Impact of extramedullary multiple myeloma on outcomes with idecabtagene vicleucel.

Idecabtagene vicleucel (Ide-cel) has demonstrated excellent efficacy and durable responses in patients with relapsed/refractory multiple myeloma (RRMM). However, the outcomes with ide-cel in patients with extramedullary disease (EMD) remain incompletely characterized. We included patients with RRMM treated with ide-cel between May 2021 and April 2023 across 11 US academic institutions. Visceral or soft tissue lesions non-contiguous from bone was classified as EMD. Time-to-event analyses were performed from date of ide-cel infusion. Among 351 patients, 84 (24%) had EMD prior to infusion. The median follow-up from ide-cel infusion was 18.2 months (95% CI: 17-19.3). The day 90 overall response rates (ORR) were 52% vs. 82% for the EMD and non-EMD cohorts, respectively (p < 0.001). The median progression-free survival (PFS) was 5.3 months (95% CI: 4.1-6.9) for the EMD cohort vs. 11.1 months (95% CI: 9.2-12.6; p < 0.0001) for the non-EMD cohort. In a multivariable analysis, EMD was an independent predictor of inferior PFS [hazard ratio 1.5 (1.1-2.2), p = 0.02]. The median overall survival was 14.8 months [95% CI: 9-Not reached (NR)] vs. 26.9 months (26.3 vs. NR, p = 0.006) for the EMD and non-EMD cohorts, respectively. Extramedullary disease represents an independent predictor of inferior day 90 ORR and PFS among patients treated with ide-cel.

Isatuximab-carfilzomib-dexamethasone immediately after failing of the quadruplet Daratumumab-bortezomib-lenalidomide-dexamethasone (Dara-VRD): Striking response with no washout in a newly diagnosed multiple myeloma.

Biochemical evolution of serum IgG-Kappa monoclonal component during the first line with VRD (x1), DARA-VRD (x4), and the second line with ISA-KD (x4).

Corrigendum: Protein arginine methyltransferase 1 is a therapeutic vulnerability in multiple myeloma.

[This corrects the article DOI: 10.3389/fimmu.2023.1239614.].

Protein arginine methyltransferase 1 is a therapeutic vulnerability in multiple myeloma.

Multiple myeloma (MM) is a devastating plasma cell malignancy characterized by the expansion of aberrant monoclonal plasma cells in the bone marrow, leading to severe clinical manifestations and poor prognosis, particularly in relapsed/refractory cases. Identifying novel therapeutic targets is crucial to improve treatment outcomes in these patients. In this study, we investigated the role of the protein arginine methyltransferase 1 (PRMT1) in MM pathogenesis and explored its potential as a therapeutic target. We observed that PRMT1, responsible for most asymmetric di-methylation in cells, exhibited the highest expression among PRMT family members in MM cell lines and primary MM cells. Importantly, PRMT1 expression was significantly elevated in relapsed/refractory patients compared to newly diagnosed patients. High expression of PRMT1 expression was strongly associated with poor prognosis. We found that genetic or enzymatic inhibition of PRMT1 impaired MM cell growth, induced cell cycle arrest, and triggered cell death. Treatment with MS023, a potent PRMT type I inhibitor, demonstrated a robust inhibitory effect on the viability of primary cells isolated from newly diagnosed and proteasome inhibitor-relapsed/refractory patients in a dose-dependent manner. Suppression of PRMT1 downregulated genes related to cell division and upregulated genes associated with apoptosis pathway. We also found that genes related to immune response and lymphocyte activation were significantly upregulated in PRMT1-suppressed cells. Notably, the activation status of T cells was strikingly enhanced upon co-culturing with PRMT1-KO MM cells. In vivo studies using a xenograft model revealed that targeting PRMT1 by either CRISPR/Cas9-mediated knockout or MS023 treatment significantly attenuated MM tumor growth and prolonged the survival of tumor-bearing mice. Histological analysis further confirmed increased apoptotic cell death in MS023-treated tumors. Collectively, our findings establish PRMT1 as an indispensable and novel therapeutic vulnerability in MM. The elevated expression of PRMT1 in relapsed/refractory patients underscores its potential as a target for overcoming treatment resistance. Moreover, our results highlight the efficacy of MS023 as a promising therapeutic agent against MM, offering new avenues for therapeutic approaches in relapsed/refractory MM.

Outcomes of Penta-Refractory Multiple Myeloma Patients Treated with or without BCMA-Directed Therapy.

Despite advances in treatment, outcomes remain poor for patients with penta-relapsed refractory multiple myeloma (RRMM). In this retrospective analysis, we evaluated the survival outcomes of penta-RRMM patients treated with (BCMA)- directed therapy (BDT). We identified 78 patients with penta-RRMM. Median age was 65 years, 29 (37%) had R-ISS stage III disease, 63 (81%) had high-risk cytogenetics, and 45 (58%) had extra-medullary disease. Median LOT prior to penta-refractory state was 5 (3-12). Amongst penta-RRMM, 43 (55%) were treated with BDT, 35 (45%) were not treated with BDT. Type of BDT received included belantamab mafadotin 15 (35%), Chimeric Antigen Receptor T-cell therapy 9 (21%), BCMA monoclonal antibody 6 (14%), and Bispecific T-cell engager 2 (5%). Eleven (25%) patients received more than one BDT. No significant differences were identified between baseline characteristics for the two groups. Patients treated with a BDT had better median overall survival, 17 vs. 6 months, HR 0.3 p-value < 0.001. Poor performance status, white race, and high-risk cytogenetics were associated with worse outcomes, whereas using a BDT was associated with better outcomes. Patients with penta-refractory MM have poor outcomes. Our retrospective analysis showed a significant survival benefit using BDT when compared to non-BDT for patients with penta-RRMM.

A Phase II, Open-Label Study of an Accelerated Infusion Rate of Daratumumab in Patients With Relapsed and Refractory Multiple Myeloma.

INTRODUCTION/BACKGROUND: Daratumumab is an anti-CD38 monoclonal antibody initially approved as a single agent for the treatment of relapsed and refractory multiple myeloma. The infusion-related reactions (IRRs) commonly seen with intravenous daratumumab have been managed by prolonging the first infusion, temporarily stopping/slowing the rate if reactions occur and using adequate pre- and post-infusion medications. Several retrospective studies have evaluated shorter infusions after ≥ 2 prior doses administered at the standard rates. Although the shorter infusions were well-tolerated, patients in these reports were given heterogeneous daratumumab regimens and had often already received multiple doses at the longer standard rates. PATIENTS AND METHODS: CMRG-009 is a prospective study designed to demonstrate the safety of accelerated daratumumab infusions commencing with the second dose. After an initial dose on Cycle 1 Day consisting of 8 mg/kg over 4 hours, all subsequent doses were given over 90 minutes. RESULTS: No grade 3 IRRs were observed with the 90-minutes infusions. Both the safety profile and anti-myeloma effects were otherwise similar to those observed with other single agent daratumumab studies using longer infusion times. CONCLUSION: This is the first formal prospective trial using infusion times shorter than the standard schedule directly after an initial 4-hours dose. This rapid infusion protocol has resulted in more efficient resource utilization and has become the standard protocol for the use in all intravenous daratumumab regimens in Canada. This approach has been particularly helpful in shortening chair time during the COVID-19 pandemic and providing a useful alternative in jurisdictions without access to subcutaneous daratumumab.

Clinical efficacy of retreatment of daratumumab-based therapy (D2) in daratumumab-refractory multiple myeloma.

Daratumumab demonstrates activity as a single agent and in combination with either immunomodulatory agents (IMiDs) or proteasome inhibitors (PIs) in relapsed refractory multiple myeloma (RRMM). However, little is known about the benefit of daratumumab retreatment in daratumumab-refractory MM. This study aimed to analyze the clinical efficacy of daratumumab-based retreatment (D2) in patients who are daratumumab refractory MM. Retrospectively, we identified 43 RRMM patients from a single-center database review. The median age was 65 years, 42% patients had high-risk cytogenetics, and 23% had an extramedullary disease, while the median time between D2 and prior daratumumab was 1 (0.25-39) month. All D2 patients received combination therapy with either pomalidomide, carfilzomib, bortezomib, or lenalidomide. The response rate, median progression-free, and overall survival were 49%, 7.97 and 32.6 months, respectively. Our study raises the possibility of re-utilizing daratumumab in combination with different classes of anti-myeloma drugs to generate responses in RRMM patients who are daratumumab-refractory.

Relapsed and refractory multiple myeloma: A systematic review and network meta-analysis of the efficacy of novel therapies.

The prognosis of multiple myeloma (MM) has dramatically improved with the development of new drugs, and it has become important to determine the appropriate combinations of these novel agents. This study was a systematic review and network meta-analysis (NMA) of randomized trials in patients with relapsed and/or refractory (RR) MM. The PubMed, Cochrane, and Embase databases were searched for randomized trials from 1 January 2002 to 28 February 2022 of patients treated for MM. The primary end-point was progression-free survival (PFS), evaluated as a hazard ratio (HR) with a 95% confidence interval (95% CI) compared to dexamethasone (DEX). The p-score was used to rank treatments. Of a total of 1136 abstracts screened, 37 studies were selected, including 34 treatment options for RRMM. Daratumumab, lenalidomide and DEX was found to be the best treatment for RRMM, with the best HR compared to DEX (HR, 0.13; 95% CI, 0.08-0.20; p-score 0.9796). There was no evidence of significant heterogeneity (I2 , 41.3%; p = 0.146). The current NMA confirmed the excellent efficacy of three-drug regimens including anti-CD38 antibodies to treat RRMM and provides background data to evaluate the efficacy of chimeric antigen receptor T-cell treatments and bispecific T-cell engager therapies.

Bortezomib-thalidomide-dexamethasone-cisplatin-doxorubicin-cyclophosphamide-etoposide as a Salvage and Bridging Regimen before Hematopoietic Stem Cell Transplantation for Relapsed or Refractory Multiple Myeloma.

Objective Currently, treatment of relapsed or refractory multiple myeloma is challenging. Although bortezomib-thalidomide-dexamethasone-cisplatin-doxorubicin-cyclophosphamide-etoposide (VTD-PACE), a potent combination of a proteasome inhibitor, immunomodulatory drug, and conventional chemotherapeutics, is a widely used regimen, its efficacy and safety are unclear. Methods We retrospectively analyzed the clinical data of 35 patients treated with VTD-PACE. Results The overall response rate was 65.7% (complete response, 5.7%). The median progression-free survival (PFS) and overall survival (OS) were 8.0 [95% confidence interval (CI), 0.9-15.0] and 20.0 (95% CI, 17.5-22.5) months, respectively. Twenty-two (62.9%) patients developed grade 3-4 infections, and no therapy-related deaths occurred. Sixteen of 25 patients (64%) underwent stem cell harvest successfully with more than 2.0×106/kg of CD34 cells after VTD-PACE. Twenty-two patients underwent autologous or allogeneic stem cell transplantation (SCT). The response and survival durations were short in patients without SCT after VTD-PACE [median PFS: 4.0 (95% CI, 2.7-5.3) months; OS: 14.0 (6.9-21.0) months]; however, these responses significantly improved with SCT following VTD-PACE. The PFS was 8.0 (NA) months (p=0.024), and the OS was 21.0 (19.1-22.8) months (p=0.019). Conclusion VTD-PACE is an effective and tolerable salvage regimen and feasible bridging therapy for SCT.

Guidance for Use and dosing of Selinexor in Multiple Myeloma in 2021: Consensus From International Myeloma Foundation Expert Roundtable.

Selinexor is a first in class selective inhibitor of nuclear export (SINE), blocks exportin 1 (XPO1), a protein transporter, that among other actions, shuttles cargo proteins such as tumor suppressor proteins (TSPs), the glucocorticoid receptor (GR), and oncoprotein messenger RNAs (mRNAs) across the nuclear membrane to cytoplasm. By blocking XPO1, selinexor facilitates nuclear preservation and activation of TSPs, and prevents mRNA translation of the oncoproteins leading to induction of apoptosis. The therapeutic value of selinexor in combination with dexamethasone has been successfully demonstrated in treating relapsed and/or refractory myeloma (RRMM), leading to the Food and Drug Administration (FDA) approval of selinexor in combination with dexamethasone in 2019 for the treatment of adult patients with RRMM who received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody (mAb) - a pentarefractory myeloma. More recently, selinexor in combination with bortezomib and dexamethasone was approved by the FDA in December 2020, based on the BOSTON study among RRMM patients who had received at least one prior line of therapy. With more available safety and efficacy data supporting the increased interval between dosing of selinexor (and lesser cumulative weekly dosing) and schedule, contrary to the originally approved dose of 160 mg per week, the supportive care guidelines needed to be revisited. The current manuscript summarizes the supportive care solutions with weekly dosing of selinexor and identifies the ideal potential patient for selinexor treatment.

Idecabtagene vicleucel (ide-cel) CAR T-cell therapy for relapsed and refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel), a novel chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA), has recently gained approval by the US FDA for relapsed and refractory multiple myeloma (RRMM) after multicenter trials have demonstrated unprecedented results in this difficult-to-treat subgroup of patients. As the first CAR T-cell product approved for myeloma, ide-cel is poised to become a practice-changing treatment option. This first-in-class therapeutic offers hope for more durable remissions, as well as better quality of life, following a single infusion in a group of patients that previously had little hope. This paper reviews the ide-cel product in terms of design, pharmacology, efficacy and toxicity as described in studies reported to date.

Lay abstract Idecabtagene vicleucel (ide-cel) is a novel therapy using a patient's own T cells that have been genetically modified to force them to recognize a target antigen called BCMA that is present on myeloma and plasma cells but not on other normal cells. This therapy, known as CAR T-cell therapy, has recently gained approval by the US FDA for relapsed multiple myeloma after clinical trials have demonstrated unprecedented results in this difficult-to-treat subgroup of patients who have failed at least four prior lines of therapy. As the first CAR T-cell product approved for myeloma, ide-cel is poised to become a practice-changing treatment option. This first-in-class therapeutic offers hope for more durable remissions, as well as a longer and better quality of life, following a single infusion. This paper reviews the ide-cel product in terms of design, pharmacology, efficacy and toxicity as described in studies reported to date.

Retrospective Study of Carfilzomib-Pomalidomide-Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients in a Tertiary Care Hospital in India.

Carfilzomib is a second-in class Proteosome Inhibitor and has been approved for Relapsed/Refractory Multiple Myeloma (RRMM). We retrospectively retrieved and analyzed data of KPd combination both biweekly and weekly regimens at our centre from 1 st August 2017 and 31 st May 2020. Sixty-nine patients were treated with KPd with median age of 58 years. Median prior lines of chemotherapy were 2(1-15). Twenty-eight (40.5%) patients underwent autoSCT. Median no. of cycles was 4(1-12) and 3(1-13) with median time to response of 4(2-12) and 2(2-6) months in biweekly and once weekly regimen cohorts respectively. At last follow-up, overall response rate (ORR) was 65.2%{CR-n = 10 (14.5%), VGPR-n = 19 (27.5%), PR-n = 16 (23.2%)} with n = 13(18.8%) patients had PD and relapse was observed in n = 24(34.8%). Thirty (43.4%) patients received maintenance therapy {n = 21(70%)} or autoSCT {n = 9(30%)}. Common toxicities were anemia {n = 11(15.9 %)}, thrombocytopenia (n = 15(21.7%) and neutropenia (n = 16 (23.2%)}, hypertension {n = 28(40.5%)}, peripheral neuropathy (grade1/2) {n = 15(21.7%)}, infections [n = 18(26%) {bacterial [n = 9(13%),viral n = 7(10.1%), fungal n = 8(11.6%)}]. At a median follow-up of 18 months, the estimated median PFS was 11.3 months (95%C.I. 8.3- 14.2) whereas the estimated median OS was 28 months (95%C.I. 20.4-35.5) for the entire cohort. Mortality rate of 2.5% and 10% in two cohorts respectively. Commonest cause of death was PD and sepsis. KPD is a well-tolerated regimen for RRMM, which can be a bridge to ASCT, however with significant side effects.

Novel Approaches to Treating Relapsed and Refractory Multiple Myeloma with a Focus on Recent Approvals of Belantamab Mafodotin and Selinexor.

Though survival outcomes in multiple myeloma patients have improved drastically over the past few decades, there still remains an ongoing need for effective and tolerable treatment options in the relapsed and refractory space. Encouragingly, there have been three recent FDA approvals for triple-class refractory multiple myeloma, and there is promising ongoing development of additional agents with varying novel mechanisms of action. Here, we will review the most recent data on both belantamab mafodotin, an antibody drug conjugate (ADC) targeting BCMA, and selinexor, a first-in-class selective inhibitor of XPO1, as well as touch on some of the recently published data for other immunotherapies in development, namely bispecific T cell engagers, ADCs, and CAR-T cell therapies.

Carfilzomib, cyclophosphamide, and dexamethasone (KCd) for the treatment of triple-class relapsed/refractory multiple myeloma (RRMM).

BACKGROUND: Multiple myeloma (MM) is an incurable hematologic malignancy, and outcomes remain poor for patients with triple-class relapsed/refractory MM (RRMM). Descriptive analyses were performed on available data for patient characteristics, disease course, and outcomes of the KCd on triple-class RRMM patients at our institution. PATIENTS AND METHODS: Twenty-three patients with triple-class RRMM treated with KCd between June 2017 and October 2020 were included in our analysis. The regimen KCd consisted of 28 days cycles of carfilzomib 20/36 mg/m2 IV on days 1, 2, 8, 9, 15, and 16, cyclophosphamide 300 mg/m2 IV weekly, and dexamethasone (20-40) mg orally weekly. RESULTS: Patients received a median of 6 (3-10) prior regimens. The median number of cycles administered was 4 (1-11) cycles. Overall response rate was 52%, 6 patients (26%) achieved very good partial response (VGPR), 6 patients (26%) achieved partial response (PR), and 5 patients (22%) achieved stable disease (SD). Progression-free survival (PFS) and Overall-survival (OS) were 4 and 11.9 months, respectively. There was no reported treatment-related mortality. The most common grade ≥3 adverse events were neutropenia (26%), thrombocytopenia (56.5%), and anemia (56.5%). CONCLUSIONS: KCd showed clinically meaningful efficacy and manageable safety profile in patients with triple-class RRMM in real-world.

CART-Cell Therapy: Recent Advances and New Evidence in Multiple Myeloma.

Despite the improvement in survival outcomes, multiple myeloma (MM) remains an incurable disease. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) represents a new strategy for the treatment of relapsed/refractory MM (R/R). In this paper, we describe several recent advances in the field of anti-BCMA CAR T-cell therapy and MM. Currently, available data on anti-BCMA CART-cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated R/R MM patients. Despite this, the main issues remain to be addressed. First of all, a significant proportion of patients eventually relapse. The potential strategy to prevent relapse includes sequential or combined infusion with CAR T-cells against targets other than BCMA, CAR T-cells with novel dual-targeting vector design, and BCMA expression upregulation. Another dark side of CART therapy is safety. Cytokine release syndrome (CRS) andneurologic toxicity are well-described adverse effects. In the MM trials, most CRS events tended to be grade 1 or 2, with fewer patients experiencing grade 3 or higher. Another critical point is the extended timeline of the manufacturing process. Allo-CARs offers the potential for scalable manufacturing for on-demand treatment with shorter waiting days. Another issue is undoubtedly going to be access to this therapy. Currently, only a few academic centers can perform these procedures. Recognizing these issues, the excellent response with BCMA-targeted CAR T-cell therapy makes it a treatment strategy of great promise.

An evaluation of isatuximab, pomalidomide and dexamethasone for adult patients with relapsed and refractory multiple myeloma.

INTRODUCTION: Despite therapeutic advances, myeloma remains an essentially incurable disease, with a median survival of approximately 8 - 10 years. Most patients will develop disease that is refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs), and treatment regimens containing drugs with different mechanisms of action are necessary. Isatuximab is one such novel agent, an anti-CD38 monoclonal antibody (MoAb), and is the second drug in this class after daratumumab. This paper will consider the current role for isatuximab with pomalidomide for the treatment of relapsed/refractory myeloma (RRMM). AREAS COVERED: This review provides an overview of the pharmacological characteristics of isatuximab, and its clinical development including safety and efficacy data to date. EXPERT OPINION: Isatuximab in combination with pomalidomide and dexamethasone offers a new treatment option for those patients with RRMM who are refractory to PIs and lenalidomide, a patient group with poor prognosis and unmet clinical need. The challenge of where it is best placed in the treatment algorithm remains, particularly with the increasing application of daratumumab particularly in the front- and second-line settings.

KRD-PACE Mobilization for Multiple Myeloma Patients With Significant Residual Disease Before Autologous Stem-Cell Transplantation.

BACKGROUND: Bortezomib has been incorporated into thalidomide and dexamethasone provided with cisplatin, doxorubicin, cyclophosphamide, and etoposide (PACE) as an intensive regimen before autologous stem-cell transplantation for multiple myeloma (MM). We examined MM patients at our center who received chemomobilization with a regimen that substituted carfilzomib and lenalidomide for bortezomib and thalidomide (KRD-PACE). PATIENTS AND METHODS: This was a retrospective study of 27 MM patients who received KRD-PACE for chemomobilization. Our analysis included patients who had circulating plasma cells (CPCs) by flow cytometry, ≥ 10% bone marrow plasma cells (BMPC), a monoclonal protein ≥ 1 g/dL, or an involved serum free light chain ≥ 10 mg/dL. RESULTS: The most common indication for KRD-PACE was BMPC ≥ 10% in 16 patients (60%), followed by CPCs in 11 (41%). The median (range) age was 61 (35-69) years, and the median (range) BMPC before treatment was 10% (5%-47%). The overall response rate was 43%, and a median (range) of 20.24 (8.08-69.88) × 106 CD34+ cells/kg were collected. CPC clearance rate was 50%, and the median reduction in BMPC was 75%. Two patients had sinus bradycardia and 5 (19%) had neutropenic fever. CONCLUSION: KRD-PACE is an effective therapy to mobilize peripheral blood stem cells in MM patients with residual disease burden. This regimen was successful at clearing CPCs and reducing BMPC burden, with an overall response rate of 43%. Despite theoretical concern regarding the combination of 3 cardiotoxic agents, we observed a low frequency of cardiac issues.

Oral azacitidine (CC-486) in combination with lenalidomide and dexamethasone in advanced, lenalidomide-refractory multiple myeloma (ROAR study).

In preclinical studies, oral azacitidine (CC-486), a hypomethylating agent, has been shown to have a direct anti-MM effect and in vitro anti-MM synergism when combined with lenalidomide (LEN). We present a phase 1b, single center, 3 × 3 dose escalation study with planned expansion at maximum tolerated dose (MTD), which assessed the safety and efficacy of combining CC-486 with LEN (25 mg d1-21/28) and dexamethasone (DEX) (40 mg weekly) in patients with relapsed/refractory MM who had previously failed LEN. Twenty-four patients were enrolled. The MTD of CC-486 was 150 mg d1-21; recommended expansion dose was 100 mg d1-21. Adverse events were predictable and manageable. ORR was 37.5%; clinical benefit rate was 50%. Median OS was 10.3 m; median PFS was 2.6 m. Correlative proteomics demonstrated that higher MM tumor cell cereblon expression (pretreatment, C1D5) was associated with superior PFS/OS. CC-486, LEN and DEX produced meaningful clinical responses in heavily treated LEN refractory MM patients. Proteomics may have utility in predicting clinical outcomes.

Clinical efficacy of daratumumab, pomalidomide, and dexamethasone in patients with relapsed or refractory myeloma: Utility of re-treatment with daratumumab among refractory patients.

BACKGROUND: The efficacy of daratumumab (DARA) both as a monotherapy and in combination with standard-of-care regimens in multiple myeloma (MM) has been established in clinical trials. This article presents a retrospective analysis of the safety and efficacy of DARA in combination with pomalidomide (POM) and dexamethasone (ie, daratumumab, pomalidomide, and dexamethasone [DARA-POM-D]) and, more importantly, the long-term follow-up of a cohort that was naive to DARA and POM as well as a cohort in which the utility of re-treatment was evaluated among patients who were DARA- and/or POM-refractory. METHODS: Thirty-four consecutive patients with relapsed and/or refractory MM treated with DARA-POM-D at the Winship Cancer Institute of Emory University from January 2015 through July 2016 were included in the analysis. The study was approved by Emory University's institutional review board. All received prior proteasome inhibitors and immunomodulatory drugs (IMiDs) and were refractory to their last line of therapy. RESULTS: All patients were lenalidomide-refractory, and 91% were bortezomib-refractory. Two cohorts were identified on the basis of prior exposure to DARA and/or POM. Cohort 1 (12 patients) was DARA- and POM-naive, and cohort 2 (22 patients) was DARA- and/or POM-refractory. A subgroup of 12 patients in cohort 2 (cohort 3) was DARA- and POM-refractory. The combination's tolerability was consistent with the results of the published phase 1b study (EQUULES) that evaluated the combination and no new safety signals were observed. The overall response rates (ORRs) were 91.7%, 40.9%, and 33.3% in cohorts 1, 2, and 3, respectively. Deep responses, including 4 stringent complete responses, were observed in cohort 1. In cohort 2, the ORR comprised 8 partial responses (PRs) and 1 very good PR. The median progression-free survival (PFS) was not reached in cohort 1 at a median follow-up of 41 months, and it was 3.2 months in cohort 2. DARA-POM-D not only was effective in DARA- and POM-naive patients but also produced clinical responses in a third of patients re-treated with these drugs. CONCLUSIONS: A better than quadrupled PFS benefit observed in cohort 1 in comparison with the previously reported benefit in the EQUULEUS trial (which led to US Food and Drug Administration approval of the DARA-POM-D combination) highlights the fact that the introduction of monoclonal antibody combination strategies and IMiDs as earlier lines of therapeutic options potentially could deliver better clinical outcomes. One-third of patients refractory to separate lines of DARA and/or POM responded when they were re-treated with a combination, and this resulted in survival benefits equivalent to those of other antimyeloma agents/combinations available for DARA-refractory patients.