ISS I), 31% as R2-ISS low-intermediate (R2-ISS II), 33% as R2-ISS intermediate-high (R2-ISS III) and 5% as R2-ISS high (R2-ISS IV), whereas 9% were classified as PCL-like MM and 91% as not PCL-like MM (i.e., intramedullary MM, i-MM). PCL-like status was associated with both an inferior PFS (HR, 1.8; 95% confidence interval (CI), 1.4 to 2.3; P = 0.001) and OS (HR, 2.2; 95% CI, 1.7 to 2.9; P < 0.001). This also applied to the R2-ISS classification when comparing R2-ISS IV to R2-ISS I, II and III (HR for PFS, 2.5; 95% CI, 1.9 to 3.4; P < 0.001 and HR for OS, 3.0; 95% CI, 2.2 to 4.2; P < 0.001). PCL-like status retained its prognostic significance in a multivariate model when combined with the R2-ISS classification, both in terms of PFS (HR, 1.8; 95% CI, 1.4 to 2.4; P = 0.001) and OS (HR, 2.2; 95% CI, 1.6 to 2.9; P < 0.001). Of note, 1% of NDMM patients were both classified as PCL-like MM and R2-ISS IV, which translated into a median PFS of 4 months (95% CI, 3 months to not reached) and a median OS of 7 months (95% CI, 4 months to not reached). Patients with PCL-like MM and R2-ISS III (3%) had a comparable median OS to those with i-MM and R2-ISS IV (4%) (35 and 30 months, respectively). Conclusions 1. PCL-like status has independent prognostic value in the context of the R2-ISS classification in NDMM. 2. The presence of both PCL-like MM and R2-ISS IV may confer exceptionally high risk in NDMM, with a median OS of only 7 months. 3. NDMM patients with PCL-like MM and R2-ISS III have a comparable OS to those with i-MM and R2-ISS IV, comprising a median OS of 35 and 30 months, respectively.

Individualized Treatment-Adjusted Risk Stratification in Newly Diagnosed Multiple Myeloma

Introduction. For newly diagnosed multiple myeloma (NDMM) patients, median overall survival (OS) and progression free survival (PFS) have dramatically improved during recent years due to the introduction of novel agents. Unfortunately, a subset of patients with NDMM does not benefit from newer therapies reflected in persisting poor outcomes. In contrast, another subset has favorable outcomes despite receiving limited therapy. Though having demonstrated that several genomic events contribute to clinical outcomes, yet the "one-size-fits-all" treatment paradigm remains dominant for NDMM. Here, we present the first artificial intelligence individualized prediction model for NDMM to facilitate individually tailored therapeutic decisions. Methods. We included 1840 patients with available clinical and genomic data from the following cohorts: MMRF CoMMpass (n=1062), MGP (n=492), Moffit AVATAR (n=177), and MSKCC (n=109). The median follow up was 42 months. To build a treatment-adjusted predictive model of individualized risk for patients with NDMM, we considered 160 variables across clinical (e.g., age, ECOG, sex, ISS), therapeutics, genomics, and time-dependent treatments such as autologous stem cell transplant (ASCT) and continuous treatment (Palumbo et al. JCO 2015). A multi-state model was designed across two phases: induction (phase 1), and post-induction (phase 2). Phase 1 included patients that: 1) completed the induction without progression (PD); 2) PD of failed to respond during induction remaining alive after; 3) PD during induction and subsequently died. Phase 2 have patients that: 4) PD after induction and were alive; 5) PD after induction and died; 6) reached remission after induction and were alive; 7) responded after induction and died due to other causes. We leveraged and compared survival methods based on deep neural networks (Neural Cox Non-proportional-hazards;NCNPH), Random Survival Forest (RSF), and Cox proportional-hazard(CPH). Results. NCNPH showed the best cross-validated prognostic performance for OS with median Uno's concordance (C=0.67), followed by RSF (C=0.65) and CPH (C=0.64; Fig. 1a-b). Overall, the model significantly outperformed R2-ISS (C=0.6), ISS (C=0.59) and R-ISS (C=0.57; Fig. 1b). Additionally, the model found 28 genomic features to increase concordance accuracy for PFS by (3% in phase 1 and 1.5% in phase 2), and with greater effect on OS (10% in phase 1 and 5% in phase 2). The 14% of patients who did not respond in phase 1 were enriched for ISS3, age >75 y, 1q amp, NSD2 translocation, TP53 mutations, and deletions on 17p13 and 1p. Varying therapies emerged as a key determinant of risk, in particular, in phase 2, supporting the idea that effective combinations can have a different impact in individual patients and have the potential to significantly change the clinical outcome despite poor prognostication. The model not only predicts patient risk but also the impact of various treatment strategies (i.e., treatment variance). We identified 9 distinct clusters (C#1-9) based on predicted risk and treatment variance. C#8 and C#9 show favorable outcome, especially with ASCT and continuous treatment. C#4 and C#5 included patients with favorable outcome but low treatment variance where ASCT had marginal impact. C#6 had a substantial presence of high-risk patients associated with low variance, age >75y, 1q gain, and NSD2 translocations. Interestingly, NSD2 translocated patients not included in C#6 had an intermediate favorable outcome (p<0.0001). Early PD was observed in C#1 and C#7, both enriched for low treatment variance, and high risk genomic and clinical features. Finally, we identified a group of high-risk patients (C#2 and C#3) with high treatment variance whose poor outcome was mostly driven by a suboptimal treatment (i.e., use of doublet, no ASCT, no continuous treatment) rather than presence of distinct clinical and genomic features, highlighting the need for treatment to be considered to build more robust and accurate prognostic models. Conclusion: This work shows the first comprehensive model integrating new and historical features to train a neural network for individualized risk prediction in NDMM. Utilizing data from 1840 patients that received a variety of therapies, the model captures the interaction of genomic, clinical and therapy factors, enabling personally-tailored therapeutic decisions in NDMM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Adolescent and Young Adults with ALL Who Complete Therapy on DFCI Consortium ALL Trials Have Excellent Long-Term Overall Survival

Background: Adolescent and young adult (AYA) patients (pts) with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) have good outcomes when treated on pediatric regimens but still face worse survival compared to younger children (Siegel JAMA Onc 2018). Pediatric patients who do not complete ALL treatment, particularly planned asparaginase (ASP), have inferior oncologic outcomes (Silverman Blood 1997). In the CALBG 10403 trial of a pediatric-inspired regimen in AYAs 17-39 years (yrs), only 39% of pts completed planned treatment (Stock Blood 2019). We aimed to describe the prevalence of treatment failure, reasons for treatment non-completion, and their effect on survival among patients treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols. Methods: We identified Philadelphia chromosome negative (Ph-) pts aged 1-49 yrs treated on 4 sequential multi-center DFCI Consortium protocols between 2000 and 2018 (00-001, 05-001, 01-175, 06-254). Additional consecutive Ph- pts treated as per these protocols were identified by chart review. All pts were intended to receive 30 continuous weeks (wks) of ASP during consolidation. Treatment failure was defined as induction failure, induction death, relapse/progression on therapy, and remission death on therapy. Treatment non-completion was defined as transplant in first complete remission (CR), withdrawal due to toxicity or other reasons, loss to follow up, and ineligible status. Treatment completion was defined as no exit from treatment protocol before its completion, approximately 2 yrs from complete remission (CR). Per protocol, no patients were recommended for allogeneic hematopoietic stem cell transplant (HSCT) in CR1. ASP completion was defined as receiving at least 26 wks of ASP during consolidation (Silverman, Blood 2001). The protocols allowed for truncation of ASP for toxicity without exit from protocol. Median follow-up time was calculated using the reverse Kaplan Meier indicator. The chi square test was used to compare proportions between groups. Overall survival (OS) among groups was compared using the log rank test. Results: A total of 1,480 pts were identified: 1,149 children (< 15 yrs, median age 4.5 yrs) and 331 AYAs (15-49 yrs, median age 24 yrs). Median follow-up was 7.9 yrs. Treatment completion rate was lower among AYAs than children (61.3% vs. 89.9%, p < 0.001) (Table 1). This was driven by higher treatment failure rates among AYAs than children (19.9% vs. 5.5%) as well as higher treatment non-completion rates (19.0% vs. 4.6%), primarily driven by transplants in CR1 among AYAs. Treatment completion rates were lower among older (30-49 yrs) AYAs compared to younger (15-29 yrs) AYAs (50.5% vs. 65.7%, p = 0.009). Among 1235 pts who completed treatment, 1086 (87.9%) received ³26 weeks of ASP. ASP completion rate was lower among AYAs vs. children (79.2% vs. 89.6%, p < 0.001). A higher percentage of AYAs discontinued ASP because of toxicity than children (11.9% vs. 5.5%, p = 0.01). In a landmark analysis of patients who survived and had follow-up for at least 2 years from diagnosis, AYAs who completed treatment (with or without ASP completion) had an estimated 5-year OS of 92.7% (95% Confidence Interval (CI): 87.5%, 95.8%), while children who completed treatment had a 5-year OS of 97.9% (95% CI: 96.7%, 98.6%) (Log-rank test p = 0.002) (Figure 1). Patients alive at 2 years who failed or did not complete treatment had worse survival outcomes with a 5-year OS of 70.5% (95% CI: 53.9%, 82.1%) among AYAs and 76.1% (95% CI: 62.2%, 85.5%) among children (Log-rank test p = 0.598) Conclusions: AYAs in our cohort completed protocol treatment at higher rates than previously reported trials. Among AYAs who completed treatment protocol, oncologic outcomes were excellent (5-year OS above 90%) and comparable to (although statistically lower than) those of children. AYAs had higher treatment failure rates, likely due to more aggressive disease biology. AYAs had lower ASP completion rates and higher ASP discontinuation rates due to toxicity compared to children; the etiology and impact of that on survival will need to be further investigated. Introduction of novel agents to improve remission induction rates and prevent early relapse in AYAs might help further improve oncologic outcomes for this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MM-202 Impact of t(11;14) in Multiple Myeloma on Response to Treatment and Survival

Identification of cytogenetic abnormalities by FISH in multiple myeloma (MM) allows for the differentiation of groups with different clinical-biological features and prognoses. The impact of t(11;14) on prognosis in the era of new treatments is not well established. To determine the outcomes of MM patients with t(11;14). An observational retrospective study was designed including patients diagnosed with MM at the Hospital of Salamanca (1984-2018). Patients were classified into 3 groups: 1) the t(11;14) group; 2) the high-risk (HR) group (defined by IMWG); and 3) the standard risk (SR) group (not t[11;14] or HR). SR and HR patients were pooled in the non-t(11;14) group. Proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies were named novel agents, and chemo-containing regimens were named conventional therapy. Of 1,111 MM patients, 600 had FISH studies and were included. N/A. Responses according to IMWG criteria, PFS, and OS. Ninety-eight (16.3%) patients belonged to the t(11;14) group, 104 (17.3%) to the HR group, and 398 (66.3%) to the SR group. With a median follow-up of 55.9 months (0-364.1), no differences in OS were observed between the t(11;14) and SR groups (75.8 vs. 93.4 months; P=0.222), but OS in these groups was longer than in the HR group (48.7 months; P=0.023). MM patients with t(11;14) treated with novel drugs had an ORR and percentage of CR similar to those of patients who received conventional therapy (ORR: 89.6% vs. 80.0%, P=0.207; and 31.3% vs. 32.5%, P=0.900). No differences were observed between t(11;14) treated with novel agents and t(11;14) treated with conventional therapy in PFS (39.5 vs. 29.9 months; P=0.461) nor OS (93.2 vs. 75.8 months; P=0.171). Within the ISS-1 group, the t(11;14) group presented worse OS than the non-t(11;14) group (63.0 vs. 117.7 months; P=0.006). Patients with t(11;14) did not benefit from the introduction of novel agents in terms of quality of response and survival. The t(11;14) and SR groups had similar prognoses, superior to the HR group. Within the ISS-1 group, the presence of t(11;14) was associated with worse OS.