Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk.

In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]). Among 123 D-KRd patients, 43.1%, 37.4%, and 19.5% had 0, 1, or ≥2 HRCAs. Among 120 D-RVd patients, 55.8%, 28.3%, and 10.8% had 0, 1, or ≥2 HRCAs. Rates of complete response or better (best on study) for 0, 1, or ≥2 HRCAs were 90.6%, 89.1%, and 70.8% for D-KRd, and 90.9%, 78.8%, and 61.5% for D-RVd. At median follow-up (MASTER, 31.1 months; GRIFFIN, 49.6 months for randomized patients/59.5 months for safety run-in patients), MRD-negativity rates as assessed by next-generation sequencing (10-5) were 80.0%, 86.4%, and 83.3% for 0, 1, or ≥2 HRCAs for D-KRd, and 76.1%, 55.9%, and 61.5% for D-RVd. PFS was similar between studies and superior for 0 or 1 versus ≥2 HRCAs: 36-month PFS rates for D-KRd were 89.9%, 86.2%, and 52.4%, and 96.7%, 90.5%, and 53.5% for D-RVd. These data support the use of daratumumab-containing regimens for transplant-eligible NDMM with HCRAs; however, additional strategies are needed for ultra-high-risk disease (≥2 HRCAs). Video Abstract.

Enhancing prognostic power in multiple myeloma using a plasma cell signature derived from single-cell RNA sequencing.

Multiple myeloma (MM) is a heterogenous plasma cell malignancy, for which the established prognostic models exhibit limitations in capturing the full spectrum of outcome variability. Leveraging single-cell RNA-sequencing data, we developed a novel plasma cell gene signature. We evaluated and validated the associations of the resulting plasma cell malignancy (PBM) score with disease state, progression and clinical outcomes using data from five independent myeloma studies consisting of 2115 samples (1978 MM, 65 monoclonal gammopathy of undetermined significance, 35 smoldering MM, and 37 healthy controls). Overall, a higher PBM score was significantly associated with a more advanced stage within the spectrum of plasma cell dyscrasias (all p < 0.05) and a shorter overall survival in MM (hazard ratio, HR = 1.72; p < 0.001). Notably, the prognostic effect of the PBM score was independent of the International Staging System (ISS) and Revised ISS (R-ISS). The downstream analysis further linked higher PBM scores with the presence of cytogenetic abnormalities, TP53 mutations, and compositional changes in the myeloma tumor immune microenvironment. Our integrated analyses suggest the PBM score may provide an opportunity for refining risk stratification and guide decisions on therapeutic approaches to MM.

Impact of Visceral Obesity on Clinical Outcome and Quality of Life for Patients with Multiple Myeloma: A Secondary Data Analysis of STaMINA (BMT CTN 0702) Trial.

Obesity is a common health problem in patients with multiple myeloma (MM) that has been linked to poor clinical outcomes and quality of life (QoL). We conducted a secondary analysis of the BMT CTN 0702, a randomized, controlled trial comparing outcomes of 3 treatment interventions after a single hematopoietic cell transplantation (HCT) (n = 758), to investigate the impact of visceral obesity, as measured by waist-to-hip ratio (WHR), on clinical outcomes and QoL in MM patients. A total of 549 MM patients, median age 55.5 years, were enrolled in the study. The majority of patients received triple-drug antimyeloma initial therapy before enrollment, and 29% had high-risk disease according to cytogenetic assessment. The median duration of follow-up was 6 years. There was no significant association between WHR and progression-free survival (PFS) or overall survival (OS) in MM patients undergoing HCT. Similarly, body mass index (BMI) did not significantly predict PFS or OS. Furthermore, there was no significant correlation between WHR and QoL measures. This study suggests that visceral obesity, as measured by WHR, might not have a significant impact on clinical outcomes in MM patients undergoing HCT. These findings add to the existing literature on the topic and provide valuable information for healthcare professionals and MM patients. Further studies are needed to confirm these results and to investigate other potential factors that may affect clinical outcomes and QoL in this patient population using modern imaging technologies to assess visceral obesity.

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.

Impact of Visceral Obesity on Clinical Outcome and Quality of Life for Patients with Multiple Myeloma: A Secondary Data Analysis of STaMINA (BMT CTN 0702) Trial.

Obesity is a common health problem among multiple myeloma (MM) patients, and it has been linked to poor clinical outcomes and quality of life (QOL). We conducted a secondary analysis of the BMT CTN 0702, a randomized, controlled trial comparing outcomes of three treatment interventions after a single hematopoietic cell transplant (HCT), to investigate the impact of visceral obesity, as measured by waist-to-hip ratio (WHR), on clinical outcomes and QOL in MM patients. 549 MM patients, median age 55.5 years, were enrolled in the study. The majority of patients received triple-drug antimyeloma initial therapy before enrollment, and 29% had high-risk disease according to cytogenetic assessment. The median follow-up time was six years. There was no significant association between WHR and progression-free survival (PFS) or overall survival (OS) in MM patients undergoing HCT. Similarly, body mass index (BMI) did not significantly predict PFS or OS. Furthermore, there was no significant correlation between WHR and QOL measures. In conclusion, this study suggests that visceral obesity, as measured by WHR, may not significantly impact clinical outcomes in MM patients undergoing HCT. Further studies utilizing imaging technologies to assess the impact of visceral obesity distribution are warranted.

Minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma (MASTER): final report of the multicentre, single-arm, phase 2 trial.

BACKGROUND: For patients with newly diagnosed multiple myeloma, reaching minimal residual disease (MRD) negativity after treatment is associated with improved outcomes; however, the use of MRD to modulate therapy remains elusive. We present the final analysis of the MASTER trial of daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) therapy in patients with newly diagnosed multiple myeloma, in which MRD status is used to modulate treatment duration and cessation. METHODS: MASTER was a multicentre, single-arm, phase 2 trial conducted in five academic medical centres in the USA. Eligible participants were 18 years or older with newly diagnosed multiple myeloma (measurable by serum or urine protein electrophoresis or serum free light chains), a life expectancy of at least 12 months, and an Eastern Cooperative Oncology Group performance status of 0-2, and had received no previous treatment for multiple myeloma except up to one cycle of therapy containing bortezomib, cyclophosphamide, and dexamethasone. The study was enriched for participants with high-risk chromosome abnormalities (HRCAs). During the induction phase, participants received four 28-day cycles of Dara-KRd, each comprising daratumumab (16 mg/kg intravenously on days 1, 8, 15, and 22), carfilzomib (56 mg/m2 intravenously on days 1, 8, and 15), lenalidomide (25 mg orally on days 1-21), and dexamethasone (40 mg orally or intravenously on days 1, 8, 15, and 22); induction was followed by autologous haematopoietic stem-cell transplantation and up to two phases of consolidation with Dara-KRd. We assessed MRD by next-generation sequencing after or during each phase. The primary endpoint was reaching MRD negativity (<10-5). Participants who reached MRD negativity after or during two consecutive phases stopped treatment and began observation with MRD surveillance (MRD-SURE); participants who did not reach two consecutive MRD-negative results received maintenance lenalidomide. Secondary endpoints included progression-free survival and cumulative incidence of progression. All analyses were conducted in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03224507, and is complete. FINDINGS: Between Mar 21, 2018, and Oct 23, 2020, 123 participants were recruited to the study, of whom 70 (57%) were men, 53 (43%) were women, 94 (76%) were non-Hispanic White, 25 (20%) were non-Hispanic Black, and four (3%) were of another race or ethnicity. The median age of participants was 61 years (IQR 55-68), and 24 (20%) were aged 70 years or older. The median duration of follow up was 42·2 months (IQR 34·5-46·0). Of the 123 participants, 53 (43%) had no HRCAs, 46 (37%) had one HRCA, and 24 (20%) had two or more HRCAs. For 118 (96%) of 123 participants, MRD was evaluable by next-generation sequencing; the remaining five had an absence of sufficiently unique clonogenic sequences to enable tracking by the assay. Of these 118 participants, 96 (81%, 95% CI 73-88) reached MRD of less than 10-5 (comprising 39 [78%, 64-88] of 50 participants with no HRCAs, 38 [86%, 73-95] of 44 participants with one HRCA, and 19 [79%, 58-93] of 24 participants with two or more HRCAs) and 84 (71%, 62-79) reached MRD-SURE and treatment cessation. 36-month progression-free survival among all 123 participants was 88% (95% CI 78-95) for participants with no HRCAs, 79% (67-88) for those with one HRCA, and 50% (30-70) for those with two or more HRCAs. For the 84 participants reaching MRD-SURE, the 24-month cumulative incidence of progression from cessation of therapy was 9% (95% CI 1-19) for participants with no HRCAs, 9% (1-18) for those with one HRCA, and 47% (23-72) for those with two or more HRCAs. 61 participants (comprising 52% of 118 MRD-evaluable participants and 73% of 84 participants who reached MRD-SURE) remain free of therapy and MRD-negative as of Feb 7, 2023. The most common grade 3-4 adverse events were neutropenia (43 patients, 35%), lymphopenia (28 patients, 23%), and hypertension (13 patients, 11%). Three treatment-emergent deaths were recorded: two sudden deaths and one due to viral infection, none of which were judged to be treatment-related. INTERPRETATION: This approach provided positive outcomes and a pathway for treatment cessation in most patients with newly diagnosed multiple myeloma. Outcomes for patients with ultra-high-risk multiple myeloma, defined as those with two or more HRCAs, remain unsatisfactory, and these patients should be prioritised for trials with early introduction of therapies with novel mechanisms of action. FUNDING: Amgen and Janssen Pharmaceuticals.

Impact of Baseline and Week 2 and Week 4 Posttransplant CMV Cell-Mediated Immunity on Risk of CMV Infections and Mortality in Recipients of Allogeneic Hematopoietic Cell Transplant.

Background: Cytomegalovirus (CMV) infection is a common opportunistic infection after allogeneic hematopoietic cell transplant (alloHCT). We explored whether a change in CMV cell-mediated immunity during the first month after transplant predicts the risk of development of CMV infection and all-cause mortality. Methods: This follow-up analysis is based on data from the REACT study, a multicenter prospective observational study of recipients of alloHCT who were CMV-seropositive. Production of interferon γ following ex vivo stimulation with CMV antigens IE1 (immediate early 1) and pp65 (phosphoprotein 65) was assessed by CMV ELISPOT assay at baseline and 2 and 4 weeks after transplant. Clinically significant CMV infection (CS-CMVi) was defined as CMV viremia and/or disease necessitating antiviral therapy. We evaluated the impact of CMV CMI changes on the risk of CS-CMVi and post transplant mortality. Results: The analysis included 226 recipients of alloHCT with CMV cell-mediated immunity data at baseline and 2 and/or 4 weeks after transplant. CS-CMVi occurred in 64 patients (28%). On Cox regression analyses, independent predictors of CS-CMVi included a negative Δ change from baseline to week 2 of pp65 spot counts (hazard ratio, 3.65 [95% CI, 1.65-8.04]; P = .001) to week 4 of IE1 spot counts (hazard ratio, 2.79 [95% CI, 1.46-5.35]; P = .002), anti-thymocyte globulin conditioning regimen, type of transplant, female sex, and corticosteroid use. Kaplan-Meir analysis showed a significant association of a negative IE1 change from baseline to week 4 and increased all-cause mortality after transplant (log rank test = 0.041). Conclusions: A decrease in CMV-specific T-cell responses during the first month after transplant may predict CS-CMVi and is associated with all-cause mortality in recipients of alloHCT.

Ciltacabtagene Autoleucel, an Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T-Cell Therapy, for Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 2-Year Follow-Up.

PURPOSE: CARTITUDE-1, a phase Ib/II study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel) in heavily pretreated patients with relapsed/refractory multiple myeloma, yielded early, deep, and durable responses at 12 months. Here, we present updated results 2 years after last patient in (median follow-up [MFU] approximately 28 months), including analyses of high-risk patient subgroups. METHODS: Eligible patients had relapsed/refractory multiple myeloma, had received ≥ 3 prior lines of therapy or were double refractory to a proteasome inhibitor and immunomodulatory drug and had received prior proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy. Patients received a single cilta-cel infusion 5-7 days after lymphodepletion. Responses were assessed by an independent review committee. RESULTS: At a MFU of 27.7 months (N = 97), the overall response rate was 97.9% (95% CI, 92.7 to 99.7); 82.5% (95% CI, 73.4 to 89.4) of patients achieved a stringent complete response. Median duration of response was not estimable. Median progression-free survival (PFS) and overall survival (OS) were not reached; 27-month PFS and OS rates were 54.9% (95% CI, 44.0 to 64.6) and 70.4% (95% CI, 60.1 to 78.6), respectively. Overall response rates were high across all subgroups (95.1%-100%). Duration of response, PFS, and/or OS were shorter in patients with high-risk cytogenetics, International Staging System stage III, high tumor burden, or plasmacytomas. The safety profile was manageable with no new cilta-cel-related cytokine release syndrome and one new case of parkinsonism (day 914 after cilta-cel) since the last report. CONCLUSION: At approximately 28 months MFU, patients treated with cilta-cel maintained deep and durable responses, observed in both standard and high-risk subgroups. The risk/benefit profile of cilta-cel remained favorable with longer follow-up.

Trajectories of quality of life recovery and symptom burden after autologous hematopoietic cell transplantation in multiple myeloma.

Early autologous hematopoietic cell transplantation (AHCT) with post-transplant maintenance therapy is standard of care in multiple myeloma (MM). While short-term quality of life (QOL) deterioration after AHCT is known, the long-term trajectories and symptom burden after transplantation are largely unknown. Toward this goal, a secondary analysis of QOL data of the BMT CTN 0702, a randomized controlled trial comparing outcomes of three treatment interventions after a single AHCT (N = 758), was conducted. FACT-BMT scores up to 4 years post-AHCT were analyzed. Symptom burden was studied using responses to 17 individual symptoms dichotomized as 'none/mild' for scores 0-2 and 'moderate/severe' for scores of 3 or 4. Patients with no moderate/severe symptom ratings were considered to have low symptom burden at 1-year. Mean age at enrollment was 55.5 years with 17% African Americans. Median follow-up was 6 years (range, 0.4-8.5 years). FACT-BMT scores improved between enrollment and 1-year and remained stable thereafter. Low symptom burden was reported by 27% of patients at baseline, 38% at 1-year, and 32% at 4 years post-AHCT. Predictors of low symptom burden at 1-year included low symptom burden at baseline: OR 2.7 (1.8-4.1), p < 0.0001; older age: OR 2.1 (1.3-3.2), p = 0.0007; and was related to being employed: OR 2.1 (1.4-3.2), p = 0.0004). We conclude that MM survivors who achieve disease control after AHCT have excellent recovery of FACT-BMT and subscale scores to population norms by 1-year post-transplant, though many patients continue to report moderate to severe severity in some symptoms at 1-year and beyond.

A Multicenter Phase II, Double-Blind, Placebo-Controlled Trial of Maintenance Ixazomib After Allogeneic Transplantation for High-Risk Multiple Myeloma: Results of the Blood and Marrow Transplant Clinical Trials Network 1302 Trial.

The role of allogeneic hematopoietic cell transplantation (allo-HCT) followed by maintenance therapy in high-risk multiple myeloma (MM) remains controversial. We evaluated the efficacy of ixazomib maintenance therapy after reduced-intensity conditioning allo-HCT from HLA-matched donors in patients with high-risk MM. The primary study endpoint was progression-free survival (PFS) postrandomization, treated as a time to event. Secondary endpoints were grade II-IV and grade II-IV acute graft-versus-host-disease (GVHD), chronic GVHD, best response, disease progression, nonrelapse mortality (NRM), overall survival (OS), toxicity, infection, and health-related quality of life. In this phase 2, double-blinded, prospective multicenter trial, we randomized patients with high-risk MM (ie, those with poor-risk cytogenetics, plasma cell leukemia, or relapsing within 24 months after autologous HCT) to ixazomib (3 mg on days 1, 8, and 15) or placebo after allo-HCT. The conditioning regimen included fludarabine/melphalan/bortezomib with tacrolimus plus methotrexate for GVHD. Fifty-seven patients were enrolled, of whom 52 (91.2%) underwent allo-HCT and 43 (82.7%) were randomized to ixazomib versus placebo. At 21 months postrandomization, the ixazomib and placebo groups had similar PFS (55.3% versus 59.1%; P = 1.00) and OS (94.7% versus 86.4%; P = .17). The cumulative incidences of grade III-IV acute GVHD at 100 days (9.5% versus 0%) and chronic GVHD at 12 months (68.6% versus 63.6%) also were similar in the 2 groups. The secondary analysis showed that at 24 months post-allo-HCT, PFS and OS were 52% and 82%, respectively, with a corresponding NRM of 11.7%. These results demonstrate the safety and durable disease control with allo-HCT in high-risk MM patients. We could not adequately assess the efficacy of ixazomib maintenance because the trial terminated early owing to enrollment delays, but there was no indication of any impact on outcomes.

Patient Perceptions Regarding Ciltacabtagene Autoleucel Treatment: Qualitative Evidence From Interviews With Patients With Relapsed/Refractory Multiple Myeloma in the CARTITUDE-1 Study.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel), a novel chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated early, deep, and durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), and improvements in health-related quality of life (HRQoL) in CARTITUDE-1 (NCT03548207). Patient perspectives on treatment provide context to efficacy outcomes and are an important aspect of therapeutic evaluation. METHODS: Qualitative interviews were conducted in a subset of CARTITUDE-1 patients (n = 36) at screening, Day 100, and Day 184 post cilta-cel on living with MM, therapy expectations, and treatment experiences during the study. RESULTS: Patients most wanted to see change in symptoms with the greatest impact on HRQoL: pain (85.2%) and fatigue (74.1%). The primary treatment expectation was achieving remission (40.7%), followed by extended life expectancy (14.8%). Patients most often defined meaningful change as improvement in symptoms (70.4%) and return to normalcy (40.7%). The percentage of patients reporting symptoms (pain, fatigue, bone fracture, gastrointestinal, neuropathy, and weakness) decreased from 85.2% to 22.2% across symptom types at baseline to 29.2% to 0% on Day 184 after cilta-cel. Improved symptoms and positive sentiments corresponded with improved perception of overall health status and reduced pain level, respectively. Most patients reported that their expectations of cilta-cel treatment had been met (70.8%) or exceeded (20.8%) at Day 184, and 70.8% of patients considered cilta-cel therapy better than their previous treatments. CONCLUSION: Overall HRQoL improvements and qualitative interviews showed cilta-cel met patient expectations of treatment and suggest the long treatment-free period also contributed to positive sentiments.

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.