Clonal Hematopoiesis and Cardiovascular Disease in Patients With Multiple Myeloma Undergoing Hematopoietic Cell Transplant.

Importance: There is a paucity of information on the association between clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular disease (CVD) in patients with cancer, including those with multiple myeloma (MM) undergoing hematopoietic cell transplant (HCT), a population at high risk of developing CVD after HCT. Objective: To examine the association between CHIP and CVD in patients with MM and to describe modifiers of CVD risk among those with CHIP. Design, Setting, and Participants: This was a retrospective cohort study of patients with MM who underwent HCT between 2010 and 2016 at City of Hope Comprehensive Cancer Center in Duarte, California, and had pre-HCT mobilized peripheral blood stem cell (PBSC) products cryopreserved and accessible for CHIP analyses. The study team performed targeted panel DNA sequencing to detect the presence of CHIP (variant allele frequency 2% or more). Main Outcomes and Measures: The primary end point was the 5-year cumulative incidence and risk for developing de novo CVD (heart failure, coronary artery disease, or stroke) after HCT. Results: Of 1036 consecutive patients with MM (580 male [56%]; median age, 60.0 years) who underwent a first autologous HCT, 201 patients had at least 1 CHIP variant (19.4%) and 35 patients had 2 or more variants (3.4%). The 5-year incidence of CVD was significantly higher in patients with CHIP (21.1% vs 8.4%; P < .001) compared with those without CHIP; the 5-year incidence among those with 2 or more variants was 25.6%. In the multivariable model, CHIP was associated with increased risk of CVD (hazard ratio [HR], 2.72; 95% CI, 1.70-4.39), as well as of individual outcomes of interest, including heart failure (HR, 4.02; 95% CI, 2.32-6.98), coronary artery disease (HR, 2.22; 95% CI, 1.06-4.63), and stroke (HR, 3.02; 95% CI, 1.07-8.52). Patients who had both CHIP and preexisting hypertension or dyslipidemia were at nearly 7-fold and 4-fold increased risk of CVD, respectively (reference: no CHIP, no hypertension, or dyslipidemia). Conclusion and Relevance: CHIP was significantly and independently associated with risk of CVD in patients with MM undergoing HCT and may serve as a novel biologically plausible biomarker for CVD in this cohort. Patients with MM and both CHIP and cardiovascular risk factors had an exceptionally high risk of CVD. Additional studies are warranted to determine if cardiovascular preventive measures can reduce CHIP-associated CVD risk.

Duvelisib for Critically Ill Patients With Coronavirus Disease 2019: An Investigator-Initiated, Randomized, Placebo-Controlled, Double-Blind Pilot Trial.

Background: Despite improvements in prevention and treatment, severe coronavirus disease 2019 (COVID-19) is associated with high mortality. Phosphoinositide 3-kinase (PI3K) pathways contribute to cytokine and cell-mediated lung inflammation. We conducted a randomized, placebo-controlled, double-blind pilot trial to determine the feasibility, safety, and preliminary activity of duvelisib, a PI3Kδγ inhibitor, for the treatment of COVID-19 critical illness. Methods: We enrolled adults aged ≥18 years with a primary diagnosis of COVID-19 with hypoxic respiratory failure, shock, and/or new cardiac disease, without improvement after at least 48 hours of corticosteroid. Participants received duvelisib (25 mg) or placebo for up to 10 days. Participants had daily semi-quantitative viral load measurements performed. Dose modifications were protocol driven due to adverse events (AEs) or logarithmic change in viral load. The primary endpoint was 28-day overall survival (OS). Secondary endpoints included hospital and intensive care unit length of stay, 60-day OS, and duration of critical care interventions. Safety endpoints included viral kinetics and AEs. Exploratory endpoints included serial cytokine measurements and cytometric analysis. Results: Fifteen patients were treated in the duvelisib cohort, and 13 in the placebo cohort. OS at 28 days was 67% (95% confidence interval [CI], 38%-88%) compared to 62% (95% CI, 32%-86%) for placebo (P = .544). Sixty-day OS was 60% versus 46%, respectively (hazard ratio, 0.66 [95% CI, .22-1.96]; P = .454). Other secondary outcomes were comparable. Duvelisib was associated with lower inflammatory cytokines. Conclusions: In this pilot study, duvelisib did not significantly improve 28-day OS compared to placebo for severe COVID-19. Duvelisib appeared safe in this critically ill population and was associated with reduction in cytokines implicated in COVID-19 and acute respiratory distress syndrome, supporting further investigation. Clinical Trials Registration: NCT04372602.

Single-Cell Discovery and Multiomic Characterization of Therapeutic Targets in Multiple Myeloma.

Multiple myeloma (MM) is a highly refractory hematologic cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single-cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and 15 encoding intracellular proteins. Of these, 20 candidate genes were highlighted that are not yet under clinical study, 11 of which were previously uncharacterized as therapeutic targets. The findings were cross-validated using bulk RNA sequencing, flow cytometry, and proteomic mass spectrometry of MM cell lines and patient BM, demonstrating high overall concordance across data types. Independent discovery using bulk RNA sequencing reiterated top candidates, further affirming the ability of single-cell transcriptomics to accurately capture marker expression despite limitations in sample size or sequencing depth. Target dynamics and heterogeneity were further examined using both transcriptomic and immuno-imaging methods. In summary, this study presents a robust and broadly applicable strategy for identifying tumor markers to better inform the development of targeted cancer therapy. SIGNIFICANCE: Single-cell transcriptomic profiling and multiomic cross-validation to uncover therapeutic targets identifies 38 myeloma marker genes, including 11 transcribing surface proteins with previously uncharacterized potential for targeted antitumor therapy.

A multicenter analysis of the outcomes with venetoclax in patients with relapsed mantle cell lymphoma.

To report the activity of venetoclax in patients with relapsed mantle cell lymphoma (MCL), we identified 81 patients treated with venetoclax monotherapy (n = 50, 62%) or in combination with a Bruton tyrosine kinase inhibitor (BTKi) (n = 16, 20%), an anti-CD20 monoclonal antibody (n = 11, 14%), or other active agents at 12 US academic medical centers. Patients had high-risk disease features including Ki67 >30% (61%), blastoid/pleomorphic histology (29%), complex karyotype (34%), and TP53 alterations (49%), and received a median of 3 prior treatments including BTKis in 91%. Venetoclax alone or in combination resulted in an overall response rate (ORR) of 40% and median progression-free (PFS) and overall survival (OS) of 3.7 and 12.5 months, respectively. The receipt of ≤3 prior treatments was associated with higher odds of response to venetoclax in a univariable analysis. In a multivariable analysis, having a high-risk Mantle Cell Lymphoma International Prognostic Index score before receiving venetoclax and disease relapse or progression within 24 months of diagnosis were associated with inferior OS whereas the use of venetoclax in combination was associated with superior OS. Although most patients (61%) had low risk for tumor lysis syndrome (TLS), 12.3% of patients developed TLS despite the implementation of several mitigation strategies. In conclusion, venetoclax resulted in good ORR but short PFS in patients with MCL who are at high risk, and may have a better role in earlier lines of treatment and/or in conation with other active agents. TLS remains an important risk in patients with MCL who initiate treatment with venetoclax.

Identifying monoclonal gammopathy of undetermined significance from electronic health records.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Use of electronic health records may facilitate large-scale epidemiologic research to elucidate risk factors for the progression of MGUS to MM or other lymphoid malignancies. AIMS: We evaluated the accuracy of an electronic health records-based approach for identifying clinically diagnosed MGUS cases for inclusion in studies of patient outcomes/ progression risk. METHODS AND RESULTS: Data were retrieved from Kaiser Permanente Southern California's comprehensive electronic health records, which contain documentation of all outpatient and inpatient visits, laboratory tests, diagnosis codes and a cancer registry. We ascertained potential MGUS cases diagnosed between 2008 and 2014 using the presence of an MGUS ICD-9 diagnosis code (273.1). We initially excluded those diagnosed with MM within 6 months after MGUS diagnosis, then subsequently those with any lymphoid malignancy diagnosis from 2007 to 2014. We reviewed medical charts for 100 randomly selected potential cases for evidence of a physician diagnosis of MGUS, which served as our gold standard for case confirmation. To assess sensitivity, we also investigated the presence of the ICD-9 code in the records of 40 randomly selected and chart review-confirmed MGUS cases among patients with a laboratory report of elevated circulating monoclonal (M-) protein (a key test for MGUS diagnosis) and no subsequent lymphoid malignancy (as described above). The positive predictive value (PPV) for the ICD-9 code was 98%. All MGUS cases confirmed by chart review also had confirmatory laboratory test results. Of the confirmed cases first identified via M-protein test results, 88% also had the ICD-9 diagnosis code. CONCLUSION: The diagnosis code-based approach has excellent PPV and likely high sensitivity for detecting clinically diagnosed MGUS. The generalizability of this approach outside an integrated healthcare system warrants further evaluation.

Bispecific Antibodies for the Treatment of Multiple Myeloma.

PURPOSE OF REVIEW: Advances in multiple myeloma therapies have greatly improved outcomes for patients living with the disease, although to date there is yet to be a cure. Cellular and immunotherapies, approved or in development, offer the promise of significantly advancing toward that possibility. The aim of this review is to provide a synopsis and commentary on the current and future states of bispecific agents aimed at harnessing the antineoplastic potential of T-cells in treating and eradicating myeloma. RECENT FINDINGS: Numerous bispecific agents are in clinical development with some on the precipice of regulatory approval. While BCMA remains the principal target, some agents are directed at novel targets such as GPRC5D and FcRH5. The constructs vary in design and pharmacokinetics which has dosing and administration implications. The toxicity profiles of these agents generally reflect that of other immune therapies, including cytokine release syndrome and rarely neurotoxicity, although immunosuppression has also led to elevated infection risks. However, the toxicities are generally manageable and offset by unprecedented efficacy seen in such heavily pretreated cohorts. Bispecific agents are poised to significantly alter the treatment paradigms for myeloma. They provide a convenient "off-the-shelf" platform with often deep and durable responses. Toxicities are often limited in duration and severity. In the early-phase trials, many patients have been able to remain on treatment for extended periods, even among those with high-risk features. Upcoming trials are likely to explore earlier implementation of these agents in order to offer this therapeutic opportunity to broader cohorts.

Chimeric Antigen Receptor T Cell Therapy versus Hematopoietic Stem Cell Transplantation: An Evolving Perspective.

Cellular therapy modalities, including autologous (auto-) hematopoietic cell transplantation (HCT), allogeneic (allo-) HCT, and now chimeric antigen receptor (CAR) T cell therapy, have demonstrated long-term remission in advanced hematologic malignancies. Auto-HCT and allo-HCT, through hematopoietic rescue, have permitted the use of higher doses of chemotherapy. Allo-HCT also introduced a nonspecific immune-mediated targeting of malignancy resulting in protection from relapse, although at the expense of similar targeting of normal host cells. In contrast, CAR T therapy, through genetically engineered immunotherapeutic precision, allows for redirection of autologous immune effector cells against malignancy in an antigen-specific and MHC-independent fashion, with demonstrated efficacy in patients who are refractory to cytotoxic chemotherapy. It too has unique toxicities and challenges, however. Non-Hodgkin lymphoma (including large B cell lymphoma, mantle cell lymphoma, and follicular lymphoma), B cell acute lymphoblastic leukemia, and multiple myeloma are the 3 main diseases associated with the use of fully developed CAR T products with widespread deployment. Recent and ongoing clinical trials have been examining the interface among the 3 cellular therapy modalities (auto-HCT, allo-HCT, and CAR T) to determine whether they should be "complementary" or "competitive" therapies. In this review, we examine the current state of this interface with respect to the most recent data and delve into the controversies and conclusions that may inform clinical decision making.

Selinexor therapy for multiple myeloma and non-Hodgkin lymphomas.

PURPOSE OF REVIEW: In this review we highlight the most recent studies furthering the clinical development of selinexor, a novel exportin-1 inhibitor, for the treatment of multiple myeloma and non-Hodgkin lymphomas. RECENT FINDINGS: Three pivotal trials, the SADAL trial for diffuse large B-cell lymphoma, and the BOSTON and selinexor treatment of refractory myeloma trials for multiple myeloma, have recently led to the regulatory approval of selinexor monotherapy or combination regimens. They are complemented by several earlier phase clinical trials with iterative combinations, adding selinexor to novel therapies and cytotoxic chemotherapy regimens at various stages in the disease courses. In some, selinexor appears synergistic, occasionally overcoming treatment refractoriness, whereas in other situations appears additive. Consistent issues with tolerability are seen across trials, although consensus guidelines on their preemption and management have recently been adopted which may improve treatment success. While comparative data are lacking, the efficacy of selinexor-based regimens does not approach that of contemporaneous cellular and immunotherapies. SUMMARY: Selinexor is a novel and potentially synergistic therapy for lymphoid malignancies, although requires refined supportive measures and strategies to improve its efficacy. Likely, for continued success, it will need to identify niches that complement recent advances, such as bridging to cellular therapies or maintenance thereafter.

What Do the Elevated Protein Levels Mean in My Patients with Myeloma, Amyloidosis, and Related Disorders?

Multiple myeloma, light chain amyloidosis, and other plasma cell dyscrasias are characterized, in part, by abnormal production of paraproteins that are often responsible for the sequelae of those diseases. These paraproteins are whole or fragmented immunoglobulins produced by clonal antibody-secreting cells (usually plasma cells, but occasionally, B lymphocytes). Significant heterogeneity exists in the presentation of these diseases, ranging from incidental detection of a monoclonal protein in an asymptomatic patient, to life-threatening manifestations that require urgent diagnostic confirmation and intervention. Successful management of such scenarios requires a fundamental understanding of the laboratory assays at one's disposal, their role in the workup of paraproteinemias, and the interpretation thereof. This review broadly covers these assays and their roles in the diagnosis, prognosis, and management of these diseases.

Post-Transplantation Cyclophosphamide Is Associated with an Increase in Non-Cytomegalovirus Herpesvirus Infections in Patients with Acute Leukemia and Myelodysplastic Syndrome.

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis in recipients of haploidentical and fully matched transplantations is on the increase. Published studies have reported an increased incidence of cytomegalovirus (CMV) infection with the use of PTCy. Limited data exist on the incidence and outcomes of infection with non-CMV herpesviruses (NCHV) in this setting. The aim of this study was to evaluate the cumulative incidence of NCHV infections and the association of NCHV infections with transplantation-specific outcomes in recipients of haploidentical transplantation with PTCy (HaploCy), matched sibling donor transplantation with PTCy (SibCy), and matched sibling donor transplantation with calcineurin inhibitor-based prophylaxis (SibCNI). We hypothesized that, like CMV infection, HaploCy recipients of also will have a higher risk of NCHV infections. Using the Center for International Blood and Marrow Transplantation Research database, we analyzed 2765 patients (HaploCy, n = 757; SibCNI, n = 1605; SibCy, n = 403) who had undergone their first hematopoietic stem cell transplantation (HCT) between 2012 and 2017 for acute myelogenous leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. The cumulative incidence of NCHV at 6 months post-NCT was 13.9% (99% confidence interval], 10.8% to 17.3%) in the HaploCy group, 10.7% (99% CI, 7.1% to 15%) in the SibCy group, and 5.7% (99% CI, 4.3% to 7.3%) in the Sib CNI group (P < .001). This was due primarily to a higher frequency of human herpesvirus 6 viremia reported in patients receiving PTCy. The incidence of Epstein-Barr viremia was low in all groups, and no cases of post-transplantation lymphoproliferative disorder were seen in either PTCy group. The incidence of NCHV organ disease was low in all 3 cohorts. The development of NCHV infection was associated with increased treatment-related mortality, particularly in the HaploCy group. There was no association with the development of GVHD, relapse, or disease-free survival. Patients in PTCy cohorts who did not develop NCHV infection had lower rates of cGVHD. This study demonstrates that the use of PTCy is associated with an increased risk of NCHV infection. The development of NCHV infection was associated with increased nonrelapse mortality, especially in the HaploCy group. Prospective trials should consider viral surveillance strategies in conjunction with assessment of immune reconstitution for a better understanding of the clinical relevance of viral reactivation in different HCT settings.

Incidence and impact of community respiratory viral infections in post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis and haploidentical stem cell transplantation.

Community respiratory viral infections (CRVIs) are associated with pulmonary function impairment, alloimmune lung syndromes and inferior survival in human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplant (HCT) recipients. Although the incidence of viral infections in HLA-haploidentical HCT recipients who receive post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is reportedly increased, there are insufficient data describing the incidence of CRVIs and the impact of donor source and PTCy on transplant outcomes. Analysing patients receiving their first HCT between 2012 and 2017 for acute myeloid leukaemia, acute lymphoblastic leukaemia and myelodysplastic syndromes, we describe comparative outcomes between matched sibling transplants receiving either calcineurin-based GVHD prophylaxis (SibCNI, N = 1605) or PTCy (SibCy, N = 403), and related haploidentical transplants receiving PTCy (HaploCy, N = 757). The incidence of CRVIs was higher for patients receiving PTCy, regardless of donor type. Patients in the HaploCy cohort who developed a CRVI by day +180 had both a higher risk of treatment-related mortality [hazard ratio (HR) 2⋅14, 99% confidence interval (CI) 1⋅13-4⋅07; P = 0⋅002] and inferior 2-year overall survival (HR 1⋅65, 99% CI 1⋅11-2⋅43; P = 0⋅001) compared to SibCNI with no CRVI. This finding justifies further research into long-term antiviral immune recovery, as well as development of preventive and treatment strategies to improve long-term outcomes in such patients.

A single center retrospective study of daratumumab, pomalidomide, and dexamethasone as 2nd-line therapy in multiple myeloma.

Daratumumab, pomalidomide, and dexamethasone (DPd) is an FDA-approved 3rd or later line of therapy for myeloma. However, as there are limited published data on the efficacy of 2nd-line DPd, we conducted a retrospective analysis (n = 33). Herein, we report our center's data for 2nd-line DPd. Our patient population had a high amount of high risk cytogenetics (45.5%). The overall response rate (ORR) was 84.9% with a 1-year Progression Free Survival (PFS) of 37.7%. In standard risk myeloma (n = 18), the ORR was 88.9% and 1-year PFS was 61.1% (95% CI 42.3-88.3%). In high risk myeloma (45.5%, n = 15), the ORR was 80% with a 1-year PFS of 7.3% (95% CI 1.1-47.9%). This suggests that the efficacy of 2nd-line DPd in myeloma with high risk cytogenetics should be further investigated.

Co-evolution of tumor and immune cells during progression of multiple myeloma.

Multiple myeloma (MM) is characterized by the uncontrolled proliferation of plasma cells. Despite recent treatment advances, it is still incurable as disease progression is not fully understood. To investigate MM and its immune environment, we apply single cell RNA and linked-read whole genome sequencing to profile 29 longitudinal samples at different disease stages from 14 patients. Here, we collect 17,267 plasma cells and 57,719 immune cells, discovering patient-specific plasma cell profiles and immune cell expression changes. Patients with the same genetic alterations tend to have both plasma cells and immune cells clustered together. By integrating bulk genomics and single cell mapping, we track plasma cell subpopulations across disease stages and find three patterns: stability (from precancer to diagnosis), and gain or loss (from diagnosis to relapse). In multiple patients, we detect "B cell-featured" plasma cell subpopulations that cluster closely with B cells, implicating their cell of origin. We validate AP-1 complex differential expression (JUN and FOS) in plasma cell subpopulations using CyTOF-based protein assays, and integrated analysis of single-cell RNA and CyTOF data reveals AP-1 downstream targets (IL6 and IL1B) potentially leading to inflammation regulation. Our work represents a longitudinal investigation for tumor and microenvironment during MM progression and paves the way for expanding treatment options.

Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis.

Prior studies suggest increased cytomegalovirus (CMV) infection after haploidentical donor transplantation with posttransplant cyclophosphamide (HaploCy). The role of allograft source and posttransplant cyclophosphamide (PTCy) in CMV infection is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection, and effects of serostatus and CMV infection on transplant outcomes. We examined patients reported to the Center for International Blood and Marrow Transplantation Research between 2012 and 2017 who had received HaploCy (n = 757), matched related (Sib) with PTCy (SibCy, n = 403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n = 1605). Cumulative incidences of CMV infection by day 180 were 42%, 37%, and 23%, respectively (P < .001). CMV disease was statistically comparable. CMV infection risk was highest for CMV-seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor (HaploCy [n = 545]: hazard ratio [HR], 50.3; SibCy [n = 279]: HR, 47.7; SibCNI [n = 1065]: HR, 24.4; P < .001). D+/R- patients also had increased risk for CMV infection. Among R+ or those developing CMV infection, HaploCy had worse overall survival and nonrelapse mortality. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic graft-versus-host disease (GVHD) overall, but CMV infection in PTCy recipients was associated with higher chronic GVHD (P = .006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally, CMV infection may negate the chronic GVHD protection of PTCy. This study supports aggressive prevention strategies in all receiving PTCy.

Newly Diagnosed Myeloma in 2020.

Over the last few years, there has been great progress in the treatment of multiple myeloma (MM), with many new agents and combinations having been approved and being now routinely incorporated into treatment strategies for newly diagnosed patients. As a result, patients are experiencing benefits in terms of survival and better tolerance. However, the multitude of treatment options also presents a challenge to select the best options tailored to the specific patient situation. Frontline autologous stem cell transplantation (ASCT) is the standard of care for fit patients younger than age 71 who are newly diagnosed with MM, and triplet combinations are the backbone of induction therapy before ASCT. Post-transplant consolidation and prolonged lower-intensity maintenance are two strategies that have been used to deepen responses and delay progression. For older patients not eligible for ASCT, lenalidomide (len) is increasingly being used as part of frontline therapy, and current approaches are now targeting combinations of anti-CD38 antibodies. Strategies for selecting therapeutic regimens for older adults newly diagnosed with MM can be augmented with use of predictive tools to better capture physiologic age and estimate treatment tolerance. Here we review a decade of trials identifying clinical endpoints and toxicities relevant for the frontline treatment of younger patients and older adults.

DCEP and bendamustine/prednisone as salvage therapy for quad- and penta-refractory multiple myeloma.

Multiple myeloma (MM) almost invariably progresses through novel therapies. Patients with quad-refractory MM (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) and penta-refractory MM (additional refractoriness to daratumumab) have few treatment options. Two chemotherapy regimens, bendamustine/prednisone (BP) and dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP), are often used in quad- and penta-refractory MM, but there are limited data on outcomes in this heavily pre-treated population. We conducted a single-center retrospective study to identify all patients who received DCEP and/or BP for quad- or penta-refractory MM. Disease response and refractoriness were defined by International Myeloma Working Group criteria. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and duration of response (DOR). We identified 27 patients who received BP for quad- or penta-refractory MM. The median number of prior lines of therapy was 6. The ORR for BP was 26%. The median PFS for BP was 1.4 months (95% CI 1.1-1.6) and median OS was 8.7 months (95% CI 2.3-15.0). Patients treated with cyclophosphamide had less response to BP. Thirty-one patients received DCEP for quad-refractory or penta-refractory MM. The median number of prior treatment regimens was 8. The ORR to DCEP was 35%. The median PFS was 2.7 months (95% CI 1.5-3.8) and median OS was 6.2 months (95% CI 4.4-7.8). DCEP and BP retain efficacy in quad- and penta-refractory MM. Our analysis supports prospective study of these regimens, possibly in combination or in comparison with other agents in this area of unmet need.