TTK/MPS1 inhibitor OSU-13 targets the mitotic checkpoint and is a potential therapeutic strategy for myeloma.

Despite substantial recent advances in treatment, multiple myeloma (MM) remains an incurable disease, with a shortage of treatment options for patients with high-risk disease, warranting the need for novel therapeutic targets and treatment approaches. Threonine and tyrosine kinase (TTK), also known as monopolar spindle 1 (MPS1), is a kinase essential for the mitotic spindle checkpoint whose expression correlates to unfavorable prognosis in several cancers. Here, we report the importance of TTK in MM, and the effects of the TTK inhibitor OSU-13. Elevated TTK expression correlated with amplification/ gain of 1q21 and decreased overall and event-free survival in MM. Treatment with OSU-13 inhibited TTK activity efficiently and selectively at a similar concentration range to other TTK inhibitor clinical candidates. OSU-13 reduced proliferation and viability of primary human MM cells and cell lines, especially those with high 1q21 copy numbers, and triggered apoptosis through caspase 3 and 7 activation. In addition, OSU-13 induced DNA damage and severe defects in chromosome alignment and segregation, generating aneuploidy. In vivo, OSU-13 decreased tumor growth in mice with NCI-H929 xenografts. Collectively, our findings reveal that inhibiting TTK with OSU-13 is a potential therapeutic strategy for MM, particularly for a subset of high-risk patients with poor outcome.

Understanding DNA Damage Response and DNA Repair in Multiple Myeloma.

Multiple myeloma (MM) is a plasma cell malignancy characterized by several genetic abnormalities, including chromosomal translocations, genomic deletions and gains, and point mutations. DNA damage response (DDR) and DNA repair mechanisms are altered in MM to allow for tumor development, progression, and resistance to therapies. Damaged DNA rarely induces an apoptotic response, given the presence of ataxia-telangiectasia mutated (ATM) loss-of-function or mutations, as well as deletions, mutations, or downregulation of tumor protein p53 (TP53) and tumor protein p73 (TP73). Moreover, DNA repair mechanisms are either hyperactive or defective to allow for rapid correction of the damage or permissive survival. Medications used to treat patients with MM can induce DNA damage, by either direct effects (mono-adducts induced by melphalan), or as a result of reactive oxygen species (ROS) production by proteasome inhibitors such as bortezomib. In this review, we will describe the mechanisms of DDR and DNA repair in normal tissues, the contribution of these pathways to MM disease progression and other phenotypes, and the potential therapeutic opportunities for patients with MM.

Impact of interval progression before autologous stem cell transplant in patients with multiple myeloma.

In transplant-eligible patients who undergo upfront autologous stem cell transplant (ASCT) for multiple myeloma (MM), standard practice is to treat with six to eight cycles of induction therapy followed by high-dose chemotherapy with ASCT. A gap between the end of induction and the day of ASCT exists to allow stem cell mobilization and collection. Despite attempts to limit the length of this interval, we noticed that some patients experience interval progression (IP) of disease between the end of induction therapy and the day of ASCT. We analyzed 408 MM patients who underwent ASCT between 2011 and 2016. The median length of the interval between end of induction and ASCT was 38 days. We observed that 26% of patients in the entire cohort and 23.6% of patients who received induction with bortezomib-lenalidomide-dexamethasone (VRD) experienced IP. These patients deepened their responses with ASCT, independently of induction regimen. In the entire cohort, IP was significantly associated with shorter PFS in the univariable analysis (Hazard Ratio, HR = 1.37, P = 0.022) but not in the multivariable analysis (HR = 1.14, P = 0.44). However, analyzing only patients who received VRD as induction, progression-free survival (PFS) remained inferior in both the univariable (HR = 2.02; P = 0.002) and the multivariable analyses (HR = 1.96; P = 0.01). T cells and natural killer (NK) cells are increasingly studied targets of immunomodulatory therapy, as immune dysfunction is known to occur in patients with MM. Peripheral blood from 35 MM patients were analyzed. At time of ASCT, patients with IP had significantly increased percentages of CD3+CD8+CD57+ CD28- (P = 0.05) and CD3+CD4+LAG3+ (P = 0.0022) T-cells, as well as less CD56bright and CD56dim NK cells bearing activated markers such as CD69, NKG2D, and CD226. These data suggest that IP can impact the length of response to ASCT; therefore, further studies on the management of these patients are needed.

Characterization of monoclonal gammopathy of undetermined significance progression to multiple myeloma through meta-analysis of GEO data.

The etiology of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is still obscure as are the processes that enable the progression of MGUS to MM. Understanding the unique vs. shared transcriptomes can potentially elucidate why individuals develop one or the other. Furthermore, highlighting key pathways and genes involved in the pathogenesis of MM or the development of MGUS to MM may allow the discovery of novel drug targets and therapies. We employed STARGEO platform to perform three separate meta-analysis to compare MGUS and MM transcriptomes. For these analyses we tagged (1) 101 MGUS patient plasma cells from bone marrow samples and 64 plasma cells from healthy controls (2) 383 MM patient CD138+ cells from bone marrow and the 101 MGUS samples in the first analysis as controls (3) 517 MM patient peripheral blood samples and 97 peripheral blood samples from healthy controls. We then utilized Ingenuity Pathway Analysis (IPA) to analyze the unique genomic signatures within and across these samples. Our study identified genes that may have unique roles in MGUS (GADD45RA and COMMD3), but also newly identified signaling pathways (EIF2, JAK/STAT, and MYC) and gene activity (NRG3, RBFOX2, and PARP15) in MGUS that have previously been shown to be involved in MM suggesting a spectrum of molecular overlap. On the other hand, genes such as DUSP4, RN14, LAMP5, differentially upregulated in MM, may be seen as tipping the scales from benignity to malignancy and could serve as drug targets or novel biomarkers for risk of progression. Furthermore, our analysis of MM identified newly associated gene/pathway activity such as inhibition of Wnt-signaling and defective B cell development. Finally, IPA analysis, suggests the multifactorial, oncogenic qualities of IFNγ signaling in MM may be a unifying pathway for these diverse mechanisms and prompts the need for further studies.

Survival outcomes following autologous stem cell transplant with melphalan 140mg/m2 versus 200mg/m2 preparative regimens in patients with multiple myeloma.

The standard preparative regimen for autologous stem cell transplant (ASCT) in multiple myeloma (MM) is 200 mg/m2 of intravenous melphalan; however, a dose of 140 mg/m2 is often used when concerns exist related to patient age, performance status, organ function, and other factors. It is unclear whether a lower dose of melphalan impacts post-transplant survival outcomes. We performed a retrospective review of 930 patients with MM who underwent ASCT with 200 mg/m2 versus 140 mg/m2 melphalan. On univariable analysis, no difference in progression-free survival (PFS) was observed, however, an overall survival (OS) benefit was observed in patients receiving 200 mg/m2 melphalan (p = 0.04). Multivariable analyses showed patients receiving 140 mg/m2 faired no worse than those receiving 200 mg/m2. While a subset of younger patients with normal renal function may achieve superior OS with a standard dose of 200 mg/m2 melphalan, these findings suggest an opportunity to individualize the ASCT preparative regimen to optimize outcomes.

Transformed Plasmablastic Lymphoma Presenting With Marked Lymphocytosis and Spontaneous Tumor Lysis Syndrome.

The clinicopathology entity of plasmablastic lymphoma (PBL), despite broad recognition by the World Health Organization (WHO), represents a diagnostic challenge due to its overlapping features and scarce occurrence. Often, PBL arises in immunodeficient, elderly male patients, most notably those who are human immunodeficiency virus (HIV)-positive. More infrequent, cases of transformed PBL (tPBL) evolved from another hematologic disease have been identified. Herein, we describe a case of a 65-year-old male transferred from a neighboring hospital with pronounced lymphocytosis and spontaneous tumor lysis syndrome (sTLS) presumed to be chronic lymphocytic leukemia (CLL). Utilizing a complete clinical, morphologic, immunophenotypic, and molecular evaluation, we arrived at a final diagnosis of tPBL with sTLS, suspected to have evolved from the NF-κB/NOTCH/KLF2 (NNK) genetic cluster of splenic marginal zone lymphoma (SMZL) (NNK-SMZL), a potential transformation and presentation, to our knowledge, not previously reported. However, definitive clonality testing was not performed. In this report, we also outline the diagnostic and educational considerations we faced in discerning tPBL from other more common B-cell malignancies which can present similarly, such as CLL, mantle cell lymphoma, or plasmablastic myeloma. We summarize recently reported molecular, prognostic, and therapeutic considerations for the treatment and recognition of PBL, including the successful implementation, in our patient, of bortezomib to an EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with prophylactic intrathecal methotrexate, who has since achieved complete remission (CR) and entered clinical surveillance. Lastly, this report briefly highlights the challenge we faced in this area of hematologic typification that necessitates additional review and discussion by the WHO: tPBL with potential double-hit cytogenetic versus double-hit lymphoma with a plasmablastic phenotype.

A phase II multi-arm study of magrolimab combinations in patients with relapsed/refractory multiple myeloma.

Magrolimab is a monoclonal antibody that blocks CD47, a 'do not eat me' signal overexpressed on tumor cells. CD47 is overexpressed in multiple myeloma (MM), which contributes to its pathogenesis. Preclinical studies have shown that CD47 blockade induces macrophage activation, resulting in elimination of myeloma cells, and that there is synergy between magrolimab and certain anticancer therapies. These findings suggest that magrolimab-based combinations may have a therapeutic benefit in MM. This phase II study investigates magrolimab in combination with commonly used myeloma therapies in patients with relapsed/refractory MM and includes a safety run-in phase followed by a dose-expansion phase. Primary end points include the incidence of dose-limiting toxicities and adverse events (safety run-in) and the objective response rate (dose expansion).

Magrolimab is a therapy that blocks a 'do not eat me' signal overexpressed by certain cancers, including multiple myeloma (MM) cells. Studies have shown that blocking this signal leads to destruction of myeloma cells and that this cancer-killing effect may be increased by combining magrolimab with certain additional anticancer therapies. These findings suggest that magrolimab-based combinations may have a therapeutic benefit in MM. This study is investigating magrolimab in combination with commonly used myeloma therapies in patients with MM who have persistent disease despite prior treatment. Goals of the trial include assessing safety and response to treatment. Clinical Trial Registration: NCT04892446 (ClinicalTrials.gov).

Comparison of Patient Outcomes With Two Different Formulations of Melphalan as Conditioning Chemotherapy for Autologous Hematopoietic Cell Transplantation in Multiple Myeloma.

BACKGROUND: High-dose melphalan (HDM) with autologous hematopoietic cell transplantation (AHCT) after induction chemotherapy is considered standard of care in transplant-eligible patients with newly-diagnosed multiple myeloma (MM). Alkeran melphalan has propylene glycol as a solvent (PG-mel) while Evomela utilizes a propylene glyclol-free formulation (PGF-mel). We evaluated the differences in efficacy and safety of the 2 formulations as there are no prospective head-to-head trials. METHODS: We retrospectively reviewed the medical records of all 259 consecutive MM patients who received PGF-mel as part of HDM-AHCT at The Ohio State University (OSU). The comparator group was the preceding 255 patients who received PG-mel. RESULTS: Baseline patient characteristics were similar between the 2 groups. Post-AHCT rates of relapse were comparable in the PG-mel and PGF-mel groups. Some adverse events were observed at a higher frequency in the PG-mel group compared to the PGF-mel group (grade ≥ 2 mucositis, febrile neutropenia, other infectious complications, and acute renal insufficiency). Time to neutrophil engraftment was slightly longer in the PG-mel group while time to platelet engraftment was longer in PGF-mel group. Red cell transfusion requirement was higher with the use of PG-mel but not platelet transfusion. Duration of hospitalization was slightly shorter with PGF-mel but readmission rates within 30 days of discharge were higher. CONCLUSION: Considering possible confounding factors could possibly account for observed differences in some adverse events, the comparable treatment responses, and difference in cost of the 2 formulation, The OSU reverted to PG-mel as the preferred formulation for HDM-AHCT in MM.

Outcomes After Salvage Autologous Hematopoietic Cell Transplant for Patients With Relapsed/Refractory Multiple Myeloma: A Single-Institution Experience.

BACKGROUND: The role of salvage autologous hematopoietic cell transplantation (sAHCT2) for patients with relapsed/refractory multiple myeloma (RRMM) in the era of modern therapeutics is unclear. As prospective data is limited, we conducted a retrospective analysis to determine the outcomes of sAHCT2. PATIENTS AND METHODS: We conducted a single-institution, retrospective analysis of patients who received sAHCT2 at The Ohio State University from 2000 to 2018. Patients who received a second transplant as part of a planned tandem or autologous-allogeneic transplant were excluded. RESULTS: Fifty-seven patients were treated with sAHCT2. Patients had a median of 2 lines of therapy after AHCT1 prior to their sAHCT2; 70% had prior immunomodulatory imide drugs, 82% had prior proteasome inhibitor, and 20% had prior anti-CD38 monoclonal antibodies as part of re-induction therapy. Forty-two percent of patients attained ≥VGPR prior to sAHCT2. Seventy-four were treated with melphalan 200 mg/m2 as conditioning regimen before infusion of a median of 3.8 × 106 CD34+ cells/kg. Fifty-eight percent patients had maintenance therapy and 81% patients attained CR/VGPR as the best response after sAHCT2. The median PFS and OS after sAHCT2 were 1.6 and 3.6 years, respectively. On multivariable analysis, high-risk cytogenetics, not having attained CR/VGPR, and having more than 2 lines of therapy post-AHCT1 were associated with inferior PFS. Melphalan 140 mg/m2 compared to melphalan 200 mg/m2 and no maintenance therapy compared to maintenance therapy were not associated with inferior PFS. There was no transplant-related mortality in this patient cohort. CONCLUSIONS: For MM patients deriving durable remission after their AHCT1, sAHCT2 was safe and resulted in deep and durable remissions.

Early versus Late Discontinuation of Maintenance Therapy in Multiple Myeloma.

Maintenance therapy after autologous stem cell transplant (ASCT) in multiple myeloma (MM) is the standard treatment and recommended to be continued until disease progression. However, in the real world, patients discontinue treatment due to various reasons. We sought to determine the effect of early versus late discontinuation on survival outcomes in MM patients who underwent ASCT at The Ohio State University. We retrospectively reviewed 340 patients who underwent ASCT from 2005 to 2016 and received maintenance therapy for at least six months without progression. We compared the outcomes of patients who received maintenance for three years or less (early group) to the patients who continued maintenance beyond three years (late group). Lenalidomide (89%) and bortezomib (10%) were the most common agents used for maintenance chemotherapy. In Kaplan−Meier analysis, patients in the late group had prolonged progression-free (PFS) (p < 0.001) and overall survival (OS) (p < 0.001). The 5-year estimated OS in late group was 96% vs. 79% in the early group and 5-year PFS was 80% in late group vs. 50% in the early group. The most common reasons for discontinuation of maintenance in early group were adverse events (55.9%) and patient preference (22.5%). For the late group, it was disease progression (23.9%) and adverse events (14.3%). Fifty-five percent of patients in the late group were still on maintenance treatment at the last follow-up. Continuation of maintenance therapy was thus associated with improved outcomes, while adverse events prevented most patients from continuing treatment.

Incidence, Treatment, and Survival of Patients With T-Cell Lymphoma, T-Cell Large Granular Leukemia, and Concomitant Plasma Cell Dyscrasias.

T-Cell malignancies are a group of heterogeneous disorders composed of primary cutaneous T-cell lymphomas (CTCLs), peripheral T-cell lymphomas (PTCLs), and T-cell leukemias, including T-cell large granular lymphocytic leukemia (T-LGLL). Cases of patients with combined T-cell malignancies and plasma cell dyscrasias (PCD) are reported in the literature, but these are mostly limited to case reports or small case series with <10 patients. Here, we described the clinical course of 26 patients and report baseline characteristics and clinical outcomes including overall survival (OS), progression-free survival (PFS), and objective response rates (ORRs) in this unique population. There was no survival difference in patients with CTCL or T-LGLL and concomitant PCD when treated with standard therapy directed at the T-cell malignancy when compared to historical controls. However, patients with PTCL and concomitant PCD had significantly inferior outcomes with rapid progression and worse OS and PFS at 1.7 years (p=0.006) and 4.8 months (p=0.08), respectively, when compared to historical controls for patients with PTCL, although the limited number of patients included in this analysis precludes drawing definitive conclusions. Treatment directed at the T-cell malignancy resulted in the eradication of the PCD clone in multiple patients (15.4%) including one with multiple myeloma (MM) who experienced a complete response after starting therapy directed at the T-cell malignancy. For patients with T-cell malignancies and concomitant PCD, treatment with standard T-cell-directed therapies is recommended based on this analysis with continued follow-up and monitoring of the concomitant PCD. Further studies are needed to definitively elucidate the increased risk of relapse in patients with PTCL and concomitant PCD, and larger, multi-center cohorts are needed to validate these findings across T-cell malignancies and PCDs.

Improvement in Post-Autologous Stem Cell Transplant Survival of Multiple Myeloma Patients: A Long-Term Institutional Experience.

Multiple myeloma (MM) represents 1.8% of all new cancer cases in the U.S. While not curable, advances in treatment, including autologous stem cell transplant (ASCT) and maintenance therapy, have dramatically improved progression-free survival (PFS) and overall survival (OS). We performed a retrospective survival analysis on newly diagnosed MM (NDMM) patients receiving ASCT from 1992−2016 at the Ohio State University. A total of 1001 consecutive NDMM patients were eligible. Patients were split into five groups based on historic changes in novel agents for the treatment of MM. Across the years (1992−2016), there was a statistically significant improvement in both PFS (p < 0.01) and OS (p < 0.01). Significant improvements in both PFS and OS were seen in patients ≤65 years (p < 0.001 and p = 0.002) and >65 years old (p < 0.001 and p = 0.001), respectively. Improved PFS and OS were seen in both standard-risk (p < 0.001 and p < 0.001) and high-risk patients (p < 0.001 and p = 0.019). The post-transplant response showed statistically significant improvement across the years (p < 0.01). Survival rates for NDMM patients have significantly improved primarily due to the inclusion of novel therapies and post-ASCT maintenance.

Redefining CD56 as a Biomarker and Therapeutic Target in Multiple Myeloma.

Multiple myeloma cells aberrantly express surface antigens compared with normal plasma cells. Among others, CD56 is present at variable levels in approximately 70% of patients with multiple myeloma; however, very little is known about CD56 role in multiple myeloma. We demonstrated that patients with multiple myeloma with more than 10% of CD56-expressing clonal multiple myeloma cells have inferior clinical outcomes. By gain-of and loss-of function models, we revealed that CD56 promotes multiple myeloma cell growth, survival, and adhesion to stromal cells. These protumoral effects are induced by the activation of the RSK2/CREB1 signaling pathway, with increased mRNA and protein levels of the anti-apoptotic genes BCL2 and MCL1. Consequently, the genomic and pharmacological inhibition of RSK2 or CREB1 specifically induced multiple myeloma cell death in CD56-expressing multiple myeloma cells. Finally, we observed that CD56 signaling decreases CRBN expression, reducing responses to lenalidomide. RSK2 or CREB1 inhibition increased CRBN levels and were synergic with lenalidomide in inducing cell death, especially in CD56-expressing multiple myeloma cells. In conclusion, our findings demonstrate that CD56 promotes multiple myeloma cell growth, and pave the way to novel therapies based on targeting CD56, along with the use of CD56 as a predictive biomarker for multiple myeloma therapies. IMPLICATIONS: Multiple myeloma is an incurable, genetically heterogeneous disease, without available tailored therapeutic approaches. CD56 signaling promotes multiple myeloma growth and adhesion, by activating CREB1 target genes, MCL1 and BCL2. Inhibition of CREB1 alone or in combination with lenalidomide is an unexplored synthetic lethal approach in CD56-expressing patients with multiple myeloma.

Functional expression of aryl hydrocarbon receptor as a potential novel therapeutic target in human multiple myeloma.

The etiology of multiple myeloma (MM) remains incompletely understood; however, epidemiologic studies have suggested a possible link between exposure to environmental aromatic hydrocarbons-which serve as exogenous ligands for the aryl hydrocarbon receptor (AHR), which has been implicated in cancer biology-and development of monoclonal gammopathy of undetermined significance (MGUS) and MM. Herein, we demonstrate the functional expression of AHR in MM cell lines and primary human MM samples. AHR is expressed in putative MM 'stem cells' and advanced clinical stages of MM, and functionally contributes to MM tumor cell phenotype and proliferation. Antagonism of AHR directly impairs MM cell viability and increases MM cell susceptibility to immune-mediated clearance. Furthermore, our findings indicate that AHR antagonism may represent an effective means to enhance the function of other drugs, such as anti-CD38 antibodies, in future clinical studies. Taken together, these data identify AHR as a novel target for MM therapy.

Multiple Myeloma: Clinical Updates from the American Society of Clinical Oncology Annual Scientific Symposium 2020.

The novel clinical data for plasma cell neoplasms (smoldering myeloma, multiple myeloma, and AL amyloidosis) that were presented in the 2020 American Society of Clinical Oncology virtual scientific symposium are summarized here. Data from large phase-3 studies (CASSIOPEIA, ENDURANCE, and TOURMALINE-MM4 trials) and phase-2 studies (SWOG 1211, GMMG CONCEPT trials) for newly diagnosed multiple myeloma patients who are eligible for autologous stem cell transplantation are described. Updates from previous important studies for multiple myeloma (STaMINA) along with studies on three different chimeric antigen receptor (CAR-) T cell products are also described. Results of clinical studies involving the use of anti-myeloma drugs with novel mechanisms of action such as immunoconjugates, selinexor, venetoclax, monoclonal antibodies, and data on minimal residual disease (MRD) are discussed. These data provide an overview of the efficacy and safety of the various treatments in multiple myeloma and could lead to changes in our clinical practice, which could pave the path for a "cure" in myeloma.