Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma.

BACKGROUND: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. METHODS: In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. RESULTS: A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). CONCLUSIONS: A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).

Chimeric antigen receptor and bispecific T-cell engager therapies in multiple myeloma patients with prior allogeneic transplantation.

Chimeric antigen receptor T-cell (CAR-T) therapy and bispecific T-cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR-T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo-HCT). Thirty-three MM patients with prior allo-HCT received CAR-T (n = 24) or BsAb (n = 9) therapy. CAR-T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR-T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR-T and 78% of BsAb recipients, while immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in three CAR-T patients. Infections of grade ≥3 were reported in 50% of CAR-T and 44% of BsAb recipients. No exacerbation of graft-versus-host disease occurred except in one BsAb recipient. CAR-T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo-HCT.

The changing spectrum of infection with BCMA and GPRC5D targeting bispecific antibody (bsAb) therapy in patients with relapsed refractory multiple myeloma.

There is a paucity of granular data on infection risk with B-cell maturation antigen (BMCA) and GPRC5D bispecific antibodies (bsAb) in relapsed/refractory multiple myeloma (RRMM). The aim of our multi-institutional study was to characterize the incidence, etiologies, and risk factors of infections from the start of therapy to the last follow-up or 90 days after study exit. A total of 66 patients received BCMA bsAb monotherapy, 15 GPRC5D bsAb monotherapy, and 15 GPRC5D bsAb combination therapy with daratumumab and/or pomalidomide. While the infection rate per 100 days was 0.57 for BCMA bsAb, it was 0.62 for GPRC5D bsAb combination and 0.13 for GPRC5D bsAb monotherapy; P=0.05. The proportion of infections that were grade ≥3 was higher in the BCMA bsAb group compared to the GPRC5D groups (58% vs. 36%; P=0.04). Grade 5 events were observed in 8% (n=8) of the patients, all treated with BCMA bsAb. The 9 month cumulative incidence of any grade of infection was similar in the BCMA and GPRC5D-combination groups (57% and 62%) and significantly higher than in the GPRC5D-mono group (16%); P=0.012. The cumulative incidence of grade ≥3 infections was highest in the BCMA group reaching 54% at 18 months; P=0.06. Multivariate analysis showed that BCMA bsAb therapy or GPRC5D combination therapy, history of previous infections, baseline lymphopenia, and baseline hypogammaglobulinemia were significantly associated with a higher risk of grade ≥3 infections. Our results indicate that BCMA bsAb and GPRC5D-combination therapies in RRMM are associated with higher cumulative incidence of infection and grade ≥3 infection compared to GPRC5D bsAb mono.

Impact of bortezomib-based versus lenalidomide maintenance therapy on outcomes of patients with high-risk multiple myeloma.

BACKGROUND: Lenalidomide maintenance after autologous stem cell transplant (ASCT) in multiple myeloma (MM) results in superior progression-free survival and overall survival. However, patients with high-risk multiple myeloma (HRMM) do not derive the same survival benefit from lenalidomide maintenance compared with standard-risk patients. The authors sought to determine the outcomes of bortezomib-based maintenance compared with lenalidomide maintenance in patients with HRMM undergoing ASCT. METHODS: In total, the authors identified 503 patients with HRMM who were undergoing ASCT within 12 months of diagnosis from January 2013 to December 2018 after receiving triplet novel-agent induction in the Center for International Blood and Marrow Transplant Research database. HRMM was defined as deletion 17p, t(14;16), t(4;14), t(14;20), or chromosome 1q gain. RESULTS: Three hundred fifty-seven patients (67%) received lenalidomide alone, and 146 (33%) received bortezomib-based maintenance (with bortezomib alone in 58%). Patients in the bortezomib-based maintenance group were more likely to harbor two or more high-risk abnormalities and International Staging System stage III disease (30% vs. 22%; p = .01) compared with the lenalidomide group (24% vs. 15%; p < .01). Patients who were receiving lenalidomide maintenance had superior progression-free survival at 2 years compared with those who were receiving either bortezomib monotherapy or combination therapy (75% vs. 63%; p = .009). Overall survival at 2 years was also superior in the lenalidomide group (93% vs. 84%; p = .001). CONCLUSIONS: No superior outcomes were observed in patients with HRMM who received bortezomib monotherapy or (to a lesser extent) in those who received bortezomib in combination as maintenance compared with lenalidomide alone. Until prospective data from randomized clinical trials are available, post-transplant therapy should be tailored to each patient with consideration for treating patients in clinical trials that target novel therapeutic strategies for HRMM, and lenalidomide should remain a cornerstone of treatment.

Promise and pitfalls of allogeneic chimeric antigen receptor therapy in plasma cell and lymphoid malignancies.

Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy in haematological malignancies. However, the currently approved products are generated from autologous T cells that require orchestration of several logistically complex steps, which include patient eligibility, apheresis capability, complex manufacturing processes and shipping logistics. Use of third-party donor-derived (allogeneic) effector cells that allows the generation of 'off-the-shelf" CAR T cells (allo-CAR) could circumvent many of the problems associated with autologous CAR T-cell therapy. Several allogeneic products are entering clinical trials, and though early, the results look promising. The recognised potential benefits of allo-CAR do not come without significant challenges, that must be overcome for their widespread use. Alloreactivity, i.e. graft-versus-host disease (GVHD), and rejection of donor T cells is one of the major barriers, while other potential barriers include immunogenicity, unknown in vivo persistence, and CAR T-cell yield. In the present review, we provide a comprehensive review of the challenges associated with autologous CAR, the benefits and potential challenges associated with allo-CAR. Finally, we review the available platforms for allo-CAR for B-cell and plasma cell malignancies.

Impact of autologous hematopoietic cell transplantation on disease burden quantified by next-generation sequencing in multiple myeloma treated with quadruplet therapy.

The incremental impact of autologous hematopoietic cell transplantation (AHCT) on disease burden with quadruplet induction in newly diagnosed multiple myeloma (NDDM) can be reappraised with the serial assessment of minimal residual disease (MRD). We describe the impact of AHCT on MM burden assessed by next-generation sequencing (NGS) for patients enrolled in a clinical trial utilizing quadruplet induction, AHCT, followed by MRD-adapted consolidation. We describe quantitative changes in MRD burden with AHCT and explore patient and disease features influencing the magnitude of MRD reduction with AHCT. Among 123 included patients, 109 underwent AHCT and had MRD assessment pre and post AHCT. Forty percent achieved MRD < 10-5 post-induction, increasing to 70% after AHCT. Of the 65 patients (60%) who remained MRD positive post-induction, 54 (83%) had a reduction in MRD burden with AHCT. The median reduction in MRD with AHCT was 1.10 log10 (range, -1.26 to 3.41). Patients with high-risk cytogenetic abnormalities (HRCA) had greater reduction in MRD burden (p = .02) after AHCT. Median relative reduction was 0.91 log10 (range, -0.75 to 2.14), 1.26 log10 (range, -0.21 to 3.26) and 1.34 log10 (range, -1.28 to 3.41) for patients with 0, 1 and 2+ HRCA, respectively. The presence of HRCA was the only factor associated with greater than 1 log10 reduction in MRD burden with AHCT. Serial NGS MRD demonstrates the incremental effect of AHCT in MM marrow burden in the context of quadruplet induction, particularly in high-risk MM.

Exploring health behaviors and the feasibility of a lifestyle intervention for patients with multiple myeloma.

PURPOSE: Multiple myeloma (MM) is the second most common hematologic malignancy in the USA, with higher rates observed in older adults and African Americans (AA). Survivors experience fatigue, bone pain, reduced functioning, and obesity, highlighting the value of developing lifestyle interventions for this diverse group. This study explores lifestyle behaviors and supportive care needs to inform future programs tailored to the MM community. METHODS: MM survivors, ≥ 100 days post autologous stem cell transplant (ASCT) with a BMI ≥ 20 kg/m2, were recruited from two university hospitals. Diet, physical activity, and quality of life (QOL) were measured using validated measures. Qualitative interviews gathered information on survivorship needs and interests related to supportive interventions. Quantitative data was analyzed using descriptive statistics; qualitative data were analyzed using deductive strategies. RESULTS: Seveny-two MM survivors participated (65% white, 35% black). Participants were 62.5 ± 15.8 years of age. Fifty percent were classified as obese and 65% were insufficiently active. Participants reported diets high in added sugars and saturated fats. QOL measures indicated clinically significant challenges in physical and sexual function. Most (87%) were interested in a lifestyle program. Predominant themes regarding survivors' desires for a lifestyle program included social support, guided exercise, meal preparation support, and disease management information. CONCLUSION: This study demonstrates the need for and interest in lifestyle change support among a racially diverse sample of MM survivors. Interventions that are group-based, target knowledge gaps, social connections, accountability, and provide structured framework with professional instruction will best address the needs of this survivor population.

Rap1A, Rap1B, and ß-Adrenergic Signaling in Autologous HCT: A Randomized Controlled Trial of Propranolol.

Successful hematopoietic cell transplantation (HCT) depends on rapid engraftment of the progenitor and stem cells that will reestablish hematopoiesis. Rap1A and Rap1B are two closely related small GTPases that may affect platelet and neutrophil engraftment during HCT through their roles in cell adhesion and migration. ß-adrenergic signaling may regulate the participation of Rap1A and Rap1B in engraftment through their inhibition or activation. We conducted a correlative study of a randomized controlled trial evaluating the effects of the nonselective ß-antagonist propranolol on expression and prenylation of Rap1A and Rap1B during neutrophil and platelet engraftment in 25 individuals receiving an autologous HCT for multiple myeloma. Propranolol was administered for 1 week prior to and 4 weeks following HCT. Blood was collected 7 days (baseline) and 2 days (Day -2) before HCT, and 28 days after HCT (Day +28). Circulating polymorphonuclear cells (PMNC) were isolated and analyzed via immunoblotting to determine levels of prenylated and total Rap1A versus Rap1B. Twelve participants were randomized to the intervention and 13 to the control. Rap1A expression significantly correlated with Rap1B expression. Rap1B expression significantly correlated with slower platelet engraftment; however, this association was not observed in the propranolol-treated group. There were no significant associations between neutrophil engraftment and Rap1A or Rap1B expression. Post hoc exploratory analyses did not reveal an association between social health variables and Rap1A or Rap1B expression. This study identifies a greater regulatory role for Rap1B than Rap1A in platelet engraftment and suggests a possible role for ß-adrenergic signaling in modulating Rap1B function during HCT.

African Americans with translocation t(11;14) have superior survival after autologous hematopoietic cell transplantation for multiple myeloma in comparison with Whites in the United States.

BACKGROUND: Multiple myeloma (MM) with the translocation t(11;14) may have inferior outcomes in comparison with other standard-risk MM, and it has been suggested to portend a worse prognosis in African Americans in comparison with Whites. This study used the Center for International Blood and Marrow Transplant Research (CIBMTR) database to examine the impact of t(11;14) on the clinical outcomes of patients with MM of African American and White descent. METHODS: This study evaluated 3538 patients who underwent autologous hematopoietic cell transplantation (autoHCT) for MM from 2008 to 2016 and were reported to the CIBMTR. Patients were analyzed in 4 groups: African Americans with t(11;14) (n = 117), African Americans without t(11;14) (n = 968), Whites with t(11;14) (n = 266), and Whites without t(11;14) (n = 2187). RESULTS: African Americans with t(11;14) were younger, had lower Karnofsky scores, and had more advanced stage MM with a higher Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI). Fewer African Americans with t(11;14) (21%) had a coexistent high-risk marker in comparison with Whites with t(11;14) (27%). In a multivariate analysis, race and t(11;14) had no association with progression-free survival. However, overall survival was superior among African Americans with t(11;14) in comparison with Whites with t(11;14) (hazard ratio, 0.53; 95% confidence interval, 0.30-0.93; P = .03). Survival was also associated with female sex, stage, time from diagnosis to transplant, a low HCT-CI, and receipt of maintenance. CONCLUSIONS: Race may have a differential impact on the survival of patients with t(11;14) MM who undergo autoHCT and needs to be further studied.

Propylene Glycol-Free Melphalan versus PG-Melphalan as Conditioning for Autologous Hematopoietic Cell Transplantation for Myeloma.

High-dose melphalan (Mel) conditioning before autologous hematopoietic cell transplantation (autoHCT) is standard of care for patients with transplantation-eligible multiple myeloma. The traditional lyophilized Mel formulation has inadequate solubility and stability after reconstitution, leading to the use of propylene glycol (PG) as a solubilizing agent. A newer PG-free Mel preparation (Evomela) uses beta cyclodextrin captisol as a solubilizing agent and was approved by the United States Food and Drug Administration as a conditioning agent based on a single-phase IIb study showing bioequivalence. We compared the outcomes of consecutive patients with myeloma undergoing autoHCT using the 2 formulations of Mel for conditioning as our center switched from using the older formulation (PG-Mel) to the newer one (PGF-Mel). Of 294 autoHCT recipients, 162 received PG-Mel conditioning and 132 received PGF-Mel conditioning. The PGF-Mel group was older and had a lower average Karnofsky Performance Status score. PGF-Mel was associated with faster neutrophil recovery (median, 12 days versus 13 days; P < .001), fewer grade 3-4 infections within 30 days of autoHCT (1.5% versus 8.0%; P = .048), and a lower 30-day rehospitalization rate (6.8% versus 17.9%; P = .04), as confirmed by propensity-weighted analysis. No significant between-group differences were detected in mucositis, organ toxicity, myeloma response, or 100-day mortality.

Utilization and Cost Implications of Hematopoietic Progenitor Cells Stored for a Future Salvage Autologous Transplantation or Stem Cell Boost in Myeloma Patients.

Autologous hematopoietic cell transplantation (autoHCT) is a standard initial treatment for multiple myeloma (MM). Consensus guidelines recommend collecting sufficient hematopoietic progenitor cells (HPCs) for 2 autoHCTs in all eligible patients. Despite a lack of published data on the utilization of HPCs stored for future use, it is common practice across transplantation programs to collect enough HPCs for 2 autoHCTs in MM patients. In this single-center retrospective study, we analyzed the utilization of HPCs collected and stored at the time of first autoHCT in patients with MM, along with the cost implications of HPC collection targets sufficient for 2 transplantations. In a cohort of 400 patients (median age, 63 years; range, 22 to 79 years), after a median follow-up of 50.4 months, 197 patients had relapsed and 36 had received HPC infusion as salvage autoHCT (n = 29) and/or HPC boost (n = 8). In this cohort, a median CD34+ cell dose of 4.3 × 106/kg (range, 1.1 to 12.94.3 × 106/kg) was used for first autoHCT, and a median of 4.4 × 106/kg (range, 1.0 to 20.2× 106/kg) CD34+ cells were stored for future use. At 6 years after the first autoHCT, the estimated cumulative incidence of salvage autoHCT was 12.0% without HPC boost and 13.9% with HPC boost. HPC utilization was significantly higher in the 60- to 64-year age group, whereas no patients who were age ≥70 years at the time of first autoHCT received salvage autoHCT. Using the CD34+ cell dose infused during the first autoHCT as the cutoff for individual patients, the estimated mean additional cost of HPC collection intended for subsequent use (over and above the HPCs used for first autoHCT) was $10,795 ($4.32 million for the entire cohort), an estimated 14% of which (ie, $583,600) was actually used up in salvage autoHCT by 6 years from first autoHCT. In conclusion, our results suggest the need for reappraisal of HPC collection targets for salvage autoHCT and argue against HPC collection and storage for salvage autoHCT in patients age ≥70 years at the time of first autoHCT.

Relapse after Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma: Survival Outcomes and Factors Influencing Them.

Many patients with multiple myeloma (MM) eventually relapse even after allogeneic hematopoietic cell transplantation (alloHCT) for curative intent. Over the past decade, outcomes for patients with MM have improved significantly with the availability of new therapies, including next-generation proteasome inhibitors, immunomodulatory agents, and, more recently, monoclonal antibodies. Although several published studies have evaluated the outcomes of alloHCT for MM, the data on survival outcomes in patients with MM experiencing disease relapse following alloHCT are limited. In addition, the predictors for postrelapse survival in these patients are not known. In this study, we examined the outcomes of a single-center cohort of 60 patients with MM who experienced relapse or progression after alloHCT. In addition, we evaluated the use of salvage regimens for treatment of relapsed MM and analyzed the predictors for improved postrelapse survival. After a median follow-up of 2.2 years from the time of relapse, the median duration of postrelapse survival was 1.8 years (95% confidence interval [CI], 1.2 to 5.0 years). Patients received a median of 3 lines of therapy (range, 0 to 10) for treatment of MM beyond the post-alloHCT relapse/progression. Multivariate analysis identified cytogenetic risk (standard risk versus high risk; hazard ratio [HR], .34; P = .01), time to relapse after alloHCT (>12 months versus ≤12 months: HR, .41; P = .04), and occurrence of acute graft-versus-host disease (GVHD) before relapse (GVHD versus no GVHD: HR, 2.89; P = .01) significantly affected postrelapse survival. These data illustrate that long-term myeloma control and survival is attainable in those relapsing/progressing after alloHCT and suggest that the synergism between novel therapies and the allogeneic immune platform is the key to improved survival in this high-risk patient population.

Fludarabine/Busulfan Conditioning-Based Allogeneic Hematopoietic Cell Transplantation for Myelofibrosis: Role of Ruxolitinib in Improving Survival Outcomes.

Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment modality for primary myelofibrosis (MF) and related myeloproliferative neoplasms. Older age at diagnosis and age-related comorbidities make most patients ineligible for allo-HCT, given concerns for nonrelapse mortality (NRM). Here we report the outcomes of 37 consecutive recipients of allo-HCT for MF performed at a single center between 2009 and 2018 with a standardized institutional protocol. Most patients received ruxolitinib before HCT (n = 32), and those with splenomegaly >22 cm received pretransplantation splenic irradiation. The median age at HCT was 60 years (range, 40 to 74 years), and 68% of the cohort carried a JAK2 driver mutation. All patients received fludarabine/busulfan-based conditioning; 22 patients (59%) received a reduced-intensity conditioning regimen. All patients received peripheral blood grafts, from a matched sibling donor in 16 patients (43%), an unrelated donor in 20 patients, and a haploidentical-related donor in 1 patient. Sixty-one percent had a Hematopoietic Cell Transplantation Comorbidity Index ≥3, 40% had a Karnofsky Performance Status score <90, and 24% had a high-risk DIPSS Plus score. With a median follow-up of 40.2 months (range, 16.9 to 115 months), the 3-year overall survival and relapse-free survival were 81.1% (95% confidence interval [CI], 64.4% to 90.5%) and 78.4% (95% CI, 61.4% to 88.5%), respectively. Only 2 patients relapsed/progressed after transplant. NRM at 2 years was 16.2% (95% CI, 6.5% to 29.9%). All patients engrafted. Sixteen patients were treated with ruxolitinib post-transplantation for graft-versus-host disease, graft rejection/relapse, or persistent MF. These results suggest that pretransplantation ruxolitinib, fludarabine/busulfan-based conditioning, and splenic management are keys to improved transplantation outcomes in patients undergoing allo-HCT for MF.

Ixazomib for Chronic Graft-versus-Host Disease Prophylaxis following Allogeneic Hematopoietic Cell Transplantation.

Chronic graft-versus-host disease (cGVHD) is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Ixazomib is an oral, second-generation, proteasome inhibitor that has been shown in preclinical models to prevent GVHD. We conducted a phase I/II trial in 57 patients to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT. Oral ixazomib was administered on a weekly basis for a total of 4 doses, beginning days +60 through +90, to recipients of matched related donor (MRD, n = 25) or matched unrelated donor (MUD, n = 26) allogeneic HCT in phase II portion of the study, once the recommended phase II dose of 4 mg was identified in phase I (n = 6). All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate. Ixazomib administration was safe and well tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints, and fatigue the most common adverse events (>10%). In phase II (n = 51), the cumulative incidence of cGVHD at 1 year was 36% (95% confidence interval [CI], 19% to 54%) in the MRD cohort and 39% (95% CI, 21% to 56%) in the MUD cohort. One-year cumulative incidence of nonrelapse mortality (NRM) and relapse was 0% and 20% (95% CI, 8% to 36%) in the MRD cohort, respectively. In the MUD cohort, the respective NRM and relapse rates were 4% (0% to 16%) and 34% (17% to 52%). The outcomes on the study were compared post hoc with contemporaneous matched Center for International Blood and Marrow Transplant Research (CIBMTR) controls. This post hoc analysis showed no significant improvement in cGVHD rates in both the MRD (hazard ratio [HR] = 0.85, P = .64) or MUD cohorts (HR = 0.68, P = .26) on the study compared with CIBMTR controls. B cell activating factor plasma levels were significantly higher after ixazomib dosing in those who remained cGVHD free compared with those developed cGVHD. This study shows that the novel strategy of short-course oral ixazomib following allogeneic HCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation compared with matched CIBMTR controls. This study is registered at www.clinicaltrials.gov as NCT02250300.

Association of adverse events and associated cost with efficacy for approved relapsed and/or refractory multiple myeloma regimens: A Bayesian network meta-analysis of phase 3 randomized controlled trials.

BACKGROUND: Several new treatment options have been approved for relapsed and/or refractory multiple myeloma (RRMM). In this systematic review, associations of the efficacy of each approved regimen with adverse events (AEs) and the total cost per cycle were compared with a Bayesian network meta-analysis (NMA) of phase 3 randomized controlled trials (RCTs). METHODS: Scopus, Cochrane, PubMed Publisher, and Web of Science were searched from January 1999 to July 2018 for phase 3 RCTs of regimens (approved by the US Food and Drug Administration) used in RRMM. The relative ranking of agents was assessed with surface under the cumulative ranking (SUCRA) probabilities. The primary efficacy, safety, and cost outcomes were progression-free survival with the regimen, grade 3 to 4 AEs, and the total cost per cycle (regimen cost plus average cost of managing AEs). RESULTS: Fifteen studies including 7718 patients and evaluating 14 different regimens were identified. Daratumumab, lenalidomide, and dexamethasone were ranked highest for reducing progression (hazard ratio, 0.13; 95% credible interval, 0.09-0.19; SUCRA, 1) but carried the highest probability of total cost per cycle ($41,420; 95% Credible Interval [CrCl], $58,665-$78,041; SUCRA, 0.02). Panobinostat, bortezomib, and dexamethasone were the least effective and least safe (SUCRA, 0.24), whereas bortezomib, thalidomide, and dexamethasone emerged as least effective with the highest total cost per cycle (SUCRA, 0.33). Carfilzomib and dexamethasone emerged as the winner when this regimen was considered in terms of efficacy and safety (SUCRA, 0.61) and efficacy and total cost per cycle (SUCRA, 0.60). CONCLUSIONS: The results of this NMA can provide additional guidance for the decision-making process when one is choosing the most appropriate regimen for RRMM.

Novel prognostic scoring system for autologous hematopoietic cell transplantation in multiple myeloma.

We studied 2,528 patients with upfront autologous haematopoietic cell transplantation (AHCT) for multiple myeloma (MM) from 2008-2017 to develop a prognostic model to predict outcomes. High-risk cytogenetics included t(4;14), t(14;16), t(14;20), del13q on karyotype, del17p, +1q or 1pdel. A Cox model identified factors prognostic of progression/relapse in a training subset (n = 1,246). A weighted score using these factors was assigned to a validation cohort (n = 774). Presence of high-risk cytogenetics [hazard ratio, (HR) 1·68 (1·3-2·17)] and pre-AHCT bone marrow plasma cells (BMPCs) ≥10% [1·68 (1·33-2·12)] were assigned 4 points each; albumin at diagnosis <3·5 g/dl [1·31 (1·07-1·61)] 2; standard risk cytogenetics 1, and no cytogenetics abnormality, BMPCs <10% at AHCT and albumin ≥3·5 g/dl at diagnosis 0 points each. A three-category system with low risk (0-3), intermediate risk (4-8) and high risk (9-10) showed 3-year progression-free survival in the low vs. intermediate vs. high risk of 58% (95% CI: 52-63) vs. 49% (95% CI: 43-56) vs. 31% (95% CI: 12-51), P < 0.001 respectively, and 3-year OS in low vs. intermediate vs. high risk of 88% (95% CI: 84-91) vs. 81% (95% CI: 76-86) vs. 64% (95% CI: 39-80); P < 0·001. Our prognostic scoring system can identify MM patients at risk for early relapse after AHCT.

Trends in the use of therapeutic plasma exchange in multiple myeloma.

INTRODUCTION: Therapeutic plasma exchange (TPE) is traditionally performed for hyperviscosity, neuropathy and to mitigate renal injury in the setting of high clonal free light chain burden in patients with multiple myeloma (MM) with unknown clinical benefit. MATERIALS AND METHODS: Retrospective study of adults ≥18 years with MM who received TPE in the in-patient setting in the United States from 1993 to 2015. We examined the temporal trends of TPE utilization in MM hospitalizations, hospital charges, in-hospital mortality, and length of hospitalization and the predictors of in-hospital mortality and length of hospitalizations. RESULTS: The number of MM-hospitalizations for TPE in adults increased significantly from 1993 to 2015 (1% in 1993-1999 to 2.1% in 2008-2015 of all MM discharges, P for trend <.0001). About 70% of TPE recipients had acute kidney injury (AKI). The median hospital charges increased 5-fold during the time period ($ 24 407 to $ 113 496; P for trend <.0001). In-hospital mortality decreased (17.5% (SE 2.66) in 1993-1997 to 8.7% (1.39) in 2007 to 2013) P for trend <.005) while the length of stay remained unchanged (11.2 days vs 11.9 days, P for trend 0.17). On adjusted analysis, significant predictors of in-hospital mortality among MM TPE recipients include, Charlson Comorbidity Index (CCI) (3 vs 2 adjusted odds ratio, aOR 2.16, 95% CI 1.26-3.71; P = .005), year (continuous) (aOR 0.93, 95% CI 0.90-0.96; P < .001) and race (other vs white; aOR 0.44, 95% CI 0.25-0.78; P = 0.004). CONCLUSIONS: There has been a substantial increase in the use and associated cost of TPE in hospitalized MM patients.

Direct HLA Genetic Comparisons Identify Highly Matched Unrelated Donor-Recipient Pairs with Improved Transplantation Outcome.

HLA matching by allele-level genotyping is largely based on genetic similarity between a few exons that encode the antigen recognition domain (ARD) of the HLA protein. Next-generation sequencing (NGS) can identify HLA genetic polymorphisms in non-ARD-encoding exons, introns, and untranslated regions, but the impact of these polymorphisms on hematopoietic cell transplantation (HCT) outcome is unclear. We performed NGS-based sequencing of 11 HLA loci on a well-characterized retrospective cohort of 166 unrelated donor-recipient HCT pairs. Genetic differences between HCT pairs were identified and visualized using a novel bioinformatics approach that directly compares phased full-length HLA sequences. Our approach was able to correctly classify HCT pairs without known HLA allele-level mismatches and also to identify a subset of HLA allele-matched HCT pairs with very few to no genetic differences in the sequenced HLA regions. This highly HLA genetically matched unrelated HCT group shows improved overall survival and reduced acute graft-versus-host disease compared with HCT pairs with HLA allele-level mismatches. These results suggest that direct genetic matching of HLA loci may offer an additional means of HCT donor selection beyond traditional HLA allele comparisons and suggests that genetic similarity as defined by HLA sequencing may have a novel role in unrelated HCT donor selection. Finally, our approach can enable larger cohort studies with adequate power to detect differences in other HCT outcomes based on genetic similarity within the HLA loci.

A Phase 2 Study of Pembrolizumab during Lymphodepletion after Autologous Hematopoietic Cell Transplantation for Multiple Myeloma.

The programmed death-1 (PD-1) axis can suppress immune surveillance against multiple myeloma (MM). We tested the safety and efficacy of pembrolizumab, an anti-PD-1 antibody, in MM after autologous hematopoietic cell transplantation (AHCT). We enrolled patients with MM who did not achieve a complete response (CR) to induction therapy. The study intervention involved a total of 9 doses of i.v. pembrolizumab, with 1 dose given every 21 days starting on day +14 post-AHCT. The primary endpoint was the rate of CR at end of treatment (EOT) in patients receiving ≥2 pembrolizumab doses. Thirty-two patients were enrolled, but 3 withdrew consent before receiving the first dose. The study was terminated early after failing to meet its interim analysis endpoint to detect a 20% difference in EOT CR rate conversion. The median patient age was 59 years. All but 1 patient received triplet induction for a median of 4 cycles (range, 2 to 7 cycles), with 69% partial response (PR) and 31% very good PR (VGPR). No grade 4/5 toxicities or graft failures occurred. Among 26 evaluable patients, 23 had an EOT evaluation, and 7 of these 23 (31%) achieved CR. Two patients had EOT serologic CR but no bone marrow confirmation (CRu), and 1 patient had no EOT evaluation. Bone marrow was minimal residual disease-negative by flow cytometry in 12 of 16 patients (75%) at day +180. With a median follow-up of 23.7 months (range, 15.1 to 33.5 months), no patient achieving EOT CR/CRu had relapsed, whereas 3 patients progressed before EOT and 1 patient progressed at 8 months after EOT VGPR. The estimated 2-year progression-free rate was 83% (95% confidence interval, 68% to 100%). Our data show that early post-AHCT pembrolizumab with lenalidomide maintenance is feasible; however, the efficacy is uncertain and requires further study. This trial was registered at ClinicalTrials.gov (NCT02331368).

Outcomes of Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation Performed in the Inpatient versus Outpatient Setting.

Allogeneic hematopoietic cell transplantation (allo-HCT) with reduced-intensity conditioning (RIC) is commonly performed as an inpatient procedure. The feasibility and outcomes of RIC allo-HCT in the outpatient setting is not known. We performed a single-center retrospective cohort study of patients aged ≥ 18years with hematologic malignancies who underwent RIC allo-HCT either in the inpatient or outpatient setting. Donor types included HLA-matched sibling and well-matched unrelated donors. The objectives were to compare the survival, complications, charges, and incidences of relapse, nonrelapse mortality (NRM), and acute and chronic graft-versus-host disease (GVHD) between the 2 groups. Between 2014 and 2017, 151 eligible patients were included, with 116 undergoing RIC allo-HCT in the inpatient setting and 35 patients undergoing RIC allo-HCT in the outpatient setting. Baseline characteristics were comparable between the 2 groups except for a higher proportion of patients with myeloma in the outpatient cohort (inpatient 15.5% versus outpatient 37.1%). The cumulative incidence of grades II to IV acute GVHD (inpatient 25.2% versus outpatient 25.7%), grades III to IV acute GVHD (inpatient 10.4% versus outpatient 8.5%), chronic GVHD (inpatient 38.3% versus outpatient 51.6%), NRM at 1 year (inpatient 10.8% versus outpatient 3.2%), and relapse (inpatient 24.8% versus outpatient 33.2%) did not significantly differ between the 2 cohorts. One-year progression-free survival (inpatient 64.4% versus outpatient 63.6%, P = .39) and overall survival (inpatient 73.8% versus outpatient 82.8%, P = .93) were also not significantly different between the 2 groups. The proportion of patients who developed neutropenic fever (inpatient 25.8% versus outpatient 8.5%, P = .03) and mucositis (inpatient 50.8% versus outpatient 8.5%, P < .001) and who required total parenteral nutrition (inpatient 20.6% versus outpatient 5.7%, P = .04) were more frequent in the inpatient cohort. About 51.5% of the outpatient cohort never required hospital admission in the first 100days. Outpatient HCT resulted in significantly lower charges than inpatient HCT in the first 100days (median charges: inpatient $339,621 versus outpatient $247,334; P < .001). On multivariate analysis the site of the HCT (outpatient versus inpatient) was not a significant predictor of either overall or progression-free survival. Outpatient RIC allo-HCT is feasible and safe with daily outpatient evaluation and aggressive supportive care resulting in outcomes comparable with those who received the transplant in the inpatient setting.