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PDF file - 58K, Study design and patient flow by intent to treat (ITT).

PDF file - 53K, Validation of gene expression data using QPCR compared to microarray values (data reported as fold change).

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Purpose:The prognosis of patients with multiple myeloma who are resistant to proteasome inhibitors, immunomodulatory drugs (IMiD), and daratumumab is extremely poor. Even B-cell maturation antigen–specific chimeric antigen receptor T-cell therapies provide only a temporary benefit before patients succumb to their disease. In this article, we interrogate the unique sensitivity of multiple myeloma cells to the alternative strategy of blocking protein translation with omacetaxine.Experimental Design:We determined protein translation levels (n = 17) and sensitivity to omacetaxine (n = 51) of primary multiple myeloma patient samples. Synergy was evaluated between omacetaxine and IMiDs in vitro, ex vivo, and in vivo. Underlying mechanism was investigated via proteomic analysis.Results:Almost universally, primary patient multiple myeloma cells exhibit >2.5-fold increased rates of protein translation compared with normal marrow cells. Ex vivo treatment with omacetaxine resulted in >50% reduction in viable multiple myeloma cells. In this cohort, high levels of translation serve as a biomarker for patient multiple myeloma cell sensitivity to omacetaxine. Unexpectedly, omacetaxine demonstrated synergy with IMiDs in multiple myeloma cell lines in vitro. In addition, in an IMiD-resistant relapsed patient sample, omacetaxine/IMiD combination treatment resensitized the multiple myeloma cells to the IMiD. Proteomic analysis found that the omacetaxine/IMiD combination treatment produced a double-hit on the IRF4/c-MYC pathway, which is critical to multiple myeloma survival.Conclusions:Overall, protein translation inhibitors represent a potential new drug class for myeloma treatment and provide a rationale for conducting clinical trials with omacetaxine alone and in combination with IMiDs for patients with relapsed/refractory multiple myeloma.

Purpose: This phase II study evaluated bortezomib-based secondary induction and stem cell mobilization in 38 transplant-eligible patients with myeloma who had an incomplete and stalled response to, or had relapsed after, previous immunomodulatory drug-based induction.Experimental Design: Patients received up to six 21-day cycles of bortezomib plus dexamethasone, with added liposomal doxorubicin for patients not achieving partial response or better by cycle 2 or very good partial response or better (≥VGPR) by cycle 4 (DoVeD), followed by bortezomib, high-dose cyclophosphamide, and filgrastim mobilization. Gene expression/signaling pathway analyses were conducted in purified CD34+ cells after bortezomib-based mobilization and compared against patients who received only filgrastim ± cyclophosphamide. Plasma samples were similarly analyzed for quantification of associated protein markers.Results: The response rate to DoVeD relative to the pre-DoVeD baseline was 61%, including 39% ≥VGPR. Deeper responses were achieved in 10 of 27 patients who received bortezomib-based mobilization; postmobilization response rate was 96%, including 48% ≥VGPR, relative to the pre-DoVeD baseline. Median CD34+ cell yield was 23.2 × 106 cells/kg (median of 1 apheresis session). After a median follow-up of 46.6 months, median progression-free survival was 47.1 months from DoVeD initiation; 5-year overall survival rate was 76.4%. Grade ≥3 adverse events included thrombocytopenia (13%), hand–foot syndrome (11%), peripheral neuropathy (8%), and neutropenia (5%). Bortezomib-based mobilization was associated with modulated expression of genes involved in stem cell migration.Conclusion: Bortezomib-based secondary induction and mobilization could represent an alternative strategy for elimination of tumor burden in immunomodulatory drug-resistant patients that does not impact stem cell yield. Clin Cancer Res; 19(6); 1534–46. ©2013 AACR.

PDF file - 72K, Most common all-grade and grade ≥3 AEs during DoVeD induction and bortezomib-based stem cell mobilization.

PDF file - 60K, Kaplan-Meier estimates of (A)PFS and (B)OS in patients in the ITT population (N-38).

PDF file - 59K, Responses rates after DoVeD induction, bortezomib- or non-bortezomib-based mobilization, and SCT.

Clinical Practice Points • Selinexor may be active even in the dire situation of early relapse after allogeneic stem cell transplantation. • Selinexor retains activity in patients who are proteasome, immunomodulatory drug, and daratumumab refractory. • Selinexor has the potential to be combined effectively with multiple standard anti-myeloma agents, including carfilzomib.

The treatment of older persons with cancer is fraught by a delicate balance of targeting the disease while avoiding treatment‐related complications. “Personalized,” or “precision” medicine approaches can ease this problem through more efficacious and less toxic treatments. Multiple myeloma epitomizes the struggle to balance treatment options and their complications, for it is an incurable disease afflicting a predominantly aged population, and treatment is administered on a continuous schedule with little or no breaks. Over the last two decades, advances in drug development have improved outcomes for younger, fit patients, but older, frail patients have not realized the same benefit. This could be related to the benefits of three drug combinations, when frail patients can often tolerate only two drugs at a time. In myeloma, personalized approaches have lagged behind some other malignancies due to its genetic complexity and a paucity of abnormalities with associated targeted therapies. In contrast, the disease is managed with an array of drugs that target phenotypic characteristics common in malignant plasma cells. To address the unmet need for personalized medicine in myeloma, we developed a functional approach by profiling the sensitivity of patients’ myeloma to clinically available drugs. Through this, we observed that receiving at least two effective drugs portended better outcomes, leaving those patients who can only tolerate two drug regimens without room for error. We now describe a frail patient's case and their drug sensitivity profile to illustrate how personalized treatment could have led to an improved disease course. Personalized treatment could provide the greatest survival improvements to older adults with cancers, such as multiple myeloma, through avoiding undertreatment, limiting attrition through subsequent lines of therapy, reducing exposure to ineffective drugs and streamlining the management of relapses. Exploring these avenues is imperative to closing the gap of cancer‐related mortality in older and frail persons.

We evaluate the safety of bendamustine as a bridge to stem cell transplantation (SCT) in patients with relapsed/refractory lymphoma and residual disease after salvage therapy. Thirty-four subjects without complete responses (CR) received bendamustine 200 mg/m

Plain language summary Treatment options have expanded in recent years for patients with relapsed/refractory multiple myeloma (RRMM) who received lenalidomide as their initial treatment and then either had a period of improvement before the disease worsened or did not respond to the medication at all. Pomalidomide is another MM treatment from the same drug class as lenalidomide. We analyzed the effect of a combination treatment containing pomalidomide versus a combination treatment without pomalidomide in patients with MM who had received routine initial treatment with lenalidomide. US-based community oncologists completed study forms to record patient characteristics and treatment response information. Results showed that patients who received pomalidomide in a combination treatment after initial lenalidomide treatment achieved higher rates of very good partial response or better and longer progression-free survival than those who did not. The results of this analysis suggest that switching to a different class of drugs following the initial treatment may not be warranted after first relapse and pomalidomide-containing combination treatments are a more effective treatment following lenalidomide for patients with RRMM.

Combination treatment regimens including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) and a corticosteroid are standards of care for initial treatment of multiple myeloma (MM). We aimed to evaluate if a sequential treatment program using PI induction followed by IMiD based consolidation and maintenance could achieve similar outcomes with reduced toxicities. This phase 2 study was designed to assess the safety and efficacy of the Car-BiRd regimen: carfilzomib and dexamethasone (Kd) induction until maximum response, followed by lenalidomide, clarithromycin and dexamethasone (BiRd) consolidation until next maximum response, then lenalidomide maintenance in patients with newly diagnosed MM. Seventy-two patients, including both transplant eligible and ineligible patients, were enrolled and evaluated for response. The overall response rate to the Car-BiRd regimen was 94% with 83% of patients achieving a ≥ VGPR and 35% achieving a CR/sCR. The rate of CR/sCR increased from 7% with Kd induction to 21% with BiRd consolidation and 35% with lenalidomide maintenance. These results did not meet the study's target endpoint of a CR rate of 55%. The median PFS using this deferred transplant approach was 37.3 months (95% CI 27.9, 52.7) and median OS was not reached with a median follow-up of 60 months. Toxicities were primarily low grade and manageable. Hematologic toxicities were lower than those expected with a combination PI/IMiD protocol. The sequential Car-BiRd regimen is an effective and safe approach for the upfront treatment of MM including patients unfit for transplant.

High-dose melphalan (MEL200) followed by autologous stem cell transplantation (ASCT) remains a standard of care for multiple myeloma (MM). Bendamustine induces responses in MM resistant to other alkylators. Our prior Phase I trial adding bendamustine to MEL200 transplant conditioning resulted in no additional toxicity. We now report a single-arm, phase II study that evaluated the efficacy of bendamustine 225 mg/m2 with MEL200 conditioning for ASCT in 18 patients with newly diagnosed MM (NDMM) and 17 with relapsed or refractory MM (RRMM). The primary end point was the complete response (CR/sCR) rate at day+ 100. Sample size was determined according to Simon's two-stage design. At stage 1, sixteen patients entered the study. As there were eight patients with CR/sCR, enrollment increased to 28 patients. Sixteen out of the first 28 evaluable patients achieved CR/sCR, meeting the design criteria. Enrollment was then expanded to a total of 35 patients. 51% achieved a CR/sCR. After a median follow-up of 65 months, 21 patients progressed, including 7 deaths. The median PFS for NDMM and RRMM was 48 and 45 months, respectively. Bendamustine/MEL200 conditioning resulted in excellent overall and depth of response as well as PFS, particularly in the RRMM patients, and is worthy of further investigation (NCT00916058).

The revised International Staging System (R-ISS) combines ISS with genetic markers and lactate dehydrogenase and can prognosticate newly diagnosed multiple myeloma (MM). Early relapse (

Introduction: Multiple myeloma (MM) is a plasma cell malignancy that remains incurable, with patients enduring multiple relapses and development of drug resistance. Immunomodulatory drugs (IMiDs) are critical anti-MM agents. IMiDs act by inducing CRBN-dependent proteasomal degradation of the transcription factors IKZF1 and IKZF3, which leads to IRF4 and MYC downregulation (collectively termed the “Ikaros axis”). Although CRBN aberrations occur, whether they are a functional mechanism of resistance in patients remains unclear. Based on the importance of CRBN in IMiD response, we hypothesized that IMiD treatment fails to downregulate the Ikaros axis in IMiD-resistant MM cells. Methods: To measure IMiD-induced Ikaros axis downregulation, we designed an intracellular flow cytometry assay that measured relative IKZF1, IKZF3, IRF4 and MYC protein levels in MM cells following ex vivo pomalidomide (Pom) treatment. We established this assay using IMiD-sensitive parental and dose-escalated Pom resistant MM1S and H929 cell lines before utilizing it in patient samples (isolated mononuclear cells). To assess the Ikaros axis in the context of MM intratumoral heterogeneity, we used mass cytometry to simultaneously characterize MM subpopulations in patient samples. Lastly, we determined ex vivo drug sensitivity in patient samples via flow cytometry. Results: Our hypothesis was supported in MM cell lines, as sensitive parental lines showed a significant decrease in all Ikaros axis protein levels following Pom treatment, while resistant lines showed no IMiD-induced decrease in any Ikaros axis protein. However, when assessed in CD38+CD138+ cells from patient samples, Pom treatment caused a significant decrease in IKZF1, IKZF3 and IRF4 regardless of IMiD sensitivity. Mass cytometry in patient samples revealed that individual Ikaros axis proteins were differentially expressed between subpopulations. When correlating this with ex vivo Pom sensitivity of MM subpopulations, we observed that low IKZF1 and IKZF3 corresponded to Pom resistance. Interestingly, most of these resistant populations still expressed MYC. We therefore assessed whether IMiD resistant MM was MYC dependent by treating Pom resistant MM cells with MYCi975. In 88% (7/8) of patient samples tested, IMiD resistant MM cells were sensitive to MYC inhibition. Conclusions: Our findings did not support our initial hypothesis, as IMiD-induced IKZF1 and IKZF3 degradation remains intact in IMiD resistant MM cells from patient samples. However, our data support a mechanism where the Ikaros axis no longer drives MYC expression in IMiD-resistant MM. Therefore, we propose that the critical mediator of IMiD resistance is conversion to a cell state where MYC expression is Ikaros axis independent. This suggests targeting MYC directly or via the as yet uncharacterized mechanism controlling MYC may be an effective strategy to eradicate IMiD resistant MM. Citation Format: Lorraine N. Davis, Zachary J. Walker, Denis Ohlstrom, Brett M. Stevens, Peter A. Forsberg, Tomer M. Mark, Craig T. Jordan, Daniel W. Sherbenou. MYC inhibition overcomes IMiD resistance in heterogeneous multiple myeloma populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3956.

Background Daratumumab is a human CD38-directed monoclonal antibody indicated for the treatment of relapsed and refractory multiple myeloma (MM). Methods A multicenter, open-label treatment protocol provided early access to daratumumab for patients who had progressive MM after they received ≥3 prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or if they were refractory to both a proteasome inhibitor and an immunomodulatory agent. Patients received daratumumab 16 mg/kg weekly for 8 weeks, every other week for 16 weeks, and monthly until they developed disease progression, unacceptable toxicity, or 60 days after the drug gained US approval. Treatment-emergent grade ≥3 adverse events (AEs), serious AEs, and AEs of special interest were collected. Results Three hundred forty-eight patients were enrolled at 39 US sites between June and December 2015. Patients received study therapy for a median of 1.9 months (range, 0.03-6.0 months). Fifty-two percent of patients transitioned to commercially-available daratumumab and 37% discontinued because of progressive disease. Grade ≥3 AEs occurred in 50% of patients, including thrombocytopenia (15%) and anemia (14%). Serious AEs occurred in 35% of patients (12% were drug-related), including infections (11%). Infusion reactions occurred in 56%, 2%, and 2% of patients during the first, second, and all subsequent infusions, respectively; respiratory symptoms (cough, dyspnea, throat irritation, nasal congestion) were common. The infusion reaction rate for the first infusion was 38% in 50 patients at 2 sites who received montelukast as premedication for their first infusion and 59% in patients who did not receive montelukast. Conclusions The current findings are consistent with previously reported trials and confirm the safety profile of daratumumab in heavily pretreated US patients who have relapsed or refractory MM. Cancer 2018;124:000-000.

Purpose:The prognosis of patients with multiple myeloma who are resistant to proteasome inhibitors, immunomodulatory drugs (IMiD), and daratumumab is extremely poor. Even B-cell maturation antigen–specific chimeric antigen receptor T-cell therapies provide only a temporary benefit before patients succumb to their disease. In this article, we interrogate the unique sensitivity of multiple myeloma cells to the alternative strategy of blocking protein translation with omacetaxine.Experimental Design:We determined protein translation levels (n = 17) and sensitivity to omacetaxine (n = 51) of primary multiple myeloma patient samples. Synergy was evaluated between omacetaxine and IMiDs in vitro, ex vivo, and in vivo. Underlying mechanism was investigated via proteomic analysis.Results:Almost universally, primary patient multiple myeloma cells exhibit >2.5-fold increased rates of protein translation compared with normal marrow cells. Ex vivo treatment with omacetaxine resulted in >50% reduction in viable multiple myeloma cells. In this cohort, high levels of translation serve as a biomarker for patient multiple myeloma cell sensitivity to omacetaxine. Unexpectedly, omacetaxine demonstrated synergy with IMiDs in multiple myeloma cell lines in vitro. In addition, in an IMiD-resistant relapsed patient sample, omacetaxine/IMiD combination treatment resensitized the multiple myeloma cells to the IMiD. Proteomic analysis found that the omacetaxine/IMiD combination treatment produced a double-hit on the IRF4/c-MYC pathway, which is critical to multiple myeloma survival.Conclusions:Overall, protein translation inhibitors represent a potential new drug class for myeloma treatment and provide a rationale for conducting clinical trials with omacetaxine alone and in combination with IMiDs for patients with relapsed/refractory multiple myeloma.

In the phase III CASTOR trial, daratumumab, bortezomib and dexamethasone (D-Vd) significantly extended progression-free survival compared with bortezomib and dexamethasone (Vd) alone in patients with relapsed/refractory multiple myeloma (RRMM). Here, we present patient-reported outcomes (PROs) from the CASTOR trial. PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EuroQol 5-dimensional descriptive system questionnaire. Treatment effects through Cycle 8 were measured by a repeated measures mixed-effects model. After Cycle 8, PROs were only collected for patients in the D-Vd group who continued on daratumumab monotherapy. Compliance rates for PRO assessments were high and similar between treatment groups. Mean changes from baseline were generally similar between treatment groups for EORTC QLQ-C30 global health status (GHS), functioning and symptoms, and did not exceed 10 points for either treatment group. Subgroup analyses were consistent with the results observed in the overall population. There was no change in patients' health-related quality of life for the first eight cycles of therapy; thereafter, patients treated with daratumumab over the long-term reported improvements in GHS and pain. These results complement the significant clinical benefits observed with D-Vd in patients with RRMM and support its use in this patient population.

We compared outcomes among adult matched related donor (MRD) patients undergoing peripheral blood stem cell transplantation and adult patients undergoing double unit cord blood transplantation (CBT) at our center between 2010 and 2017. A total of 190 CBT patients were compared with 123 MRD patients. Median follow-up was 896 days (range, 169-3350) among surviving CBT patients and 1262 days (range, 249-3327) among surviving MRD patients. Comparing all CBT with all MRD patients, overall survival (OS) was comparable (P = .61) and graft-versus-host disease (GVHD) relapse-free survival (GRFS) was significantly improved among CBT patients (P = .0056), primarily because of decreased moderate to severe chronic GVHD following CBT (P < .0001; hazard ratio [HR], 3.99; 95% confidence interval [CI], 2.26-7.04). Among patients undergoing our most commonly used MRD and umbilical cord blood (CB) myeloablative regimens, OS was comparable (P = .136) and GRFS was significantly improved among CBT patients (P = .006). Cumulative incidence of relapse trended toward decreased in the CBT group (P = .075; HR, 1.85; CI 0.94-3.67), whereas transplant-related mortality (TRM) was comparable (P = .55; HR, 0.75; CI, 0.29-1.95). Among patients undergoing our most commonly used nonmyeloablative regimens, OS and GRFS were comparable (P = .158 and P = .697). Cumulative incidence of both relapse and TRM were comparable (P = .32; HR, 1.35; CI, 0.75-2.5 for relapse and P = .14; HR, 0.482; CI, 0.18-1.23 for TRM). Our outcomes support the efficacy of CBT and suggest that among patients able to tolerate more intensive conditioning regimens at high risk for relapse, CB may be the preferred donor source.

The oncogenic drivers and progression factors in multiple myeloma (MM) are heterogeneous and difficult to target therapeutically. Many different MM drugs have emerged, however, that attack various phenotypic aspects of malignant plasma cells. These drugs are administered in numerous, seemingly interchangeable combinations. Although the availability of many treatment options is useful, no clinical test capable of optimizing and sequencing the treatment regimens for an individual patient is currently available. To overcome this problem, we developed a functional ex vivo approach to measure patients’ inherent and acquired drug resistance. This method, which we termed myeloma drug sensitivity testing (My-DST), uses unselected bone marrow mononuclear cells with a panel of drugs in clinical use, followed by flow cytometry to measure myeloma-specific cytotoxicity. We found that using whole bone marrow cultures helped preserve primary MM cell viability. My-DST was used to profile 55 primary samples at diagnosis or at relapse. Sensitivity or resistance to each drug was determined from the change in MM viability relative to untreated control samples. My-DST identified progressive loss of sensitivity to immunomodulatory drugs, proteasome inhibitors, and daratumumab through the disease course, mirroring the clinical development of resistance. Prospectively, patients’ ex vivo drug sensitivity to the drugs subsequently received was sensitive and specific for clinical response. In addition, treatment with

© The Author(s)., Background: Multiple myeloma (MM) patients with high cytogenetic risk have poor outcomes. In CASTOR, daratumumab plus bortezomib/dexamethasone (D-Vd) prolonged progression-free survival (PFS) versus bortezomib/dexamethasone (Vd) alone and exhibited tolerability in patients with relapsed or refractory MM (RRMM). [Methods]: This subgroup analysis evaluated D-Vd versus Vd in CASTOR based on cytogenetic risk, determined using fluorescence in situ hybridization and/or karyotype testing performed locally. High-risk patients had t(4;14), t(14;16), and/or del17p abnormalities. Minimal residual disease (MRD; 10-5 sensitivity threshold) was assessed via the clonoSEQ® assay V2.0. Of the 498 patients randomized, 40 (16%) in the D-Vd group and 35 (14%) in the Vd group were categorized as high risk. [Results]: After a median follow-up of 40.0 months, D-Vd prolonged median PFS versus Vd in patients with standard (16.6 vs 6.6 months; HR, 0.26; 95% CI, 0.19-0.37; P < 0.0001) and high (12.6 vs 6.2 months; HR, 0.41; 95% CI, 0.21-0.83; P = 0.0106) cytogenetic risk. D-Vd achieved deep responses, including higher rates of MRD negativity and sustained MRD negativity versus Vd, regardless of cytogenetic risk. The safety profile was consistent with the overall population of CASTOR. [Conclusion]: These updated data reinforce the effectiveness and tolerability of daratumumab-based regimens for RRMM, regardless of cytogenetic risk status. Trial registration: ClinicalTrials.gov, NCT02136134. Registered 12 May 2014, This CASTOR study was sponsored by Janssen Research & Development, LLC. Open access funding provided by Projekt DEAL.

Administration of granulocyte colony-stimulating factor (G-CSF) after autologous peripheral blood stem cell transplantation (PBSCT) is generally recommended to reduce the duration of severe neutropenia; however, there is limited and conflicting data regarding the optimal timing of G-CSFs post-transplant. A retrospective study was performed at NewYork-Presbyterian/Weill Cornell Medical Center (NYP/WC) from November 5, 2013 to August 9, 2016 of adult inpatient autologous PBSCT patients who received G-CSF empirically starting on day +5 (early) versus day +12 only if absolute neutrophil count (ANC) was

Introduction Therapeutic options for multiple myeloma (MM) are growing, yet clinical outcomes remain heterogeneous. Cytogenetic analysis and disease staging are mainstays of risk stratification, but data suggest a complex interplay between numerous abnormalities. Myeloma cell proliferation is a metric shown to predict outcomes, but available methods are not feasible in clinical practice. Patients and Methods Multiplex immunohistochemistry (mIHC), using multiple immunostains simultaneously, is universally available for clinical use. We tested mIHC as a method to calculate a plasma cell proliferation index (PCPI). By mIHC, marrow trephine core biopsy samples were costained for CD138, a plasma cell–specific marker, and Ki-67. Myeloma cells (CD138 + ) were counted as proliferating if coexpressing Ki-67. Retrospective analysis was performed on 151 newly diagnosed, treatment-naive patients divided into 2 groups on the basis of myeloma cell proliferation: low (PCPI ≤ 5%, n = 87), and high (PCPI > 5%, n = 64). Results Median overall survival (OS) was not reached versus 78.9 months ( P = .0434) for the low versus high PCPI groups. Multivariate analysis showed that only high-risk cytogenetics (hazard ratio [HR] = 2.02; P = .023), International Staging System (ISS) stage > I (HR = 2.30; P = .014), and PCPI > 5% (HR = 1.70; P = .041) had independent effects on OS. Twenty-three (36%) of the 64 patients with low-risk disease (ISS stage 1, without high-risk cytogenetics) were uniquely reidentified as high risk by PCPI. Conclusion PCPI is a practical method that predicts OS in newly diagnosed myeloma and facilitates broader use of MM cell proliferation for risk stratification.

Duration of initial disease response remains a strong prognostic factor in multiple myeloma (MM) particularly for upfront autologous hematopoietic cell transplant (AHCT) recipients. We hypothesized that new drug classes and combinations employed prior to AHCT as well as after post-AHCT relapse may have changed the natural history of MM in this population. We analyzed the Center for International Blood and Marrow Transplant Research database to track overall survival (OS) of MM patients receiving single AHCT within 12 months after diagnosis (N=3,256) and relapsing early post-AHCT (1 line of induction and lack of maintenance. Post-AHCT early relapse remains a poor prognostic factor, even though outcomes have improved over time.

Background Cluster of differentiation 46 (CD46) is highly expressed in multiple myeloma, especially in patients (pts) with gain of chromosome 1q and in the refractory setting. In vitro studies show upregulation and enhanced cytotoxicity upon treatment with pomalidomide, dexamethasone or lenalidomide. FOR46, an anti-CD46 antibody-drug conjugate with vc-MMAE, recognizes a tumor selective epitope of CD46 and is taken up by malignant cells by macropinocytosis, which is a relatively tumor selective uptake mechanism. Methods Pts with MM were enrolled who had progressed on proteasome inhibitors, immunomodulatory drugs and CD38-targeted therapies. An accelerated titration followed by 3+3 dose escalation design was used. FOR46, at protocol specified doses, was infused intravenously over 30-60 minutes on Day 1 of 21-day cycles. Following excess toxicity (neutropenia and fatigue) in a patient (pt) with high body mass index (BMI), dosing was changed from actual weight (AW) to adjusted body weight (ABW). G-CSF secondary prophylaxis was required for pts experiencing grade (gr) ≥ 3 neutropenia during a previous treatment cycle. The initial protocol had 2.4 mg/kg AW as the highest dose. When the MTD was not defined using ABW dosing, escalation was held pending protocol amendment to allow a higher dose and expansion to 10 patients at 2.4 mg/kg ABW began. Safety was evaluated using CTCAE v5.0 and efficacy was evaluated per IMWG criteria. Dexamethasone was only allowed for infusion reaction prophylaxis. CD46 antigen density was determined on patient MM cells via flow cytometry. Results Fifteen pts were enrolled at 6 pre-defined dose levels from 0.1 to 2.4 mg/kg with 1 patient each at the 0.1, 0.3 and 0.6 mg/kg dose levels, 3 at 1.2 and 1.8 mg/kg and 6 at 2.4 mg/kg. Median age was 68 (range 33 – 79) with 4 females. Gain 1q was present in 9 pts, absent in 5 pts and unknown in 1. The median number of prior lines of therapy was 6 (range 3-17). The only dose-limiting toxicity (DLT) was gr 4 neutropenia in 1 high BMI patient dosed by AW. This was the only DLT among 6 pts at 2.4 mg/kg dosed by a mix of AW (n=3) and ABW (n=3). One of 3 at 2.4 mg/kg ABW had non-dose limiting gr 4 neutropenia. The most common related adverse event was gr 4 neutropenia in 3 pts (20%). One patient (6.7%) had gr 4 thrombocytopenia and 1 each (6.7%) had gr 3 AST elevation, neutropenia, anemia, nausea, and peripheral neuropathy (PN). Of the 6 response-evaluable pts in the 1.8 and 2.4 mg/kg cohorts, 3 had partial responses (PRs) lasting 21, 30, and 15 weeks, respectively. Of the PRs, 1 pt did not have gain of 1q21. In addition to the fifteen pts in dose escalation cohorts, 10 have been enrolled in an expansion cohort at 2.4 mg/kg by ABW. Conclusion FOR46 demonstrates an acceptable toxicity profile using ABW dosing. There is encouraging evidence of efficacy in triple refractory MM. A protocol amendment allowing additional dose escalation to 2.7 mg/kg by ABW has been approved. NCT03650491

Background: Daratumumab-refractory multiple myeloma (MM) patients have limited treatment options and a dire prognosis. Daratumumab (Dara) targets the overexpressed myeloma antigen CD38, and its mechanism of resistance has been partially associated with downregulation of CD38 expression (Nijhof et al. Blood, 2016). Dara is a key agent in the relapsed setting and is being integrated into upfront treatment. In addition, isatuximab (Isa) has become the second FDA-approved anti-CD38 monoclonal antibody (mAb). Thus, when and how patients can be retreated with this important drug-class has become a critical question. We developed a platform for measuring drug efficacy ex vivo, including mAbs, termed Myeloma Drug Sensitivity Testing (My-DST) (Walker et al. Blood Advances, 2020). Here, we addressed whether My-DST could determine if retreatment with the anti-CD38 mAbs Dara and Isa can be effective in patients that had previously developed Dara-resistance. Methods: Bone marrow aspirates were obtained from the hematologic tissue bank (HTB) from patients at the University of Colorado Blood Cancer Program after informed consent and IRB approval. Mononuclear cells (MNCs) were isolated by Ficoll density gradient centrifugation, cells incubated for 48 h with 20 nM Dara, Isa and untreated controls in triplicate wells. Flow cytometry was performed on a BD FACSCelesta. To identify the viable MM population, samples were stained with fluorophore-conjugated mAbs to CD38, CD138, CD45, CD19, CD56 and CD46. Stained samples were washed and resuspended in Live/Dead dye Near-IR. Results were analyzed through FlowJo and Graphpad Prism software. Results: My-DST for Dara (20 nM) cytotoxicity has been performed in 67 patients, 52 of which were Dara-naïve and 15 of which were clinically Dara-refractory. Of Dara-naïve patients, 38/52 (73%) showed >20% reduction in viable MM cells whereas only 3/15 (20%) of the Dara-refractory patients showed >20% decrease (Fig 1A). Provocatively, the patients that showed potential "re-sensitization" had been off Dara for >12 months, and there was a significant correlation between response to Dara and months off treatment (r= -0.5096, p= 0.0457, Fig 1B). Furthermore, we evaluated two timepoints in one of the responders (HTB1749), and the later sample (HTB1749.3) showed a deeper response, further supporting the correlation. Surprisingly, in Dara-refractory patients the median CD38 expression was not significantly different between the three ex vivo responders and those who did not respond (p = 0.439, Fig 1C). Isa was tested in seven of the Dara-refractory patient samples, showing >20% decrease in viable MM cells in five, of which three did not respond ex vivo to Dara (Fig 1D). Interestingly, the Isa responders were only off Dara treatment for an average of 7.5 months. We further investigated HTB1059.3 and HTB1749.2, which responded to Dara, and found that these patients had multiple distinct MM cell subpopulations with different levels of CD38 expression, with the subpopulation with higher CD38 MFI accounting for the decreased viability (Fig 1E-F). When we compared HTB1059.3 with a prior sample available, these differential populations were not present before Dara treatment (data not shown), indicating these subpopulations evolved after treatment. Likewise, the same phenomenon of subpopulations with differential CD38 expression was observed in the Dara-refractory patients who responded to Isa (Fig 1G-H). Conclusion: These data support the possibility of retreatment with anti-CD38 mAbs in patients who once became refractory to Dara. Although our findings need to be confirmed with additional samples, they suggest that Isa may have efficacy earlier in this setting, supporting an approach to switch agents when retreating with this drug class. Anti-CD38 mAb sensitivity in the Dara-refractory population appears to be heavily influenced by the different CD38 expression levels on the heterogeneous MM cell subpopulations that emerge when a patient is off Dara for a period of time. Furthermore, My-DST with anti-CD38 mAbs may be applied to help guide the treatment approach in this population. Still, the presence of CD38-low subpopulations in these patients may represent resistant cells that shorten the remission times on retreatment. Thus, the combination drug partner choice will likely be critical to successfully optimizing depth and duration of response in Dara-refractory patients. Figure 1 Disclosures Forsberg: Genentech, Inc., Sanofi, Karyopharm, Abbvie: Research Funding; Celgene: Speakers Bureau. Mark:Bristol-Myers Squibb: Research Funding; Janssen: Research Funding; Celgene: Consultancy; Amgen: Consultancy; Kayopharm: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Sherbenou:Oncopeptides Inc.: Research Funding.

Introduction: Despite the progress that has been made for standard risk multiple myeloma (MM), subsets of patients with the most advanced and aggressive plasma cell dyscrasias still suffer comparatively poor outcomes. One example is plasma cell leukemia (PCL), which carries a median overall survival of under two years. For patients with PCL, response to front line therapy occurs but is often short-lived, ultimately giving way to aggressive multi-drug resistant disease and patient mortality. Thus, there is a need for the development of new strategies that improve the prognoses for these patients. Melflufen (melphalan flufenamide) is a first-in-class peptide-drug conjugate that is currently in late-phase clinical trials for multiple myeloma. This highly lipophilic agent is preferentially retained in malignant plasma cells (MPCs), where overexpressed aminopeptidases lead to trapping of the alkylator melphalan. We evaluated the anti-myeloma effects of melflufen on patient samples treated ex vivo, and found pronounced sensitivity to melflufen in most samples, with particularly potent efficacy in PCL samples. Methods: Bone marrow aspirate or peripheral blood samples were obtained from patients with plasma cell disorders after IRB approval and informed consent. Ex vivo efficacy of melflufen and melphalan were compared using our Myeloma Drug Sensitivity Testing (My-DST) platform that optimizes viability and tests the malignant cells in the context of the normal cells from their microenvironment (Walker et al, Blood Advances, 2020). In brief, mononuclear cells from patients with plasma cell dyscrasia, including MM and PCL, were isolated and cultured in triplicate wells with titrations of melphalan, melflufen or untreated controls for 48 hours. Post-treatment survival was measured by high-throughput flow cytometry with antibodies for CD138, CD38, CD45 and CD19, and a live/dead dye to discriminate viable MPCs from normal bone marrow cells. EC50 values were determined from these titrations using nonlinear regression curve fits. When the EC50 for melflufen was established in My-DST, a single dose concentration of 10 nM was used to screen patient samples and distinguish relative sensitivity or resistance. Results: Using the My-DST approach with 48 hour drug treatments, melflufen significantly decreased the viable MPC populations, whereas melphalan had little effect (Fig 1A). Concurrent titrations revealed significantly higher MPC sensitivity to melfufen (mean melphalan EC50 = not reached, mean melflufen EC50 = 22.9 nM) (Fig 1B). By comparison to another alkylator, cyclophosphamide's active metabolite has an EC50 of 3.75 µM in this assay. Response to melflufen was accentuated in 2/3 PCL samples tested (HTB-1802.1, HTB-1389.1), with the EC50 < 1nM (Fig 1B). Melflufen demonstrated toxicity in CD45 positive white blood cells, which is consistent with neutropenia observed in clinical trials (data not shown). In single dose screening studies in additional MM patient samples, 4/8 (50%) showed >20% decrease in viable MPCs after incubation with melflufen at 10 nM (Fig 1C). Overall, using those parameters for ex vivo "response" to meflufen, 3/3 patients with PCL responded, 5/6 patients with del(17p) responded, and 3/3 patients with c-MYC translocations responded (Fig 1C, italics). In addition, 3/5 samples from patients that were clinically daratumumab-refractory displayed sensitivity to melflufen. Of five samples from patients with prior exposure to alkylators, four were sensitive to melflufen. Conclusion: Overall, these data support that the peptide-drug-conjugate melflufen shows a broad efficacy across samples from patients with plasma cell disorders. Patients facing poor prognoses, including those with PCL, high-risk cytogenetics and daratumumab-refractory disease, have a great need for new treatments. Thus, the encouraging ex vivo results with melflufen in samples from these aggressive subsets support further clinical exploration. In particular, our preliminary data suggest that plasma cell leukemia patients may be exquisitely sensitive to melflufen. To follow-up these findings, we will expand the number of samples tested from PCL and other forms of high-risk MM samples. Ultimately, if the trend for accentuated sensitivity in plasma cell leukemia holds, a clinical approach for melflufen in these patients may improve outcomes for this group. Figure 1 Disclosures Lockerbie: Oncopeptides AB: Current Employment. Flanagan:Oncopeptides AB: Current Employment. Lehmann:Oncopeptides AB: Current Employment. Forsberg:Celgene: Speakers Bureau; Genentech, Inc., Sanofi, Karyopharm, Abbvie: Research Funding. Mark:Takeda: Consultancy; Kayopharm: Consultancy; Bristol-Myers Squibb: Research Funding; Janssen: Research Funding; Celgene: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Sherbenou:Oncopeptides Inc.: Research Funding.

Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is characterized by lymphoplasmacytic proliferation, lymph node and spleen enlargement, bone marrow involvement, and immunoglobulin M production. Treatment varies based on the extent and biology of disease. In some patients, the use of allogeneic hematopoietic cell transplantation (alloHCT) may have curative potential. We evaluated long-term outcomes of 144 patients that received adult alloHCT for WM/LPL. Data was obtained from the Center for International Blood and Marrow Transplant Research database (2001-2013). Patients received myeloablative (n=67) or reduced intensity conditioning (RIC; n=67). Median age at alloHCT was 53 years, and median time from diagnosis to transplantation was 41 months. Thirteen percent (n=18) failed prior autologous hematopoietic cell transplantation. About half (n=82, 57%) had chemo-sensitive disease at the time of transplantation, while 22% had progressive disease. Progression free survival, overall survival, rate of relapse, and non-relapse mortality at 5-years were 46%, 52%, 24%, and 30% respectively. Patients with chemo-sensitive disease and better pre-transplant disease status experienced significantly superior overall survival. There were no significant differences in progression-free survival based on conditioning (myeloablative 50% vs. RIC 41%) or graft source. Conditioning intensity did not impact treatment-related mortality or relapse. The most common causes of death were primary disease and graft-versus-host disease (GVHD). AlloHCT yielded durable survival in select patients with WM/LPL. Strategies to reduce mortality from GVHD and post-transplant relapse are necessary to improve this approach.

High-dose melphalan (MEL200) followed by autologous stem cell transplantation (ASCT) remains a standard of care for multiple myeloma (MM). Bendamustine induces responses in MM resistant to other alkylators. Our prior Phase I trial adding bendamustine to MEL200 transplant conditioning resulted in no additional toxicity. We now report a single-arm, phase II study that evaluated the efficacy of bendamustine 225 mg/m

Management of relapsed and refractory multiple myeloma (RRMM) remains challenging given the clinical and genetic heterogeneity of disease in this setting and the increasing therapeutic options that...

The Revised International Staging System (R-ISS) and the International Myeloma Working Group 2014 (IMWG 2014) are newer staging systems used to prognosticate multiple myeloma (MM) outcomes. We hypothesized that these would provide better prognostic differentiation for newly diagnosed multiple myeloma (MM) compared with ISS. We analyzed the Center for International Blood and Marrow Transplant Research database from 2008 to 2014 to compare the 3 systems (N = 628) among newly diagnosed MM patients undergoing upfront autologous hematopoietic cell transplantation (AHCT). The median follow-up of survivors was 48 (range, 3 to 99) months. The R-ISS provided the greatest differentiation between survival curves for each stage (for overall survival [OS], the differentiation was 1.74 using the R-ISS, 1.58 using ISS, and 1.60 using the IMWG 2014) . Univariate analyses at 3 years for OS showed R-ISS I at 88% (95% confidence interval [CI], 83% to 93%), II at 75% (95% CI, 70% to 80%), and III at 56% (95% CI, 3% to 69%; P < .001). An integrated Brier score function demonstrated the R-ISS had the best prediction for PFS, though all systems had similar prediction for OS. Among available systems, the R-ISS is the most optimal among available prognostic tools for newly diagnosed MM undergoing AHCT. We recommend that serum lactate dehydrogenase and cytogenetic data be performed on every MM patient at diagnosis to allow accurate prognostication.

The addition of clarithromycin enhances the efficacy of lenalidomide plus dexamethasone in treatment-naive multiple myeloma (MM). We conducted a phase 2 trial to evaluate the safety and efficacy of clarithromycin, pomalidomide, and dexamethasone (ClaPd) in relapsed or refractory multiple myeloma (RRMM) with prior lenalidomide exposure. One hundred twenty patients with a median of 5 prior lines of therapy received clarithromycin 500 mg orally twice daily, pomalidomide 4 mg orally on days 1 to 21, and dexamethasone 40 mg orally on days 1, 8, 15, and 22 of a 28-day cycle. The overall response rate (ORR) was 60% with 23% achieving at least a very good partial response. There was no statistical difference in response rates for patients who were refractory to lenalidomide (ORR, 58%), bortezomib (ORR, 55%), or both lenalidomide and bortezomib (ORR, 54%). Median progression-free survival (PFS) for the cohort was 7.7 months and median overall survival (OS) was 19.2 months. A history of dual-refractoriness to lenalidomide and bortezomib did not significantly impact either PFS or OS. The most common toxicities were neutropenia (83%), lymphopenia (74%), and thrombocytopenia (71%). The most common grade ≥3 toxicities included neutropenia (58%), thrombocytopenia (31%), and anemia (28%). ClaPd is an effective combination in RRMM with response and survival outcomes that are independent of lenalidomide- or bortezomib-refractory status. Toxicities are manageable with low rates of nonhematologic or high-grade events. ClaPd is a convenient, all-oral option in RRMM with comparable efficacy to other highly active, 3-drug, pomalidomide-based combinations. This trial was registered at www.clinicaltrials.gov as #NCT01159574.

Background: Clinical response data from trials of investigational agents performed over the past several years in various B-cell malignancies has demonstrated significant improvements in the treatment of these diseases. Despite greatly improved overall response rates, a subset of patients relapses in the short-term while others enjoy prolonged disease-free intervals. These short-term relapses are attributable to residual tumor cells after treatment, but at levels too low for detection by standard clinical assessments. Minimal residual disease (MRD) has emerged as a highly sensitive response assessment tool to measure tumor cells present at a level of 1:10,000 cells or lower via a variety of technologies and platforms. The clonoSEQ® Assay has been cleared by the Food and Drug Administration to detect MRD in the bone marrow of patients with acute lymphoblastic leukemia (ALL) and multiple myeloma (MM) and in either blood or bone marrow for patients with chronic lymphocytic leukemia (CLL). The clonoSEQ Assay can also be used as a laboratory developed test (LDT) to detect MRD in other B-cell malignancies including non-Hodgkin lymphoma (NHL) and in additional sample types such as blood and plasma. Methods: The clonoSEQ Assay utilizes multiplex polymerase chain reaction (PCR) and next generation sequencing (NGS) to identify frequency and distribution of clonal sequences associated with a malignant lymphocyte population in an individual patient sample. The principle of this assay is based on the identification of rearranged IgH (VDJ), IgH (DJ), IgK, and IgL receptor gene sequences, as well as translocated BCL1/IgH (J) and BCL2/IgH (J) sequences. The sensitivity of the assay is < 1:1,000,000 when provided sufficient sample input. The Watch Registry is a prospective, multicenter observational study being conducted in the U.S. and is collecting data from health care providers who use the clonoSEQ Assay as part of routine clinical practice for their patients with ALL, MM, CLL, and NHL. Data collection is focused on the rationale for clonoSEQ Assay use and the subsequent treatment decisions by participating investigators in order to better understand the implementation and impact of this assay in the standard care of hematologic malignancies. The Watch Registry will also evaluate changing practice patterns over a period of at least 3 years. Patients are eligible if they are ³ 18 years old, have been diagnosed with NHL, MM, ALL, or CLL, are not simultaneously enrolled in an interventional clinical study, and their treating physician is currently or will be using clonoSEQ to monitor their disease burden over the course of the study. Patients may be in any phase of treatment at the time of enrollment. Planned enrollment is 528 patients in order to achieve a target of 476 who have their initial baseline sample plus at least one MRD tracking sample during the course of the study. The study will collect data on an ongoing basis for approximately 3 years in order to longitudinally understand the utilization of the clonoSEQ Assay and the impact this MRD assessment tool has on clinical care. The primary endpoint of the study is the assessment of the physicians' rationale for MRD testing with clonoSEQ, and the secondary endpoint is the assessment of how those MRD results inform and impact treatment decisions. For each clonoSEQ MRD test ordered, an eCRF questionnaire will capture the rationale for that order (e.g., patient is at end of induction, post-hematopoietic cell transplantation (HCT), monitoring during maintenance, etc) as well as any decisions made regarding patient treatment based upon those results (e.g., patient moved to maintenance therapy, patient will undergo HCT, next line of therapy initiated, etc). Changes in therapeutic regimens will be captured for each patient whether or not those changes are made based upon clonoSEQ results. The Watch Registry is anticipated to begin enrollment in Q3 2020. A ClinicalTrials.gov post will be submitted prior to study opening. Disclosures Patel: Adaptive Biotechnologies, AstraZeneca, Pharmacyclics, Janssen, Genentech, Celgene/BMS, BeiGene, Kite: Consultancy. Gasparetto:Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Sanofi: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria. Mark:Genzyme: Consultancy; BMS: Consultancy; Adaptive Biotechnologies: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Shah:Kite/Gilead, Jazz, Incyte: Research Funding; Kite/Gilead, Celgene/Juno/BMS, Novartis, Pfizer, Amgen, Spectrum/Acrotech, Precision Biosciences, Beigene, AstraZeneca, Pharmacyclics/Jansen, Adaptive: Honoraria; Moffitt Cancer Center: Current Employment; NCCN: Vice-Chair, Acute Lymphoblastic Leukemia Working Group: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Precision Biosciences, Novartis, AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Svoboda:AstraZeneca: Consultancy; Seattle Genetics: Consultancy; Imbrium: Consultancy; Atara: Consultancy; Adaptive Biotechnologies: Consultancy; Genmab: Consultancy; BMS: Consultancy. Thompson:Denovo: Honoraria; UpToDate: Other; AIM Specialty Health: Consultancy; Doximity: Other; LynxBio: Honoraria; VIA Oncology (now Elsevier Clinical Path): Consultancy; Adaptive Biotechnologies: Consultancy; Lilly: Honoraria; Takeda: Consultancy, Honoraria; TG Therapeutics: Honoraria; GSK: Consultancy; Strata Oncology: Honoraria; Syapse Precision Medical Council: Consultancy; Abbvie: Honoraria; BMS/Calgene: Consultancy, Honoraria; CRAB CTC: Honoraria; Hoosier Research Network: Honoraria. Simmons:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Schliekelman:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Jacob:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Baldo:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company.

Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (45 chromosomes excluding -Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher compared with non-HRM (56% versus 43%, P .001) with similar pretransplant complete response (CR) rates (14% versus 16%, P .1). At day 100 post-transplant, at least a very good partial response was 59% in HRM and 61% in non-HRM (P = .6). More HRM patients received post-transplant therapy with bortezomib and imids (26% versus 12%, P = .004). Three-year post-transplant progression-free (PFS) and overall survival (OS) rates in HRM versus non-HRM were 37% versus 49% (P .001) and 72% versus 85% (P .001), respectively. At 3 years, PFS for HRM patients with and without post-transplant therapy was 46% (95% confidence interval [CI], 33 to 59) versus 14% (95% CI, 4 to 29) and in non-HRM patients with and without post-transplant therapy 55% (95% CI, 49 to 62) versus 39% (95% CI, 32 to 47); rates of OS for HRM patients with and without post-transplant therapy were 81% (95% CI, 70 to 90) versus 48% (95% CI, 30 to 65) compared with 88% (95% CI, 84 to 92) and 79% (95% CI, 73 to 85) in non-HRM patients with and without post-transplant therapy, respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM (P = .08). In addition to HRM, higher stage, less than a CR pretransplant, lack of post-transplant therapy, and African American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day 100 post-transplant responses compared with non-HRM patients, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM.

Carfilzomib and dexamethasone (Kd) has significant activity in relapsed and refractory multiple myeloma. Kd has not previously been evaluated in newly diagnosed multiple myeloma (NDMM). We report a single-arm phase 2 study of 72 patients with NDMM to evaluate the efficacy and tolerability of Kd induction. Carfilzomib was administered in two dosing cohorts with dosing of 20/45 mg/m2 in the first 25 patients and 20/56 mg/m2 in the subsequent 47 patients. Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle, dexamethasone 20 mg was administered orally on days 1, 2, 8, 9, 15, 16, 22 and 23. Treatment was continued to maximum response, progression of disease, or regimen intolerability. Endpoints included overall response rate (ORR), regimen toxicity and impact of carfilzomib on CD34+ stem cell collection yield. Sixty-five pts achieved at least a partial response (PR) for an ORR of 90%. The maximum response achieved was complete response or better in 5 (7%), very good partial response (VGPR) in 42 (58%), PR in 18 (25%) and stable disease in 7 pts (10%). Toxicities were predominantly low grade with 547 grade 1/2 adverse events and 44 grade ≥3 events. The rate of grade ≥3 cardiovascular adverse events was 11.1% with eight observed events. The activity of Kd described represents the highest rate of overall response and ≥VGPR for any 2-agent combination in NDMM reported to date. Kd demonstrated a safety profile consistent with previously reported carfilzomib studies.

Introduction: The prognosis of patients with multiple myeloma (MM) who are resistant to proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) is extremely poor. Even daratumumab and BCMA CAR-T cell therapies appear to provide only temporary benefit before patients eventually succumb to their disease. We show that protein translation is upregulated in MM cells. We also demonstrate that translational inhibition with omacetaxine (Oma) is specifically cytotoxic in a manner that is preserved in MM cells from PI/IMiD resistant patients. Furthermore, protein translation inhibition is synergistic with IMiDs, even in IMiD refractory patients. We hypothesize these findings stem from the origin of MM cells as professional antibody secretory cells, with highly active protein translation fundamental to their biology. Here, we show these findings and provide support to test the translation inhibitor omacetaxine with a clinical trial in multiple myeloma patients. Methods: Primary MM cells in mononuclear cell (MNC) cultures were assayed ex vivo for Oma effect at 48-hrs by high-throughput flow cytometry using our myeloma drug sensitivity testing (My-DST) platform. Protein synthesis rates were measured via flow cytometry using the Cayman OP-puromycin assay. Initial drug combination matrices were performed in MM cell lines via MTS assay after 96-hr incubation. Cell line xenograft study of the Oma and IMiD combination in vivo were performed using an orthometastatic MM model with MM1.S luciferase-expressing cells injected IV in NSG mice. Vehicle control, Oma, pomalidomide (Pom) and the combination were dosed 5 days/week by IP injection beginning on day 30. Disease burden was monitored with imaging of luciferase bioluminescence. Results: Oma had specific cytotoxicity across 5 MM cell lines (EC50 = 15-35 nM, data not shown). Oma also showed MM cell specific cytotoxicity in patient samples with EC50 ranging from 25-100 nM (Fig 1A). Ex vivo treatment with 50 nM Oma for 48 hrs caused >50% reduction in viable MM cells in 39/50 (78%) patient samples. Importantly, 50 nM Oma retained activity in PI/IMiD-refractory patients compared to sensitive patients (64.2% vs 71.6% mean decrease in MM cell viability, respectively, P = 0.44, Fig 1B). Primary MM cells exhibited significantly higher levels of baseline protein translation than other bone marrow MNCs with mean 3.9-fold increase (n = 14, P = Conclusion: Protein translation inhibitors represent a potential new drug class for clinical myeloma treatment. We have shown that the protein synthesis inhibitor omacetaxine possesses a potent and specific killing effect against MM cells. Importantly, this anti-myeloma cytotoxicity was equally active in biopsy samples obtained from patients at diagnosis and patients with disease advanced to the late stage of PI/IMiD resistance. The pretreatment level of MM cell protein translation may serve as a biomarker for clinical response. In further exploration of the optimized treatment approach for clinical trials, we found synergy between omacetaxine and pomalidomide in vitro, in vivo and using patient samples ex vivo. A phase I clinical trial of omacetaxine single agent and in combination with pomalidomide is currently in development at the University of Colorado. Disclosures Mark: Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria.

Background: Autologous hematopoietic stem cell transplantation (ASCT) is the current standard of care in patients with multiple myeloma (MM) to support reconstitution of the bone marrow after myeloablative chemotherapy. Mobilization of blood progenitor cells to the peripheral circulation is stimulated via administration of granulocyte colony-stimulating factor (G-CSF) with or without chemotherapy. The addition of chemotherapy, typically cyclophosphamide, increases the yield of peripheral blood stem cells (also known as CD34+ cells) at the expense of additional toxicity. The unpredictability of harvest yield and the potential need for weekend apheresis sessions complicates mobilization planning when using chemotherapy. Plerixafor, a CXCR4 antagonist, in combination with G-CSF has been shown to be superior to G-CSF alone, leading to higher CD34+ yields in fewer apheresis sessions [Giralt et al, 2014]. However, the advantage of the combination of plerixafor with G-CSF is less well described in the context of new treatment options that can impair stem cell harvest yields when using G-CSF as the sole mobilization agent. Objective: The primary objective of this study was to determine clinical outcomes associated with G-CSF alone vs G-CSF + chemomobilization vs G-CSF + plerixafor from initiation of mobilization until 6 to 12 months after ASCT. Method: This is a retrospective study in patients with MM, carried out at 10 centers in the US. Patients were eligible if ≥ 18 years and undergoing first ASCT (≤ 12 months from initial diagnosis and no disease progression). Eligible patients were identified through a database query of hospital records of oncology patients diagnosed with MM and eligible for ASCT before June 2016. Patients fulfilling inclusion and exclusion criteria were attributed to three treatment arms depending on the mobilization regimen received:Arm 1: G-CSF + plerixaforArm 2: G-CSF + chemomobilizationArm 3: G-CSF Patients will be selected until 170 patients are assigned to each treatment arm or patient records are exhausted. Demographics, induction regimen, mobilization regimens and outcomes, apheresis, transplantation outcomes and survival status were extracted from medical charts and entered in the electronic case report form. Here, we present interim results from data collected at three centers as of June 24, 2019. Results: At the interim analysis cut-off date, 130 patients were included in the database (G-CSF: 52; G-CSF + plerixafor: 78; G-CSF + chemomobilization: 0). Demographic and baseline characteristics were comparable between the two treatment arms. More male patients were included (male: 63%, female: 37%) and the mean age was 58 and 59 years in the G-CSF and G-CSF + plerixafor groups, respectively (Table 1). Disease stage and the proportion of patients with poor-, intermediate- and high-cytogenetic risk status were similar in the two treatment groups. Few patients had a complete response (CR) after chemotherapy, but response rate (CR + partial response) was 91% in both treatment arms. The burden of apheresis in terms of number of sessions and blood volume processed was lower in patients receiving G-CSF + plerixafor compared with patients receiving G-CSF only (Table 2). CD34+ yield was higher in the G-CSF + plerixafor treatment arm, especially after the first apheresis session (Table 2). There was no difference in ASCT outcome between the two treatment groups. All patients had neutrophil engraftment except for one patient in the G-CSF only group, and all patients had platelet engraftment except one patient in each treatment group. There was no significant difference in the proportion of patients experiencing relapse between the two treatment groups at 6 and 12 months of follow-up. Overall, ≥ 90% of patients avoided relapse at 12 months. 96% and 93% of patients were still alive at 12 months in the G-CSF only and G-CSF + plerixafor treatment groups, respectively (Table 3). For the purpose of this study, safety data was not reviewed [Mozobil PI, 2019]. Conclusions: Per interim results, plerixafor reduced the burden of apheresis and increased CD34+ yields. Transplantation outcomes, relapse and overall survival at 6 and 12 months were not significantly different between the two treatment arms. Therefore, plerixafor could increase apheresis efficiency without compromising ASCT success in the context of currently used chemotherapy regimens. Disclosures Mark: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Bubalo:Sanofi: Other: Research and writing support. Barnes:Sanofi: Employment. Drea:Sanofi-Genzyme: Employment. Fausel:Sanofi-Genzyme: Other: Grant to cover costs of data collection.