A phase I study of selinexor combined with weekly carfilzomib and dexamethasone in relapsed/refractory multiple myeloma.

We performed a phase I study of weekly selinexor, carfilzomib, and dexamethasone (wSKd) in patients with relapsed/refractory multiple myeloma (MM). The primary objective was to identify the maximum tolerated dose (MTD) of wSKd. Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Prior exposure/refractoriness to carfilzomib was permitted. Thirty patients were enrolled; 26 (87%) had triple-class exposed disease and 6 (20%) received chimeric antigen receptor (CAR) T-cell therapy. Dose level 2 (carfilzomib 70 mg/m2 Intravenous [IV] on Days 1, 8, and 15; selinexor 100 mg PO on Days 1, 8, 15, 22; dexamethasone 40 mg on Days 1, 8, 15, 22 of 28-day cycles) was chosen as the MTD, with no DLTs having occurred. The most common hematologic adverse events (AE) were thrombocytopenia (83%), anemia (70%), lymphopenia (50%), and neutropenia (50%). The most common nonhematologic AE were fatigue (70%), nausea (70%), diarrhea (53%), and anorexia (47%). The ORR was 21/30 (70%) overall and 18/23 (78%) at the MTD. At a median follow-up of 12.3 months, the median PFS was 5.3 months and median OS 23.3 months. Responses were similar in carfilzomib naïve and exposed patients. Long-term efficacy of wSKd is modest; wSKd could be employed as a bridging strategy to immunotherapies.

Carfilzomib, lenalidomide, and dexamethasone plus transplant in newly diagnosed multiple myeloma.

In this phase 2 multicenter study, we evaluated the incorporation of autologous stem cell transplantation (ASCT) into a carfilzomib-lenalidomide-dexamethasone (KRd) regimen for patients with newly diagnosed multiple myeloma (NDMM). Transplant-eligible patients with NDMM received 4 cycles of KRd induction, ASCT, 4 cycles of KRd consolidation, and 10 cycles of KRd maintenance. The primary end point was rate of stringent complete response (sCR) after 8 cycles of KRd with a predefined threshold of ≥50% to support further study. Seventy-six patients were enrolled with a median age of 59 years (range, 40-76 years), and 35.5% had high-risk cytogenetics. The primary end point was met, with an sCR rate of 60% after 8 cycles. Depth of response improved over time. On intent-to-treat (ITT), the sCR rate reached 76%. The rate of minimal residual disease (MRD) negativity using modified ITT was 70% according to next-generation sequencing (<10-5 sensitivity). After median follow-up of 56 months, 5-year progression-free survival (PFS) and overall survival (OS) rates were 72% and 84% for ITT, 85% and 91% for MRD-negative patients, and 57% and 72% for patients with high-risk cytogenetics. For high-risk patients who were MRD negative, 5-year rates were 77% and 81%. Grade 3 to 4 adverse events included neutropenia (34%), lymphopenia (32%), infection (22%), and cardiac events (3%). There was no grade 3 to 4 peripheral neuropathy. Patients with NDMM treated with KRd with ASCT achieved high rates of sCR and MRD-negative disease at the end of KRd consolidation. Extended KRd maintenance after consolidation contributed to deepening of responses and likely to prolonged PFS and OS. Safety and tolerability were manageable. This trial was registered at www.clinicaltrials.gov as #NCT01816971.

Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma.

Selinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non-clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose-escalation trial of twice-weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib-refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose-limiting toxicity (cardiac failure). The RP2D of twice-weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg. The most common grade 3/4 treatment-emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual-class refractory (PI and immunomodulatory drug)/quad-exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression-free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re-established disease control in RRMM patients, including carfilzomib-refractory patients. Registered at ClinicalTrials.gov (NCT02199665).

Proteomic profiling of naïve multiple myeloma patient plasma cells identifies pathways associated with favourable response to bortezomib-based treatment regimens.

Toward our goal of personalized medicine, we comprehensively profiled pre-treatment malignant plasma cells from multiple myeloma patients and prospectively identified pathways predictive of favourable response to bortezomib-based treatment regimens. We utilized two complementary quantitative proteomics platforms to identify differentially-regulated proteins indicative of at least a very good partial response (VGPR) or complete response/near complete response (CR/nCR) to two treatment regimens containing either bortezomib, liposomal doxorubicin and dexamethasone (VDD), or lenalidomide, bortezomib and dexamethasone (RVD). Our results suggest enrichment of 'universal response' pathways that are common to both treatment regimens and are probable predictors of favourable response to bortezomib, including a subset of endoplasmic reticulum stress pathways. The data also implicate pathways unique to each regimen that may predict sensitivity to DNA-damaging agents, such as mitochondrial dysfunction, and immunomodulatory drugs, which was associated with acute phase response signalling. Overall, we identified patterns of tumour characteristics that may predict response to bortezomib-based regimens and their components. These results provide a rationale for further evaluation of the protein profiles identified herein for targeted selection of anti-myeloma therapy to increase the likelihood of improved treatment outcome of patients with newly-diagnosed myeloma.

Phase 1/2 study of carfilzomib, pomalidomide, and dexamethasone with and without daratumumab in relapsed multiple myeloma.

We conducted a phase 1/2 study of carfilzomib, pomalidomide, and dexamethasone (KPd) and KPd with daratumumab (Dara-KPd) in relapsed/refractory multiple myeloma. The primary end points were identification of a maximum tolerated dose (MTD) of KPd for phase 1, and rates of overall response (ORR) and near complete response (nCR) after 4 cycles of KPd and Dara-KPd, respectively, for phase 2. The MTD for KPd was carfilzomib 20/27 mg/m2 on days 1, 2, 8, 9, 15, and 16 (cycles 1-8) and days 1, 2, 15, and 16 for cycles 9 and beyond; oral pomalidomide 4 mg on days 1 to 21; and oral dexamethasone 40 mg weekly in 28-day cycles. Sixty-six patients received KPd, including 34 at the MTD. The ORR after 4 cycles of KPd at the MTD was 27/34 (79%; 95% confidence interval [CI], 62%-91%), meeting the statistical threshold for efficacy. At a median follow-up of 44 months, the median progression-free survival (PFS) was 13 months and overall survival (OS) 44 months. Twenty-eight patients received Dara-KPd. The rate of nCR or better after 4 cycles was 11/28 (39%; 95% CI, 22%-59%), meeting the statistical threshold for efficacy. As the best response to Dara-KPd, the ORR was 25/28 (89%) and the rate of measurable residual disease negativity by flow cytometry (10-5) was 17/26 (65%). At a median follow-up of 26 months, the median PFS and OS for Dara-KPd were not reached. Dara-KPd induced deeper and more durable responses than KPd without compromising safety in a predominantly high-risk, lenalidomide-refractory population, warranting further evaluation of this quadruplet. This trial is registered at www.clinicaltrials.gov as #NCT01665794.

Efficacy and safety of carfilzomib-lenalidomide-dexamethasone in newly diagnosed multiple myeloma: pooled analysis of four single-arm studies.

Pooled analyses of four single-arm phase 1 and 2 studies (NCT01816971, NCT02405364, NCT01029054, NCT01402284) investigated the clinical effectiveness of carfilzomib-lenalidomide-dexamethasone (KRd) in newly diagnosed multiple myeloma (NDMM). Patients who did (Cohort 1; n = 122) and did not (Cohort 2; n = 99) undergo autologous stem cell transplant (high-dose melphalan [HDM]-ASCT) were included. Patients received a 28-day cycle of induction KRd. The rate of very good partial response or better, the primary endpoint, was 93% in Cohort 1 and 90% in Cohort 2. Two-year progression-free survival and overall survival rates were 88% and 96% for Cohort 1, and 85% and 97% for Cohort 2. At least 90% of patients in each cohort reported ≥1 grade 3 or 4 treatment-emergent adverse events. Subgroup analyses by age, International Staging System stage, and cytogenetic risk were consistent with the overall population. KRd is an effective and tolerable treatment option for patients with NDMM regardless of HDM-ASCT eligibility.

Elotuzumab and Weekly Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Without Transplant Intent: A Phase 2 Measurable Residual Disease-Adapted Study.

Importance: Treatment of newly diagnosed multiple myeloma (NDMM) with a quadruplet regimen consisting of a monoclonal antibody, proteasome inhibitor, immunomodulatory imide, and corticosteroid has been associated with improved progression-free survival (PFS) compared with triplet regimens. The optimal quadruplet combination, and whether this obviates the need for frontline autologous stem cell transplant (ASCT), remains unknown. We evaluated elotuzumab and weekly carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) without ASCT in NDMM. Objective: To investigate the efficacy of Elo-KRd using a measurable residual disease (MRD)-adapted design in NDMM regardless of ASCT eligibility. Design, Setting, and Participants: This multicenter, single-arm, phase 2 study enrolled patients between July 2017 and February 2021. Median follow-up was 29 months. Interventions: Twelve to 24 cycles of Elo-KRd; consecutive MRD-negative results at 10-6 by next-generation sequencing (NGS) after cycles 8 (C8) and 12 determined the duration of Elo-KRd. This was followed by Elo-Rd (no carfilzomib) maintenance therapy until disease progression. Main Outcomes and Measures: The primary end point was the rate of stringent complete response (sCR) and/or MRD-negativity (10-5) after C8 Elo-KRd. Secondary end points included safety, rate of response, MRD status, PFS, and overall survival (OS). As an exploratory analysis, MRD was assessed using liquid chromatography mass spectrometry (MS) on peripheral blood samples. Results: Forty-six patients were enrolled (median age 62 years, 11 [24%] aged >70 years). Overall, 32 (70%) were White, 6 (13%) were Black, 3 (6%) were more than 1 race, and 5 (11%) were of unknown race. Thirty-three (72%) were men and 13 (28%) were women. High-risk cytogenetic abnormalities were present in 22 (48%) patients. The rate of sCR and/or MRD-negativity after C8 was 26 of 45 (58%), meeting the predefined statistical threshold for efficacy. Responses deepened over time, with the MRD-negativity (10-5) rate increasing to 70% and MS-negativity rate increasing to 65%; concordance between MRD by NGS and MS increased over time. The most common (>10%) grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively). There was 1 grade 5 myocardial infarction. The estimated 3-year PFS was 72% overall and 92% for patients with MRD-negativity (10-5) at C8. Conclusions and Relevance: An MRD-adapted design using elotuzumab and weekly KRd without ASCT showed a high rate of sCR and/or MRD-negativity and durable responses. This approach provides support for further evaluation of MRD-guided deescalation of therapy to decrease treatment exposure while sustaining deep responses. Trial Registration: ClinicalTrials.gov Identifier: NCT02969837.

Recommendations and outcomes from a geriatric assessment guided multidisciplinary clinic prior to autologous stem cell transplant in older patients.

BACKGROUND: Autologous hematopoietic stem cell transplant (autoHCT) is a mainstay of treatment for multiple myeloma and non-Hodgkin lymphoma but is underutilized in older adults. We investigated the association of vulnerabilities identified by a geriatric assessment (GA)-guided multidisciplinary clinic (MDC) on the receipt of autoHCT and evaluated its ability to predict outcomes in older autoHCT candidates. METHODS: Patients 50+ years received GA-informed optimization recommendations: 'decline' if unlikely to realize benefits of autoHCT, 'defer' if optimization necessary before autoHCT, and 'proceed' if autoHCT could proceed without delay. We compared characteristics and outcomes of autoHCT recipients (n = 62) to non-autoHCT patients (n = 29) and evaluated GA deficits on outcomes. RESULTS: 91 patients were evaluated; the MDC recommendation was 'decline' for 5 (6%), 'defer' for 25 (27%), and 'proceed' for 61 (67%). AutoHCT recipients had fewer GA-rated impairments relative to non-autoHCT patients, as did patients with a 'proceed' recommendation relative to 'defer'. Among autoHCT recipients, 1-year and 3-year non-relapse morality (NRM) was 0% and 5%, and there was no difference in length of hospitalization, readmission rate, or mortality after transplant by MDC recommendation. Frail grip strength and poor performance status were associated with inferior post-autoHCT progression-free survival and overall survival. CONCLUSIONS: Patients pursuing autoHCT after MDC-directed optimization achieved excellent outcomes, including patients deferred but ultimately receiving autoHCT. GA-identified functional deficits, especially frail grip strength, may improve risk stratification in older autoHCT candidates. Employing a GA earlier in the disease trajectory to inform early referral to an MDC may increase autoHCT safety and utilization in older patients.

Racial differences in treatment and outcomes in multiple myeloma: a multiple myeloma research foundation analysis.

Findings on racial differences in survival in multiple myeloma (MM) have been inconclusive. We assessed differences in outcomes between White and Black individuals among 639 newly diagnosed MM patients in the MM Research Foundation CoMMpass registry with baseline cytogenetic data. Survival curves were constructed using the Kaplan-Meier method. Hazard ratios and 95% confidence intervals were derived from Cox proportional hazard regression models. Age, gender, and stage were similar between Whites (n = 526) and Blacks (n = 113). Blacks had inferior overall survival (OS) compared with Whites and were less likely to receive triplet therapies or frontline autologous stem cell transplant (ASCT). The following factors were significantly associated with inferior OS in multivariate analysis: higher international staging system (ISS) score, ≥1 or ≥2 high-risk cytogenetic abnormalities (HRCA), high-risk gene expression profile (GEP), and lack of ASCT. Multivariate analysis in the Black subset found that only lack of ASCT was significantly associated with inferior OS. The receipt of both triplet induction and ASCT only partly abrogated the effect of race on survival. HRCA did not track with survival in Blacks, emphasizing the need for race-specific risk prognostication schema to guide optimal MM therapy.

Impact of an Oncology Clinical Pharmacist Specialist in an Outpatient Multiple Myeloma Clinic.

INTRODUCTION: Improvements in cancer treatment and supportive care, as well as the approval of oral chemotherapy medications over the past decade, have resulted in an increasing number of cancer patients being treated in outpatient settings. Transitioning cancer treatments to the outpatient setting places greater emphasis on proper medication counseling and optimal management of adverse effects. We therefore evaluated the clinical and financial impact of an oncology clinical pharmacist specialist in an interdisciplinary multiple myeloma clinic by using a validated scoring tool. METHODS: The oncology clinical pharmacist specialist was available for consult by the multiple myeloma clinic staff. The pharmacist may be consulted for any medication-related inquiry. On the basis of the consult, the pharmacist categorized interventions into 12 predefined intervention categories. RESULTS: Implementation of a clinical pharmacy specialist into a multiple myeloma clinic over 39 clinic days resulted in 241 patient consults and 474 interventions made by the pharmacist. The most frequent interventions made by the pharmacist were medication teaching (n = 97), dose adjustments (n = 82), and medication reconciliation (n = 63). The value of interventions made by the pharmacist during the study period was $189,441, with a predicted annual value of $757,764. CONCLUSION: The addition of an oncology pharmacist to an outpatient multiple myeloma clinic can improve clinical and financial outcomes.

Results from a multidisciplinary clinic guided by geriatric assessment before stem cell transplantation in older adults.

Limitations found on geriatric assessment (GA) track with worse outcomes after hematopoietic cell transplantation (HCT). We report on a multidisciplinary team clinic (MDC), consisting of a cancer-specific GA and a multidisciplinary team of providers, to assess candidacy and create an individualized optimization plan for allogeneic HCT candidates aged ≥60 years and autologous HCT and adoptive T-cell therapy candidates aged ≥70 years. Among the 247 patients evaluated in the MDC, allogeneic HCT candidates comprised the majority (60%), followed by autologous HCT (37%) with occasional older cellular therapy candidates (3%). Almost all patients meeting program-required minimum ages for MDC optimization at our institution were assessed (98%). Relative to historical control subjects undergoing GA alone, allogeneic HCT patients aged ≥60 years who underwent MDC appraisal had similar frequencies of high-risk disease, reduced intensity regimens, and high comorbidity but fewer GA-graded functional impairments. The MDC cohort experienced fewer inpatient deaths, shorter length of stay, and fewer discharges to nursing facilities compared with control subjects. Improvements in early mortality were observed over time; 1-year overall survival improved from 43% in the pre-MDC era to 70% in the recent MDC era, and 1-year nonrelapse mortality decreased from 43% to 18%. The 31 autologous HCT recipients aged ≥70 years optimized by the MDC achieved 0% nonrelapse mortality and 97% overall survival at 1 year. A GA-guided MDC for older HCT candidates is feasible and seems to reduce transplant-associated morbidity and mortality. An MDC should encourage broader and safer utilization of transplantation in older patients.

Synergistic Myeloma Cell Death via Novel Intracellular Activation of Caspase-10-Dependent Apoptosis by Carfilzomib and Selinexor.

Exportin1 (XPO1; also known as chromosome maintenance region 1, or CRM1) controls nucleo-cytoplasmic transport of most tumor suppressors and is overexpressed in many cancers, including multiple myeloma, functionally impairing tumor suppressive function via target mislocalization. Selective inhibitor of nuclear export (SINE) compounds block XPO1-mediated nuclear escape by disrupting cargo protein binding, leading to retention of tumor suppressors, induction of cancer cell death, and sensitization to other drugs. Combined treatment with the clinical stage SINE compound selinexor and the irreversible proteasome inhibitor (PI) carfilzomib induced synergistic cell death of myeloma cell lines and primary plasma cells derived from relapsing/refractory myeloma patients and completely impaired the growth of myeloma cell line-derived tumors in mice. Investigating the details of SINE/PI-induced cell death revealed (i) reduced Bcl-2 expression and cleavage and inactivation of Akt, two prosurvival regulators of apoptosis and autophagy; (ii) intracellular membrane-associated aggregation of active caspases, which depended on caspase-10 protease activity; and (iii) novel association of caspase-10 and autophagy-associated proteins p62 and LC3 II, which may prime activation of the caspase cascade. Overall, our findings provide novel mechanistic rationale behind the potent cell death induced by combining selinexor with carfilzomib and support their use in the treatment of relapsed/refractory myeloma and potentially other cancers.

Current approaches to the initial treatment of symptomatic multiple myeloma.

The treatment of newly diagnosed multiple myeloma has dramatically changed since the emergence of proteasome inhibitors and immunomodulatory drugs. Front-line combination regimens incorporating novel drugs such as thalidomide, bortezomib and lenalidomide, have significantly improved response rates and are the standard of care for induction regimens. Although the timing and role of autologous stem cell transplant are now being questioned, it remains an important part of the treatment paradigm in eligible patients. In addition, the concept of extended sequential therapy has recently emerged, including consolidation and/or maintenance in both the post-transplant setting and in nontransplant candidates. In this article we focus on management strategies in newly diagnosed multiple myeloma, including choice of induction regimens in transplant-eligible and -ineligible patients, as well as the role of autologous stem cell transplant, consolidation therapy and maintenance therapy.

Initiation of aspirin therapy modulates angiogenic protein levels in women with breast cancer receiving tamoxifen therapy.

Aspirin has a range of antineoplastic properties linked to inhibition of cyclooxygenase enzymes in tumor cells, platelet inhibition and to inhibition of angiogenesis. We undertook a prospective study to determine the influence of a 45-day course of aspirin therapy on circulating and intraplatelet levels of selected proangiogenic (vascular endothelial growth factor [VEGF]) and antiangiogenic (thrombospondin-1 [TSP-1]) proteins, and platelet protein release in women diagnosed with breast cancer who were receiving tamoxifen therapy. Initiation of aspirin therapy increases serum and intraplatelet levels of TSP-1 without a corresponding increase in VEGF levels. Following aspirin therapy, VEGF levels decreased (relative to pretreatment levels) while TSP-1 returned to pretreatment levels. Plasma TSP-1 and VEGF levels did not change on aspirin therapy. Aspirin use also decreased thrombin receptor mediated release of TSP-1 and VEGF from platelets. The selective impact on platelet angiogenic protein content and release supports one mechanism by which aspirin can modify the angiogenic balance in women receiving tamoxifen therapy. Aspirin therapy appears to favor an overall antiangiogenic balance in women with breast cancer who are receiving tamoxifen therapy.

Evolving strategies in the initial treatment of multiple myeloma.

Until the advents of novel agents, partial response (PR) or better was the established gold standard to initial therapy of multiple myeloma (MM), and treatment goals were focused on relieving symptoms, prevention of organ damage, and modest improvements in survival. With the introduction of autologous stem cell transplant (ASCT), deeper responses, including complete responses (CRs) were more frequent, and contributed to longer survival. In the era of novel therapies, ASCT remains commonly used and its impact on outcome appears superior, albeit less so than when compared with conventional therapy, and its survival benefit is yet to be established in either setting. In addition, in non-transplant candidates, novel therapies have now significantly improved the overall response rates, depth of response, and clinical benefit, to the levels previously only observed with ASCT, which now increasingly challenges the role and timing of ASCT in eligible patients. Nevertheless, the two approaches of treatment, transplant or no transplant, remain commonly accepted. With an improvement in the tolerability of newer regimens and the deferral of ASCT in transplant candidates, the debate has emerged whether the two-pathway approach to the treatment of newly diagnosed myeloma should be re-evaluated. At the same time, treatment goals are also shifting. Many believe that MM can be converted into a chronic disease and that a functional cure maybe a realistic goal, for at least a proportion of patients. This contribution will review these points of discussion and the evolving approach to treatment of newly diagnosed MM.