Multiple myeloma: clinical characteristics, current therapies and emerging innovative treatments targeting ribosome biogenesis dynamics.

Multiple myeloma (MM) is a clinical disorder characterized by aberrant plasma cell growth in the bone marrow microenvironment. Globally, the prevalence of MM has been steadily increasing at an alarming rate. In the United States, more than 30,000 cases will be diagnosed in 2024 and it accounts for about 2% of cancer diagnoses and more than 2% of cancer deaths, more than double the worldwide figure. Both symptomatic and active MM are distinguished by uncontrolled plasma cell growth, which results in severe renal impairment, anemia, hypercalcemia, and bone loss. Multiple drugs have been approved by the FDA and are now widely used in clinical practice for MM. Although triplet and quadruplet induction regimens, autologous stem cell transplantation (ASCT), and maintenance treatment are used, MM continues to be an incurable illness characterized by relapses that may occur at various phases of its progression. MM patients with frailty, extramedullary disease, plasma cell leukemia, central nervous system recurrence, functional high risk, and the elderly are among those with the greatest current unmet needs. The high cost of care is an additional challenge. MM cells are highly protein secretary cells and thus are dependent on the activation of certain translation pathways. MM also has a high chance of altering ribosomal protein-encoding genes like MYC mutation. In this article we discuss the importance of ribosome biogenesis in promoting MM and RNA polymerase I inhibition as an upcoming treatment with potential promise for MM patients.

Predicting relapsed/refractory disease in childhood hemophagocytic lymphohistiocytosis based on clinical features at diagnosis: A 13-year single-institute retrospective study in Thailand.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease. Relapsed/refractory disease is the main cause of death. This study aims to determine the prognostic indicators for relapsed/refractory disease in childhood HLH (R/R HLH). Infants and children under 18 years of age who were diagnosed with HLH according to HLH-2004 criteria, MAS-HLH criteria for rheumatologic diseases, or H-score undergoing treatment in Chiang Mai University hospital between 2010 and 2022 were included. Demographic data, clinical characteristics, and laboratory parameters were retrospectively reviewed. Out of 86 childhood HLH cases, 30 patients (34.9%) experienced R/R HLH. All patients with primary HLH developed R/R HLH. The most common form of secondary HLH was infection-associated hemophagocytic syndrome (IAHS), comprising 43 cases. Of these, 37.2% had relapsed or refractory disease. Univariable analysis identified several potential risk factors for R/R HLH, including younger age, severe disease status, higher HLH-2004 criteria scores, higher H-scores, overt DIC, higher pSOFA scores, and increased levels of aspartate aminotransferase, total bilirubin, and direct bilirubin. Multivariable logistic regression analysis revealed that a pSOFA score of ≥ 8 and age < 3 years were independent risk factors for R/R HLH, with adjusted odds ratios of 6.35 (95% confidence interval [CI], 1.18-34.19; P = 0.032) and 3.62 (95% CI, 1.04-12.63; P = 0.044), respectively. Children with HLH who have a pSOFA score of ≥ 8, or are younger than 3 years, are at a higher risk of relapsed or refractory disease. Further evaluation of management strategies in this context is warranted.

Dismantling relapsed/refractory mantle cell lymphoma.

Despite recent therapeutic advancements in the general field of non-Hodgkin lymphoma, effective treatment of relapsed or refractory (R/R) mantle cell lymphoma (MCL) remains a challenge. The development of Bruton tyrosine kinase (BTK) inhibitors has revolutionized the field and these agents are now the mainstay of R/R MCL management. However, BTK inhibitors are not curative, and as they are increasingly being incorporated into frontline regimens, the shifting treatment landscape for R/R disease presents new challenges. Here we review data for commonly employed treatment strategies including BTK inhibitors, the BCL2-inhibitor venetoclax, lenalidomide-based regimens, and chimeric antigen receptor T-cell therapy. We additionally review data for promising novel agents including antibody-drug conjugates and bispecific antibodies before highlighting some emerging targeted agents that continue to bring promise for improved outcomes in R/R MCL.

Tafasitamab for the treatment of patients with diffuse large B-cell lymphoma.

Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) require additional treatments, especially those not eligible or not responding to high dose cytotoxic chemotherapy and stem cell transplantation. Over the last few years, several new treatments have been developed and approved for these patients, among them of particular relevance are those targeting CD19. Tafasitamab is a humanized monoclonal antibody targeting CD19, composed of a modified fragment crystallizable (Fc) region engineered with higher affinity for Fc gamma receptors (FcγR) receptors, leading to increased cytotoxicity through natural killer cells and macrophages (antibody-dependent cellular cytotoxicity and antibody-dependent cell-mediated phagocytosis). In this product review, we will discuss its mechanism of action, safety profile and efficacy results from clinical trials that led to its approval in combination with lenalidomide for patients with R/R DLBCL ineligible for high-dose chemotherapy and autologous transplantation.

Multiple Myeloma in 2023 Ways: From Trials to Real Life.

Multiple myeloma is a chronic hematologic malignancy that obstinately tends to relapse. Basic research has made giant strides in better characterizing the molecular mechanisms of the disease. The results have led to the manufacturing of new, revolutionary drugs which have been widely tested in clinical trials. These drugs have been approved and are now part of the therapeutic armamentarium. As a consequence, it is essential to combine what we know from clinical trials with real-world data in order to improve therapeutic strategies. Starting with this premise, our review aims to describe the currently employed regimens in multiple myeloma and compare clinical trials with real-life experiences. We also intend to put a spotlight on promising therapies such as T-cell engagers and chimeric antigen receptor T-cells (CAR-T) which are proving to be effective in changing the course of advanced-stage disease.

Next-Generation Sequencing-Optimal Sequencing of Therapies in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).

PURPOSE OF REVIEW: This research paper aims to provide an overview of evidence-based sequencing of therapies in relapsed/refractory chronic lymphocytic leukemia (CLL) in the era of targeted drugs. RECENT FINDINGS: In the absence of data from randomized clinical trials comparing novel agents head-to-head, growing evidence suggests that patients with late relapse (> 2 years) after fixed-duration therapies benefit from identical retreatment, whereas a class switch is favorable in those with short-lived remissions or progressive disease on continuous drug intake. Treatment of patients previously exposed to both covalent inhibitors of BTK and BCL2 remains an unmet medical need. Novel drugs, in particular noncovalent BTKI, show promising efficacy in this difficult-to-treat subgroup in early clinical trials. The optimal sequencing of therapies in CLL requires consideration of individual patient factors and disease characteristics. Double-refractory disease continuous to pose a clinical challenge with a focus on participation in clinical trials whenever possible.

Efficacy and Safety of Ixazomib Plus Lenalidomide and Dexamethasone Following Injectable PI-Based Therapy in Relapsed/Refractory Multiple Myeloma.

This nationwide, multicenter, open-label, single-arm study evaluated the efficacy and safety of the oral proteasome inhibitor (PI), ixazomib plus lenalidomide (LEN) and dexamethasone (DEX) (IRd) following injectable PI-based therapy for relapsed/refractory multiple myeloma (RRMM). Of 45 patients enrolled, 36 patients received IRd after achieving at least a minor response to 3 cycles of bortezomib or carfilzomib plus LEN + DEX (VRd, n=6; KRd, n=30). At median follow-up of 20.8 months, the 12-month event-free survival rate (primary endpoint) was 49% (90% CI: 35.9-62.0), counting 11 events of progressive disease/death, 8 dropouts and 4 missing response data. The 12-month progression-free survival (PFS) rate by Kaplan-Meier analysis (dropouts as censoring) was 74% (95% CI: 56-86). Median PFS and time to next treatment (95% CI) were 29.0 (21.3-NE) and 32.3 (14.9-35.4) months, respectively; median OS was not evaluable. The overall response rate was 73%, and 42% of patients had a very good partial response or better. Frequent (≥10% incidence) grade ≥3 treatment emergent adverse events were decreased neutrophil and platelet counts (n=7 [16%] each). Two deaths occurred (one during KRd treatment and one during IRd treatment), both due to pneumonia. IRd following injectable PI-based therapy was tolerable and efficacious in RRMM patients. TRIAL REGISTRATION NUMBER: NCT03416374; Date of registration: January 31, 2018.

A Phase Ib Dose-Escalation Study of LCL161 Plus Oral Topotecan for Patients With Relapsed/Refractory Small Cell Lung Cancer and Select Gynecologic Malignancies.

BACKGROUND: This was an open-label, multicenter, single-arm phase Ib dose-escalation study of oral LCL161 administered in combination with oral topotecan in patients with relapsed/refractory small cell lung cancer (SCLC) and select gynecological cancers. METHODS: Cohorts of 3-6 patients initiated treatment with LCL161 and topotecan in escalating doses. LCL161 was administered orally on days 1, 8, and 15 of each 21-day cycle; topotecan was administered orally for the first 5 days of each 21-day cycle. RESULTS: A total of 35 patients were enrolled in 6 cohorts; 30 patients were female; 4 patients had SCLC and 19 patients had ovarian cancer. Median prior lines of therapy were 3 (1-10). Median duration of treatment was 7.1 weeks (0.1-174). The most frequent grade 3/4 treatment-related adverse events were thrombocytopenia (51.43%) and anemia (31.43%). ORR was 9.7%; 58% of patients had SD. The study was stopped early before the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) were determined. CONCLUSION: The addition of LCL161 to oral topotecan caused more myelosuppression when dosed together than what was associated with either drug alone. Moreover, the drug combination did not improve outcomes. The study was terminated early (ClinicalTrials.gov Identifier: NCT02649673).

Incidence of second primary malignancies in relapsed/refractory B-cell non-Hodgkin's lymphoma patients in England.

BACKGROUND: Treatments for relapsed/refractory (r/r) B-cell non-Hodgkin's lymphoma (NHL) may be associated with an increased risk of second primary malignancies (SPMs). Currently available SPM incidence benchmarks are unreliable due to small sample sizes. METHODS: The Cancer Analysis System (CAS), a population-level cancer database in England, was used to identify patients with incident B-cell NHL diagnosed during 2013-2018 with evidence of r/r disease. Incidence rates (IRs) of SPMs after r/r disease diagnosis were calculated per 1000 person-years (PYs) and stratified by age, sex, and SPM type. RESULTS: We identified 9444 patients with r/r B-cell NHL disease. Of those who were eligible for SPM analysis, nearly 6.0% (470/7807) developed at least one SPM after r/r disease diagnosis (IR: 44.7; 95% confidence interval [CI]: 40.9-48.9). Of note, 205 (2.6%) had a non-melanoma skin cancer (NMSC) SPM. IR of SPMs was the highest for patients with r/r chronic lymphocytic leukemia/small lymphocytic leukemia (80.0) and lowest for diffuse large B-cell lymphoma (DLBCL) (30.9). Patients with DLBCL had the shortest overall survival after r/r disease diagnosis. CONCLUSIONS: This real-world data study suggests that the IR of SPM among patients with r/r B-cell NHL is 44.7 per 1000 PY and that most SPMs diagnosed after r/r disease diagnosis are NMSCs, establishing a basis for the comparison of safety outcomes for new treatments being developed for r/r B-cell NHL.

Characteristics and Outcomes of Adult Patients in the PETHEMA Registry with Relapsed or Refractory FLT3-ITD Mutation-Positive Acute Myeloid Leukemia.

This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 + 7. Subsequently, patients received salvage with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care only (n = 80). Active salvage therapy (i.e., intensive or non-intensive therapy) resulted in a complete remission (CR) or CR without hematological recovery (CRi) rate of 42%. More patients achieved a CR/CRi with intensive (48%) compared with non-intensive (19%) salvage therapy (p < 0.001). In the overall population, median overall survival (OS) was 5.5 months; 1- and 5-year OS rates were 25% and 7%. OS was significantly (p < 0.001) prolonged with intensive or non-intensive salvage therapy compared with supportive therapy, and in those achieving CR/CRi versus no responders. Of 280 evaluable patients, 61 (22%) had an allogeneic stem-cell transplant after they had achieved CR/CRi. In conclusion, in this large cohort study, salvage treatment approaches for patients with FLT3-ITD mutated R/R AML were heterogeneous. Median OS was poor with both non-intensive and intensive salvage therapy, with best long-term outcomes obtained in patients who achieved CR/CRi and subsequently underwent allogeneic stem-cell transplant.

Targeted inhibitors and antibody immunotherapies: Novel therapies for paediatric leukaemia and lymphoma.

Despite improved outcomes achieved in the last decades for children with newly diagnosed leukaemia and lymphoma, treatment of patients with refractory/relapsed disease remains a challenge. The cure rate is still unsatisfactory and often achieved at the cost of significant morbidity. Exploring treatment with novel agents should offer less toxic therapeutic options, without compromising efficacy. Bispecific and antibody-drug conjugates targeting CD19 and CD22 (blinatumomab and inotuzumab ozogamicin) play an important role in the treatment of relapsed and refractory B-cell precursor acute lymphoblastic leukaemia (BCP-ALL); antibodies targeting CD123 and CD38 are also under investigation for acute myeloid leukaemia (AML) and T-ALL, respectively. Targeted therapy with small molecules is of primary importance for specific genetic subtypes, such as BCR-ABL-positive ALL, FLT3-ITD AML and anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma. KMT2A-directed targeted therapy with menin inhibitors holds promise to be of relevance in KMT2A-rearranged leukaemias, known to have dismal prognosis. Target inhibition in cellular pathways such as BCL-2, RAS, MEK, Bruton's tyrosine kinase, JAK-STAT or CDK4/CDK6 inhibition may be suitable for different diseases with common mutated pathways. Nevertheless, development and approval of new agents for paediatric cancers lags behind adult therapeutic options. New regulations were implemented to accelerate drug development for children. Considering the number of oncology medicinal products available for adults and the rarity of paediatric cancers, prioritisation based on scientific evidence and medical need, as well as international collaboration, is critical. Herein, we review the current status of drug development for children with leukaemia and lymphoma, excluding cellular therapy despite its well-known significance.

Novel Approaches Outside the Setting of Immunotherapy for the Treatment of Multiple Myeloma: The Case of Melflufen, Venetoclax, and Selinexor.

Although the survival rate of patients with multiple myeloma has significantly improved in the last years thanks to the introduction of various classes of new drugs, such as proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies, the vast majority of these subjects relapse with a more aggressive disease due to the acquisition of further genetic alterations that may cause resistance to current salvage therapies. The treatment of these often "triple" (or even more) refractory patients remains challenging, and alternative approaches are required to overcome the onset of that resistance. Immunotherapies with novel monoclonal, drug-conjugated, or bi-specific antibodies, as well as the use of chimeric antigen receptor T cells, have been recently developed and are currently investigated. However, other non-immunologic therapeutic regimens based on melfluflen, venetoclax, or selinexor, three molecules with new mechanisms of action, have also shown promising results in the setting of relapsed/refractory myeloma. Here we report the most recent literature data regarding these three drugs, focusing on their efficacy and safety in multiple myeloma.

Single agent oral selinexor as a key to potential cure in refractory diffuse large B-cell lymphoma: case report and literature review.

Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) portends a poor prognosis, with an estimated overall survival of less than 6 months. In the presented case, a female patient with DLBCL refractory to multiple lines of therapy, including chimeric antigen receptor T-cells, was treated with single-agent selinexor, achieving partial response following 5 months of treatment, which allowed the patient to proceed to potentially curative allogeneic stem cell transplantion. This approach enabled the patient, who would otherwise have been considered a candidate for palliative care, to achieve the most prolonged complete response since her first lymphoma-specific treatment. This outcome implies that early identification of relapsed/refractory patients who may benefit most from this drug - either as a single agent or in drug combinations - is imperative.

Treatment Patterns and Health Care Costs in Commercially Insured Patients with Follicular Lymphoma.

BACKGROUND: Few studies have estimated the real-world economic burden such as all-cause and follicular lymphoma (FL)-related costs and health care resource utilization (HCRU) in patients with FL. OBJECTIVES: This study evaluated outcomes in patients who were newly initiated with FL indicated regimens by line of therapy with real-world data. METHODS: A retrospective study was conducted among patients with FL from MarketScan® databases between January 1, 2010 and December 31, 2013. Patients were selected if they were ≥18 years old when initiated on a FL indicated therapy, had at least 1 FL-related diagnosis, ≥1 FL commonly prescribed systemic anti-cancer therapy after diagnosis, and did not use any FL indicated regimen in the 24 months prior to the first agent. These patients were followed up at least 48 months and the outcomes, including the distribution of regimens by line of therapy, the treatment duration by line of therapy, all-cause and FL-related costs, and HCRU by line of therapy were evaluated. RESULTS: This study identified 598 patients who initiated FL indicated treatment. The average follow-up time was approximately 5.7 years. Of these patients, 50.2% (n=300) were female, with a mean age of 60.7 years (SD=13.1 years) when initiating their treatment with FL indicated regimens. Overall, 598 (100%) patients received first-line therapy, 180 (43.6%) received second-line therapy, 51 received third-line therapy, 21 received fourth-line therapy, and 10 received fifth-line therapy. Duration of treatment by each line of therapy was 370 days, 392 days, 162 days, 148 days, and 88 days, respectively. The most common first-line regimens received by patients were rituximab (n=201, 33.6%), R-CHOP (combination of rituximab, cyclophosphamide, doxorubicin hydrochloride [hydroxydaunomycin]; n=143, 24.0%), BR (combination of bendamustine and rituximab; n=143, 24.0%), and R-CVP (combination of rituximab, cyclophosphamide, vincristine, and prednisone; n=71, 11.9%). The most common second-line treatment regimens were (N=180): rituximab (n=78, 43.3%) and BR (n=41, 22.8%). Annualized all-cause health care costs per patient ranged from US$97 141 (SD: US$144 730) for first-line to US$424 758 (SD: US$715 028) for fifth-line therapy. CONCLUSIONS: The primary regimens used across treatment lines conform to those recommended by the National Comprehensive Cancer Network clinical practice guidelines. The economic burden for patients with FL is high and grows with subsequent lines of therapy.

Quality of life in patients with relapsed/refractory multiple myeloma during ixazomib-thalidomide-dexamethasone induction and ixazomib maintenance therapy and comparison to the general population.

This trial evaluated quality of life (QoL) using the EORTC QLQ-C30 and the EORTC QLQ-MY20 instruments in 90 patients with relapsed/refractory multiple myeloma during induction and maintenance therapy with eight cycles of ixazomib-thalidomide-dexamethasone, followed by 12 months of ixazomib maintenance therapy. When patient's baseline QoL was compared with data of the general population, a significant impairment in health-related QoL, physical, role, and social functioning and several other dimensions, as well as more pain and fatigue, was noted. Induction therapy resulted in significant improvement of pain and worsening of neuropathy, with no significant variation of other parameters. During maintenance treatment, scores for most dimensions including health-related QoL, physical functioning and pain, improved, while for neuropathy no improvement was observed. Time to deterioration (≥10 score points) of health-related QoL, physical functioning, pain, and neuropathy was distinctly shorter than time to progression. Health-related QoL and physical functioning at baseline correlated with overall survival.

Illness Perceptions in Chronic Lymphocytic Leukemia: Testing Leventhal's Self-regulatory Model.

BACKGROUND: Leventhal's Self-regulatory Model proposes that somatic characteristics of a health threat (e.g., symptom severity), and prior experience with the threat (e.g., unsuccessful treatment), are determinants of illness perceptions. Chronic lymphocytic leukemia (CLL) is appropriate for test of these postulates, having three phases differing in symptom severity and prior treatment experiences: indolent disease requiring no treatment (active surveillance; AS), symptomatic disease requiring a first treatment (FT), and highly symptomatic disease in those who have relapsed and/or failed to respond to prior treatments (relapsed/refractory; RR). PURPOSE: To test symptom severity and prior treatment experiences as determinants of illness perceptions, illness perceptions were characterized and contrasted between CLL groups. METHODS: Three hundred and thirty CLL patients (AS, n = 100; FT, n = 78; RR, n = 152) provided illness perception data on one occasion during a surveillance visit (AS) or prior to beginning treatment (FT, RR). RESULTS: Analysis of variance with planned comparisons revealed that consequences, identity, and concern were least favorable among RR patients, followed by FT, then AS (ps < .01). AS patients endorsed the lowest levels of coherence (ps < .01), and the most chronic illness timeline (ps < .01). FT patients endorsed the highest levels of personal and treatment control (ps < .01). CONCLUSIONS: Data provide preliminary empirical support for Self-regulatory Model postulates that symptom severity and prior disease experiences influence illness perceptions. Unique knowledge needs for AS patients and elevated psychological/physical symptoms for later-stage CLL patients may warrant clinical attention.

Pomalidomide.

Pomalidomide (originally CC-4047 or 3-amino-thalidomide) is a derivative of thalidomide that is antiangiogenic and also acts as immunomodulatory. Pomalidomide, the recent immunomodulatory agent (IMiD), has shown substantial in vitro antiproliferative and proapoptotic effects. In vivo studies have suggested limited cross-resistance between lenalidomide and pomalidomide. Moreover, pomalidomide achieved very convincing responses in relapsed and refractory multiple myeloma (RRMM) patients, including those, who are refractory to both lenalidomide and bortezomib. Since pomalidomide plus low-dose dexamethasone has shown better responses, progression-free survival (PFS) and overall survival (OS) than high-dose dexamethasone or pomalidomide alone, subsequent trials have pursued or are still investigating pomalidomide triplet combinations, using cyclophosphamide or other novel agents, such as proteasome inhibitors (PI: bortezomib, carfilzomib) or antibodies, like elotuzumab or daratumumab. Pomalidomide has also been assessed in AL amyloidosis, MPNs (myelofibrosis [MF]), Waldenstrom's macroglobulinemia, solid tumors (sarcoma, lung cancer), or HIV, and-for AL amyloidosis and MF-has already been proven to be remarkably active. Due to its potency, pomalidomide was approved for RRMM by the US Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) in 2013 and for drug combination with low-dose dexamethasone in 2015. In June 2017, the FDA further expanded approval for pomalidomide in combination with daratumumab and low-dose dexamethasone for patients with RRMM.

Carfilzomib.

Carfilzomib (CFZ) is a potent, second-generation proteasome inhibitor (PI), with significant activity as a single agent and in combination with other antimyeloma agents in patients with relapsed or refractory multiple myeloma (RRMM). CFZ binds selectively and irreversibly to its target and leads to antiproliferative and proapoptotic effects on cancer cells. This irreversible inhibition is dose- and time-dependent in vitro and in vivo. CFZ as monotherapy and in combination with other antimyeloma agents (e.g., as CFZ and dexamethasone [Kd]) achieved very good responses, progression-free survival (PFS) and overall survival (OS). In several ongoing studies, CFZ is being investigated in triplet and quadruplet schedules of CFZ, lenalidomide and dexamethasone (KRd), CFZ, cyclophosphamide, dexamethasone (KCd) and with antibodies, like elotuzumab or daratumumab. The multitude of completed and ongoing studies confirmed a tolerable safety profile of CFZ, a significantly lower incidence of neuropathy compared to bortezomib (BTZ) and a slightly higher incidence of cardiotoxicity, which is closely observed and precautions taken to avoid them as best as possible. In July 2012, the US Food and Drug Administration (FDA) approved CFZ as a single agent for RRMM patients with disease progression after two prior therapies, including BTZ and immunomodulatory drugs (IMiDs). The combination of KRd and Kd followed, being approved by both FDA and European Medicines Agency (EMA) in 2015 and 2016, respectively. Moreover, CFZ is being evaluated in patients with newly diagnosed MM (NDMM), in high-risk smoldering MM and for maintenance approaches.