New Biological Therapies for Multiple Myeloma.

Multiple myeloma is a cancer of bone marrow plasma cells that represents approximately 10% of hematologic malignancies. Though it is typically incurable, a remarkable suite of new therapies developed over the last 25 years has enabled durable disease control in most patients. This article briefly introduces the clinical features of multiple myeloma and aspects of multiple myeloma biology that modern therapies exploit. Key current and emerging treatment modalities are then reviewed, including cereblon-modulating agents, proteasome inhibitors, monoclonal antibodies, other molecularly targeted therapies (selinexor, venetoclax), chimeric antigen receptor T cells, T cell-engaging bispecific antibodies, and antibody-drug conjugates. For each modality, mechanism of action and clinical considerations are discussed. These therapies are combined and sequenced in modern treatment pathways, discussed at the conclusion of the article, which have led to substantial improvements in outcomes for multiple myeloma patients in recent years.

Rational design of proteasome inhibitors based on the structure of the endogenous inhibitor PI31/Fub1.

Proteasome inhibitors are widely used anticancer drugs. The three clinically approved agents are modified small peptides that preferentially target one of the proteasome's three active sites (ß5) at physiologic concentrations. In addition to these drugs, there is also an endogenous proteasome inhibitor, PI31/Fub1, that enters the proteasome's interior to simultaneously yet specifically inhibit all three active sites. Here, we have used PI31's evolutionarily optimized inhibitory mechanisms to develop a suite of potent and specific ß2 inhibitors. The lead compound strongly inhibited growth of multiple myeloma cells as a standalone agent, indicating the compound's cell permeability and establishing ß2 as a potential therapeutic target in multiple myeloma. The lead compound also showed strong synergy with the existing ß5 inhibitor bortezomib; such combination therapies might help with existing challenges of resistance and severe side effects. These results represent an effective method for rational structure-guided development of proteasome inhibitors.

An orthotopic syngeneic mouse model of bortezomib-resistant multiple myeloma.

While bortezomib has significant benefits in multiple myeloma (MM) therapy, the disease remains incurable due to the invariable development of bortezomib resistance. This emphasises the need for advanced models for preclinical evaluation of new therapeutic approaches for bortezomib-resistant MM. Here, we describe the development of an orthotopic syngeneic bortezomib-resistant MM mouse model based on the most well-characterised syngeneic MM mouse model derived from spontaneous MM-forming C57BL/KaLwRij mice. Using bortezomib-resistant 5TGM1 cells, we report and characterise a robust syngeneic mouse model of bortezomib-resistant MM that is well suited to the evaluation of new therapeutic approaches for proteasome inhibitor-resistant MM.

Characteristics and outcomes of patients developing pulmonary hypertension associated with proteasome inhibitors.

BACKGROUND: Pulmonary arterial hypertension (PAH) has been described in patients treated with proteasome inhibitors (PIs). Our objective was to evaluate the association between PIs and PAH. METHODS: Characteristics of incident PAH cases previously treated with carfilzomib or bortezomib were analysed from the French pulmonary hypertension registry and the VIGIAPATH programme from 2004 to 2023, concurrently with a pharmacovigilance disproportionality analysis using the World Health Organization (WHO) global database (VigiBase) and a meta-analysis of randomised controlled trials. RESULTS: 11 incident cases of PI-associated PAH were identified (six with carfilzomib and five with bortezomib) with a female:male ratio of 2.7:1, a median age of 61 years, and a median delay between PI first exposure and PAH of 6 months. Four patients died (two from right heart failure, one from respiratory distress and one from an unknown cause). At diagnosis, six were in New York Heart Association Functional Class III/IV with severe haemodynamic impairment (median mean pulmonary arterial pressure 39 mmHg, cardiac index 2.45 L·min-1·m-2 and pulmonary vascular resistance 7.2 WU). In the WHO pharmacovigilance database, 169 cases of PH associated with PI were reported since 2013 with significant signals of disproportionate reporting (SDR) for carfilzomib, regardless of the definition of cases or control group. However, SDR for bortezomib were inconsistent. The systematic review identified 17 clinical trials, and carfilzomib was associated with a significantly higher risk of dyspnoea, severe dyspnoea and PH compared with bortezomib. CONCLUSION: PIs may induce PAH in patients undergoing treatment, with carfilzomib emitting a stronger signal than bortezomib, and these patients should be monitored closely.

How I treat frontline transplantation-eligible multiple myeloma.

High-dose melphalan supported by autologous transplantation has been the standard of care for eligible patients with newly diagnosed multiple myeloma (MM) for >25 years. Several randomized clinical trials have recently reaffirmed the strong position of transplantation in the era of proteasome inhibitors and immunomodulatory drugs combinations, demonstrating a significant reduction of progression or death in comparison with strategies without transplantation. Immunotherapy is currently changing the paradigm of MM management, and daratumumab is the first-in-class human monoclonal antibody targeting CD38 approved in the setting of newly diagnosed MM. Quadruplets have become the new standard in transplantation programs, but outcomes remain heterogeneous, with various response depth and duration. The development of sensitive and specific tools for disease prognostication allows the consideration of strategies adaptive to dynamic risk. This review discusses the different options available for the treatment of transplantation-eligible patients with MM in frontline setting.

Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: a multicenter, retrospective, real-world experience with 200 cases outside of controlled clinical trials.

In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved to have a superior clinical benefit over pomalidomide and dexamethasone with a manageable toxicity profile, leading to its approval for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. We report here a real-world experience of 200 cases of RRMM treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was two, with 51% of cases undergoing autologous stem cell transplant and 73% having been exposed to daratumumab. After a median follow-up of 9 months, 126 patients had stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate was 55.4%, a finding in line with the pivotal trial results. Regarding adverse events, the toxicity profile in our cohort was similar to that in the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival was 7 months, which was shorter than that observed in ELOQUENT-3, probably because of the different clinical characteristics of the two cohorts. Interestingly, International Staging System stage III disease was associated with worse progression-free survival (hazard ratio=2.55). Finally, the median overall survival of our series was shorter than that observed in the ELOQUENT-3 trial (17.5 vs. 29.8 months). In conclusion, our real-world study confirms that EloPd is a safe and possible therapeutic choice for patients with RRMM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: potential therapeutic application in multiple myeloma.

Multiple myeloma (MM) remains incurable due to drug resistance. Ribosomal protein S3 (RPS3) has been identified as a non-Rel subunit of NF-κB. However, the detailed biological roles of RPS3 remain unclear. Here, we report for the first time that RPS3 is necessary for MM survival and drug resistance. RPS3 was highly expressed in MM, and knockout of RPS3 in MM inhibited cell growth and induced cell apoptosis both in vitro and in vivo. Overexpression of RPS3 mediated the proteasome inhibitor resistance of MM and shortened the survival of MM tumor-bearing animals. Moreover, our present study found an interaction between RPS3 and the thyroid hormone receptor interactor 13 (TRIP13), an oncogene related to MM tumorigenesis and drug resistance. We demonstrated that the phosphorylation of RPS3 was mediated by TRIP13 via PKCδ, which played an important role in activating the canonical NF-κB signaling and inducing cell survival and drug resistance in MM. Notably, the inhibition of NF-κB signaling by the small-molecule inhibitor targeting TRIP13, DCZ0415, was capable of triggering synergistic cytotoxicity when combined with bortezomib in drug-resistant MM. This study identifies RPS3 as a novel biomarker and therapeutic target in MM.

High-content analysis identified synergistic drug interactions between INK128, an mTOR inhibitor, and HDAC inhibitors in a non-small cell lung cancer cell line.

BACKGROUND: The development of drug resistance is a major cause of cancer therapy failures. To inhibit drug resistance, multiple drugs are often treated together as a combinatorial therapy. In particular, synergistic drug combinations, which kill cancer cells at a lower concentration, guarantee a better prognosis and fewer side effects in cancer patients. Many studies have sought out synergistic combinations by small-scale function-based targeted growth assays or large-scale nontargeted growth assays, but their discoveries are always challenging due to technical problems such as a large number of possible test combinations. METHODS: To address this issue, we carried out a medium-scale optical drug synergy screening in a non-small cell lung cancer cell line and further investigated individual drug interactions in combination drug responses by high-content image analysis. Optical high-content analysis of cellular responses has recently attracted much interest in the field of drug discovery, functional genomics, and toxicology. Here, we adopted a similar approach to study combinatorial drug responses. RESULTS: By examining all possible combinations of 12 drug compounds in 6 different drug classes, such as mTOR inhibitors, HDAC inhibitors, HSP90 inhibitors, MT inhibitors, DNA inhibitors, and proteasome inhibitors, we successfully identified synergism between INK128, an mTOR inhibitor, and HDAC inhibitors, which has also been reported elsewhere. Our high-content analysis further showed that HDAC inhibitors, HSP90 inhibitors, and proteasome inhibitors played a dominant role in combinatorial drug responses when they were mixed with MT inhibitors, DNA inhibitors, or mTOR inhibitors, suggesting that recessive drugs could be less prioritized as components of multidrug cocktails. CONCLUSIONS: In conclusion, our optical drug screening platform efficiently identified synergistic drug combinations in a non-small cell lung cancer cell line, and our high-content analysis further revealed how individual drugs in the drug mix interact with each other to generate combinatorial drug response.

Interplay between proteasome inhibitors and NF-κB pathway in leukemia and lymphoma: a comprehensive review on challenges ahead of proteasome inhibitors.

The current scientific literature has extensively explored the potential role of proteasome inhibitors (PIs) in the NF-κB pathway of leukemia and lymphoma. The ubiquitin-proteasome system (UPS) is a critical component in regulating protein degradation in eukaryotic cells. PIs, such as BTZ, are used to target the 26S proteasome in hematologic malignancies, resulting in the prevention of the degradation of tumor suppressor proteins, the activation of intrinsic mitochondrial-dependent cell death, and the inhibition of the NF-κB signaling pathway. NF-κB is a transcription factor that plays a critical role in the regulation of apoptosis, cell proliferation, differentiation, inflammation, angiogenesis, and tumor migration. Despite the successful use of PIs in various hematologic malignancies, there are limitations such as resistant to these inhibitors. Some reports suggest that PIs can induce NF-κB activation, which increases the survival of malignant cells. This article discusses the various aspects of PIs' effects on the NF-κB pathway and their limitations. Video Abstract.

Teclistamab-cqyv in multiple myeloma.

Multiple myeloma (MM) is an incurable neoplasm characterized by significant morbidity and mortality. Despite advances in treatment, MM patients eventually experienced a relapse of the disease. Penta-drug refractory patients continue to be the hard core of relapsed/refractory (RR) settings. Teclistamab-cqyv is a humanized IgG4 antibody and a bispecific BCMA-director CD3 T-cell engager. It recruits endogenous T cells, by targeting CD3 receptors expressed on their surface, resulting in their activation against BCMA, an antigen expressed by plasma cells. US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved Teclistamab-cqyv in monotherapy for the treatment of RRMM patients who have received at least three prior therapies, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (MoAbs) and have demonstrated disease progression during the last therapy. Its effectiveness was demonstrated in a pivotal clinical trial where the overall response rate (ORR) reached 60%. Other clinical studies are currently ongoing to investigate the association of the bispecific antibody with novel drugs with encouraging preliminary results, especially in the setting of heavily pretreated patients. In this review, the authors will provide a comprehensive overview of the drug, including its mechanism of action, major clinical trials, and future perspectives.

A single-day polychemotherapy regimen with proteasome inhibitor combinations for relapsed/refractory myeloma in the era of novel therapies.

PCAB (prednisone, cyclophosphamide, doxorubicin, carmustine) is a single-day regimen previously used for induction and now in relapsed/refractory multiple myeloma (RRMM). We retrospectively analysed the outcomes of 85 patients from five Australian centres. These included 30 patients (35.3%) who received PCAB with one additional agent (bortezomib most frequently). Median age of the patients was 65 years (37-80), with a median of four (1-8) prior lines of therapy. ORR was 37% (CR 4.9%). Median progression free survival and overall survival were 4.4 months (95% CI 3.5-6.7) and 7.4 months (95% CI 6.4-10.2), respectively. Extramedullary disease (EMD) was associated with shorter survival. Grade 3 or 4 cytopenia and febrile neutropenia occurred in 76.2% and 39.1%, respectively, with six (7.1%) treatment-related mortalities. Median inpatient stay was 3.3 days/28-day cycle (IQR 0.6-13), and for patients who died, a median of 20.2% of days alive were spent inpatient (IQR 6.4-39.1%). Three patients were successfully bridged to CAR T-cell therapy using PCAB, despite being penta-exposed and having EMD. PCAB may be considered as a useful salvage therapy amongst other polychemotherapy regimens in late relapse. Further studies is warranted to investigate and define its role as a bridging therapy to novel therapeutics.

Impact of prior lenalidomide or proteasome inhibitor exposure on the effectiveness of ixazomib-lenalidomide-dexamethasone for relapsed/refractory multiple myeloma: A pooled analysis from the INSURE study.

OBJECTIVES: To characterize the impact of prior exposure and refractoriness to lenalidomide or proteasome inhibitors (PIs) on the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma (RRMM). METHODS: INSURE is a pooled analysis of adult RRMM patients who had received IRd in ≥2 line of therapy from three studies: INSIGHT MM, UVEA-IXA, and REMIX. RESULTS: Overall, 391/100/68 were lenalidomide-naïve/-exposed/-refractory and 37/411/110 were PI-naïve/-exposed/-refractory. Median duration of therapy (DOT) was 15.3/15.6/4.7 months and median progression-free survival (PFS) was 21.6/25.8/5.6 months in lenalidomide-naïve/exposed/refractory patients. Median DOT and PFS in PI-naïve/exposed/refractory patients were 20.4/15.2/6.9 months and not reached/19.8/11.4 months, respectively. The proportion of lenalidomide-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to adverse events (AEs) was ixazomib, 31.6/28.2/28.0% and 18.6/6.7/10.5%; lenalidomide, 21.9/28.2/16.0% and 16.1/6.7/10.5%; dexamethasone, 18.4/20.5/16.0% and 10.6/0/10.5%, respectively. The proportion of PI-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to AEs was: ixazomib, 44.4/28.8/27.8% and 22.2/16.7/15.7%; lenalidomide, 33.3/22.0/19.4% and 16.7/15.9/11.8%; dexamethasone, 33.3/17.4/16.7% and 16.7/9.5/7.8%, respectively. REMIX AE discontinuation rates were unavailable. CONCLUSION: IRd appeared to be effective in RRMM patients in routine clinical practice regardless of prior lenalidomide or PI exposure, with better outcomes seen in lenalidomide- and/or PI-nonrefractory versus refractory patients.

Different Strategies to Overcome Resistance to Proteasome Inhibitors-A Summary 20 Years after Their Introduction.

Proteasome inhibitors (PIs), bortezomib, carfilzomib, and ixazomib, are the first-line treatment for multiple myeloma (MM). They inhibit cytosolic protein degradation in cells, which leads to the accumulation of misfolded and malfunctioned proteins in the cytosol and endoplasmic reticulum, resulting in cell death. Despite being a breakthrough in MM therapy, malignant cells develop resistance to PIs via different mechanisms. Understanding these mechanisms drives research toward new anticancer agents to overcome PI resistance. In this review, we summarize the mechanism of action of PIs and how MM cells adapt to these drugs to develop resistance. Finally, we explore these mechanisms to present strategies to interfere with PI resistance. The strategies include new inhibitors of the ubiquitin-proteasome system, drug efflux inhibitors, autophagy disruption, targeting stress response mechanisms, affecting survival and cell cycle regulators, bone marrow microenvironment modulation, and immunotherapy. We list potential pharmacological targets examined in in vitro, in vivo, and clinical studies. Some of these strategies have already provided clinicians with new anti-MM medications, such as panobinostat and selinexor. We hope that further exploration of the subject will broaden the range of therapeutic options and improve patient outcomes.

Promising Therapeutic Strategies for Hematologic Malignancies: Innovations and Potential.

In this review we explore innovative approaches in the treatment of hematologic cancers by combining various therapeutic modalities. We discuss the synergistic potential of combining inhibitors targeting different cellular pathways with immunotherapies, molecular therapies, and hormonal therapies. Examples include combining PI3K inhibitors with proteasome inhibitors, NF-κB inhibitors with immunotherapy checkpoint inhibitors, and neddylation inhibitors with therapies targeting the tumor microenvironment. Additionally, we discuss the potential use of small molecules and peptide inhibitors in hematologic cancer treatment. These multidimensional therapeutic combinations present promising strategies for enhancing treatment efficacy and overcoming resistance mechanisms. However, further clinical research is required to validate their effectiveness and safety profiles in hematologic cancer patients.

Multiple myeloma-A painful disease of the bone marrow.

Multiple myeloma is a bone marrow neoplasia with an incidence of 6/100,000/year in Europe. While the disease remains incurable, the development of novel treatments such as autologous stem cell transplantation, proteasome inhibitors and monoclonal antibodies has led to an increasing subset of patients living with long-term myeloma. However, more than two thirds of patients suffer from bone pain, often described as severe, and knowledge on the pain mechanisms and its effect on their health-related quality of life (HRQoL) is limited. In this review, we discuss the mechanisms of myeloma bone disease, the currently available anti-myeloma treatments and the lessons learnt from clinical studies regarding HRQoL in myeloma patients. Moreover, we discuss the mechanisms of cancer-induced bone pain and the knowledge that animal models of myeloma-induced bone pain can provide to identify novel analgesic targets. To date, information regarding bone pain and HRQoL in myeloma patients is still scarce and an effort should be made to use standardised questionnaires to assess patient-reported outcomes that allow inter-study comparisons of the available clinical data.

Effects of invivo CXCR4 blockade and proteasome inhibition on bone marrow plasma cells in HLA-sensitized kidney transplant candidates.

To date, plasma cell (PC)-targeted therapies have been limited by suboptimal PC depletion and antibody rebound. We hypothesized this is partly because of PC residence in protective bone marrow (BM) microenvironments. The purpose of this proof-of-concept study was to examine the effects of the CXCR4 antagonist, plerixafor, on PC BM residence; its safety profile (alone and in combination with a proteasome inhibitor, bortezomib); and the transcriptional effect on BMPCs in HLA-sensitized kidney transplant candidates. Participants were enrolled into 3 groups: group A (n = 4), plerixafor monotherapy; and groups B (n = 4) and C (n = 4), plerixafor and bortezomib combinations. CD34+ stem cell and PC levels increased in the blood after plerixafor treatment. PC recovery from BM aspirates varied depending on the dose of plerixafor and bortezomib. Single-cell RNA sequencing on BMPCs from 3 group C participants pretreatment and posttreatment revealed multiple populations of PCs, with a posttreatment enrichment of oxidative phosphorylation, proteasome assembly, cytoplasmic translation, and autophagy-related genes. Murine studies demonstrated dually inhibiting the proteasome and autophagy resulted in greater BMPC death than did monotherapies. In conclusion, this pilot study revealed anticipated effects of combined plerixafor and bortezomib on BMPCs, an acceptable safety profile, and suggests the potential for autophagy inhibitors in desensitization regimens.

Adjusted comparison of outcomes between patients from CARTITUDE-1 versus multiple myeloma patients with prior exposure to proteasome inhibitors, immunomodulatory drugs and anti-CD38 antibody from the prospective, multinational LocoMMotion study of real-world clinical practice.

Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy studied in patients with multiple myeloma exposed to three classes of treatment in the single-arm CARTITUDE-1 study. To assess the effectiveness of cilta-cel compared to real-world clinical practice (RWCP), we performed adjusted comparisons using individual patients' data from CARTITUDE-1 and LocoMMotion, a prospective, multinational study of patients with multiple myeloma triple-class exposed of treatment. Comparisons were performed using inverse probability weighting. In CARTITUDE-1, 113 patients were enrolled, and 97 patients were infused with cilta-cel. In LocoMMotion, 248 patients were enrolled, and 170 patients were included in the comparisons versus infused patients. Ninety-two unique regimens were used in LocoMMotion, most frequently carfilzomib-dexamethasone (13.7%), pomalidomide-cyclophosphamide-dexamethasone (13.3%) and pomalidomidedexamethasone (11.3%). Adjusted comparisons showed that patients treated with cilta-cel were 3.12-fold more likely to respond to treatment than those managed by RWCP (response rate, 3.12, 95% confidence interval [95% CI]: 2.24-4.00), had their risk of progression or death reduced to by 85% (progression-free survival hazard ratio=0.15, 95% CI: 0.08-0.29), and a risk of death lowered by 80% (overall survival hazard ratio HR=0.20, 95% CI: 0.09-0.41). The incremental improvement in healthrelated quality of life from baseline for cilta-cel versus RWCP at week 52, as measured by EORTC QLQ-C30 Global Health Status, was 13.4 (95% CI: 3.5-23.6) and increased to 30.8 (95% CI: 21.8-39.8) when including death as additional information regarding patients' health status. Patients treated with cilta-cel experienced more adverse events than those managed with RWCP (any grade: 100% vs. 83.5%). The results from this study demonstrate improved efficacy outcomes of cilta-cel versus RWCP and highlight its potential as a novel and effective treatment option for patients with multiple myeloma triple-class exposed of antimyeloma treatment. CARTITUDE-1 is registered with clinicaltrials gov. Identifier: NCT03548207. LocoMMotion is registered with clinicaltrials gov. Identifier: NCT04035226.

High-dose carfilzomib achieves superior anti-tumor activity over low-dose and recaptures response in relapsed/refractory multiple myeloma resistant to lowdose carfilzomib by co-inhibiting the ß2 and ß1 subunits of the proteasome complex.

Optimal carfilzomib dosing is a matter of debate. We analyzed the inhibition profiles of proteolytic proteasome subunits ß5, ß2 and ß1 after low-dose (20/27 mg/m2) versus high-dose (≥36 mg/m2) carfilzomib in 103 pairs of peripheral blood mononuclear cells from patients with relapsed/refractory (RR) multiple myeloma (MM). ß5 activity was inhibited (median inhibition >50%) in vivo by 20 mg/m2, whereas ß2 and ß1 were co-inhibited only by 36 and 56 mg/m2, respectively. Coinhibition of ß2 (P=0.0001) and ß1 activity (P=0.0005) differed significantly between high-dose and low-dose carfilzomib. Subsequently, high-dose carfilzomib showed significantly more effective proteasome inhibition than low-dose carfilzomib in vivo (P=0.0003). We investigated the clinical data of 114 patients treated with carfilzomib combinations. High-dose carfilzomib demonstrated a higher overall response rate (P=0.03) and longer progression-free survival (PFS) (P=0.007) than low-dose carfilzomib. Therefore, we escalated the carfilzomib dose to ≥36 mg/m2 in 16 patients who progressed during low-dose carfilzomib-containing therapies. High-dose carfilzomib recaptured response (≥ partial remission) in nine (56%) patients with a median PFS of 4.4 months. Altogether, we provide the first in vivo evidence in RRMM patients that the molecular activity of high-dose carfilzomib differs from that of low-dose carfilzomib by coinhibition of ß2 and ß1 proteasome subunits and, consequently, high-dose carfilzomib achieves a superior anti-MM effect than low-dose carfilzomib and recaptures the response in RRMM resistant to low-dose carfilzomib. The optimal carfilzomib dose should be ≥36 mg/m2 to reach a sufficient anti-tumor activity, while the balance between efficacy and tolerability should be considered in each patient.

The applicability of the Second Revision of the International Staging System for patients with multiple myeloma receiving immunomodulatory drugs or proteasome inhibitor-based regimens as induction treatment: A real-world analysis.

The Second Revision of the International Staging System (R2-ISS) was recently introduced to improve risk stratification over that provided by the extensively applied standard revised International Staging System (R-ISS). In addition to the variables included in the R-ISS, the R2-ISS incorporates chromosome 1q gain/amplification and divides the patients into 4 groups with different survival outcomes, better stratifying patients within the R-ISS intermediate-risk. The new model was developed based on a great quantity of data from patients participating in uniform clinical trials and has not been validated in real-world clinical practice. Therefore, we retrospectively analyzed the prognostic value of the R2-ISS in 474 consecutive patients with multiple myeloma receiving immunomodulatory drugs or proteasome inhibitor-based regimens as their first-line treatment. According to the R2-ISS, 41 (8.6%), 76 (16%), 275 (58%), and 82 (17.3%) patients were identified as R2-ISS I, R2-ISS II, R2-ISS III, and R2-ISS IV, respectively. The median progression-free survival (PFS) was 48 (95% CI: 38-58), 35 (95% CI: 23-47), 24 (95% CI: 21-27), and 12 (95% CI: 7-17) months, and the estimated median overall survival (OS) was 110 (95% CI: 42-178), 88 (95% CI: 75-101), 50 (95% CI: 43-57), and 26 (95% CI: 19-33) months (p < 0.001) in the 4 groups, respectively. The R2-ISS could also classify groups with distinct survival among patients with renal impairment or classified as R-ISS II. Adjusted by age, sex, treatment approaches and transplantation status, the R2-ISS was an independent prognostic factor associated with OS with a hazard ratio of 7.055 (95% CI: 3.626-13.726) (p < 0.001) for R2-ISS IV versus R2-ISS I and 2.707 (95% CI: 1.436-5.103) (p = 0.002) for R2-ISS III versus R2-ISS I. In conclusion, our results suggest that the R2-ISS is a simple and robust risk stratification tool for patients with multiple myeloma treated with novel drugs and could be used in everyday clinical practice.

Phase I study of opaganib, an oral sphingosine kinase 2-specific inhibitor, in relapsed and/or refractory multiple myeloma.

Multiple myeloma (MM) remains an incurable disease and there is an unmet medical need for novel therapeutic drugs that do not share similar mechanisms of action with currently available agents. Sphingosine kinase 2 (SK2) is an innovative molecular target for anticancer therapy. We previously reported that treatment with SK2 inhibitor opaganib inhibited myeloma tumor growth in vitro and in vivo in a mouse xenograft model. In the current study, we performed a phase I study of opaganib in patients with relapsed/refractory multiple myeloma (RRMM). Thirteen patients with RRMM previously treated with immunomodulatory agents and proteasome inhibitors were enrolled and treated with single-agent opaganib at three oral dosing regimens (250 mg BID, 500 mg BID, or 750 mg BID, 28 days as a cycle). Safety and maximal tolerated dose (MTD) were determined. Pharmacokinetics, pharmacodynamics, and correlative studies were also performed. Opaganib was well tolerated up to a dose of 750 mg BID. The most common possibly related adverse event (AE) was decreased neutrophil counts. There were no serious AEs considered to be related to opaganib. MTD was determined as at least 750 mg BID. On an intent-to-treat basis, one patient (7.7%) in the 500 mg BID dose cohort showed a very good partial response, and one other patient (7.7%) achieved stable disease for 3 months. SK2 is an innovative molecular target for antimyeloma therapy. The first-in-class SK2 inhibitor opaganib is generally safe for administration to RRMM patients, and has potential therapeutic activity in these patients. Clinicaltrials.gov: NCT02757326.