An open-label, first-in-human, single agent, dose escalation study for the evaluation of safety and efficacy of SAR442085 in patients with relapsed or refractory multiple myeloma.

OBJECTIVES: Cluster of differentiation 38 (CD38) is a key target on multiple myeloma (MM) cells. This multi-centre, Phase 1, single-agent study (NCT04000282) investigated SAR442085, a novel fragment crystallisable (Fc)-modified anti-CD38 monoclonal antibody (mAb), with enhanced affinity towards Fc-gamma receptor on effector cells in patients with relapsed and/or refractory (RR) MM. METHODS: This study comprised two parts: Part-A (dose-escalation involving anti-CD38 mAb pre-treated and naïve patients) and Part-B (dose expansion). Primary endpoints were maximum tolerated dose and recommended Phase 2 dose (RP2D). RESULTS: Thirty-seven heavily pre-treated patients were treated in Part A. Part-B (dose-expansion) was not studied. Seven dose-limiting toxicities were reported at DL3, DL5, DL6, and DL7. RP2D was determined to be 5-7·5 mg/kg. Most common treatment-emergent adverse events were infusion-related reactions in 70·3% (26/37) patients. Grade ≥3 thrombocytopenia was reported in 48·6% (18/37). Overall response rate was 70% in anti-CD38 mAb naïve and 4% in anti-CD38 pre-treated patients, with a median progression-free survival of 7·62 (95%CI: 2·858; not calculable) months and 2·79 (95%CI: 1·150; 4·172) months and, respectively. CONCLUSIONS: The efficacy of SAR442085 was promising in anti-CD38 mAb naïve patients but did not extend to the larger cohort of anti-CD38 mAb pre-treated patients. This observation, along with transient high-grade thrombocytopenia, could potentially limit its clinical use.

Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN.

The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]). Patients received 4 induction cycles (D-RVd/RVd), high-dose therapy/transplant, 2 consolidation cycles (D-RVd/RVd), and lenalidomide±daratumumab maintenance (≤ 2 years). Minimal residual disease-negativity (10-5) rates were higher for D-RVd versus RVd in patients ≥ 65 years (67.9% vs 17.9%), with HRCAs (54.8% vs 32.4%), and with gain/amp(1q21) (61.8% vs 28.6%). D-RVd showed a trend toward improved progression-free survival versus RVd (hazard ratio [95% confidence interval]) in patients ≥ 65 years (0.29 [0.06-1.48]), with HRCAs (0.38 [0.14-1.01]), and with gain/amp(1q21) (0.42 [0.14-1.27]). In the functional high-risk subgroup (not MRD negative at the end of consolidation), the hazard ratio was 0.82 (0.35-1.89). Among patients ≥ 65 years, grade 3/4 treatment-emergent adverse event (TEAE) rates were higher for D-RVd versus RVd (88.9% vs 77.8%), as were TEAEs leading to discontinuation of ≥ 1 treatment component (37.0% vs 25.9%). One D-RVd patient died due to an unrelated TEAE. These results support the addition of daratumumab to RVd in transplant-eligible patients with high-risk NDMM. Video Abstract.

Health-related quality of life in transplant-eligible patients with newly diagnosed multiple myeloma treated with daratumumab, lenalidomide, bortezomib, and dexamethasone: Patient-reported outcomes from GRIFFIN.

In the phase 2 GRIFFIN trial (ClinicalTrials.gov identifier: NCT02874742), daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) improved depth of response and progression-free survival (PFS) versus lenalidomide, bortezomib, and dexamethasone (RVd) alone in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) collected using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30-item (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module 20-item (QLQ-MY20), and EuroQol 5-Dimension 5-Level (EQ-5D-5L) tools on day 1 of cycles 1, 2, and 3; on day 21 of cycle 4 (end of induction therapy); on day 1 of cycle 5; on day 21 of cycle 6 (end of posttransplant consolidation therapy); and at months 6, 12, 18, and 24 of maintenance therapy. Meaningful improvements from baseline were seen in most of the PRO scales with both treatments after consolidation and were sustained for at least 2 years of maintenance treatment. Large reductions from baseline (~20 points) were especially observed in pain symptoms for both treatment groups, although these were numerically higher for patients receiving D-RVd during the majority of the time points. In addition, improvements in key scales, such as global health status, fatigue symptoms, and physical functioning, were also seen with both D-RVd and RVd. These improvements in health-related quality of life contribute to the totality of evidence supporting the improvement in clinical outcomes such as response rates and PFS with D-RVd in induction, consolidation, and maintenance therapy in TE patients with NDMM.

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.

Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial.

BACKGROUND: Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone (D-RVd) in the GRIFFIN study improved the stringent complete response rate by the end of consolidation in transplantation-eligible patients with newly diagnosed multiple myeloma. Here, we report the findings of the predefined final analysis. METHODS: GRIFFIN was an open-label, randomised, active-controlled, phase 2 trial done in 35 research centres in the USA. Patients had newly diagnosed multiple myeloma with measurable disease by M protein or free light chain, were aged 18-70 years, had an ECOG performance score of 0-2, and were eligible for autologous haematopoietic stem-cell transplantation (HSCT). Patients were randomly assigned (1:1) to four D-RVd or RVd induction cycles, autologous HSCT, two D-RVd or RVd consolidation cycles, and lenalidomide with or without daratumumab maintenance therapy for 2 years. Patients received 21-day cycles of oral lenalidomide (25 mg on days 1-14), subcutaneous bortezomib (1·3 mg/m2 on days 1, 4, 8, and 11), oral dexamethasone (40 mg weekly) with or without intravenous daratumumab (16 mg/kg weekly, cycles 1-4; day 1, cycles 5-6). Maintenance therapy (28-day cycles) was oral lenalidomide (10 mg on days 1-21) with or without daratumumab (16 mg/kg intravenously every 4 or 8 weeks, or 1800 mg subcutaneously monthly). Patients could continue lenalidomide maintenance after study treatment completion. The primary endpoint was stringent complete response rate by the end of consolidation in the response-evaluable population, and has already been reported. Here we report updated stringent complete response rates and secondary outcomes including progression-free survival and overall survival. The trial is registered with ClinicalTrials.gov (NCT02874742) and ended on April 8, 2022. FINDINGS: Between Dec 20, 2016, and April 10, 2018, 104 patients were randomly assigned to the D-RVd group and 103 were randomly assigned to the RVd group; most patients were White (85 [82%] in the D-RVd group and 76 [74%] in the RVd group) and male (58 [56%] in the D-RVd group and 60 [58%] in the RVd group). At a median follow-up of 49·6 months (IQR 47·4-52·1), D-RVd improved rates of stringent complete response (67 [67%] of 100] vs 47 [48%] of 98]; odds ratio 2·18 [95% CI 1·22-3·89], p=0·0079), and 4-year progression-free survival was 87·2% (95% CI 77·9-92·8) for D-RVd versus 70·0% (95% CI 55·9-80·3) for RVd, with a hazard ratio (HR) of 0·45 (95% CI 0·21-0·95, p=0·032) for risk of disease progression or death with D-RVd. Median overall survival was not reached for either group (HR 0·90 [95% CI 0·31-2·56], p=0·84). The most common grade 3-4 treatment-emergent adverse events in the D-RVd versus RVd groups were neutropenia (46 [46%] of 99 vs 23 [23%] of 102), lymphopenia (23 [23%] vs 23 [23%]), leukopenia (17 [17%] vs eight [8%]), thrombocytopenia (16 [16%] vs nine [9%]), pneumonia (12 [12%] vs 14 [14%]), and hypophosphataemia (ten [10%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 46 (46%) of 99 patients in the D-RVd group and in 53 (52%) of 102 patients in the RVd group. One patient in each treatment group reported a treatment-emergent adverse event that resulted in death (bronchopneumonia in the D-RVd group; cause unknown in the RVd group); neither was related to study treatment. No new safety concerns occurred with maintenance therapy. INTERPRETATION: Addition of daratumumab to RVd improved the depth of response and progression-free survival in transplantation-eligible patients with newly diagnosed multiple myeloma. These results justify further evaluation in phase 3 studies. FUNDING: Janssen Oncology.

Pancreatic Adenocarcinoma: Real World Evidence of Care Delivery in AccessHope Data.

BACKGROUND: Pancreatic adenocarcinoma is an aggressive disease and the delivery of comprehensive care to individuals with this cancer is critical to achieve appropriate outcomes. The identification of gaps in care delivery facilitates the design of interventions to optimize care delivery and improve outcomes in this population. METHODS: AccessHope™ is a growing organization that connects oncology subspecialists with treating providers through contracts with self-insured employers. Data from 94 pancreatic adenocarcinoma cases (August 2019-December 2022) in the AccessHope dataset were used to describe gaps in care delivery. RESULTS: In all but 6% of cases, the subspecialist provided guideline-concordant recommendations anticipated to improve outcomes. Gaps in care were more pronounced in patients with non-metastatic pancreatic cancer. There was a significant deficiency in germline testing regardless of the stage, with only 59% of cases having completed testing. Only 20% of cases were receiving palliative care or other allied support services. There was no difference in observed care gaps between patients receiving care in the community setting vs. those receiving care in the academic setting. CONCLUSIONS: There are significant gaps in the care delivered to patients with pancreatic adenocarcinoma. A concurrent subspecialist review has the opportunity to identify and address these gaps in a timely manner.

Stimulation of Potent Humoral and Cellular Immunity via Synthetic Dual-Antigen MVA-Based COVID-19 Vaccine COH04S1 in Cancer Patients Post Hematopoietic Cell Transplantation and Cellular Therapy.

Hematopoietic cell transplantation (HCT) and chimeric antigen receptor (CAR)-T cell patients are immunocompromised, remain at high risk following SARS-CoV-2 infection, and are less likely than immunocompetent individuals to respond to vaccination. As part of the safety lead-in portion of a phase 2 clinical trial in patients post HCT/CAR-T for hematological malignancies (HM), we tested the immunogenicity of the synthetic modified vaccinia Ankara-based COVID-19 vaccine COH04S1 co-expressing spike (S) and nucleocapsid (N) antigens. Thirteen patients were vaccinated 3-12 months post HCT/CAR-T with two to four doses of COH04S1. SARS-CoV-2 antigen-specific humoral and cellular immune responses, including neutralizing antibodies to ancestral virus and variants of concern (VOC), were measured up to six months post vaccination and compared to immune responses in historical cohorts of naïve healthy volunteers (HV) vaccinated with COH04S1 and naïve healthcare workers (HCW) vaccinated with the FDA-approved mRNA vaccine Comirnaty® (Pfizer, New York, NY, USA). After one or two COH04S1 vaccine doses, HCT/CAR-T recipients showed a significant increase in S- and N-specific binding antibody titers and neutralizing antibodies with potent activity against SARS-CoV-2 ancestral virus and VOC, including the highly immune evasive Omicron XBB.1.5 variant. Furthermore, vaccination with COH04S1 resulted in a significant increase in S- and N-specific T cells, predominantly CD4+ T lymphocytes. Elevated S- and N-specific immune responses continued to persist at six months post vaccination. Furthermore, both humoral and cellular immune responses in COH04S1-vaccinated HCT/CAR-T patients were superior or comparable to those measured in COH04S1-vaccinated HV or Comirnaty®-vaccinated HCW. These results demonstrate robust stimulation of SARS-CoV-2 S- and N-specific immune responses including cross-reactive neutralizing antibodies by COH04S1 in HM patients post HCT/CAR-T, supporting further testing of COH04S1 in immunocompromised populations.

Stem Cell Mobilization Yields with Daratumumab- and Lenalidomide-Containing Quadruplet Induction Therapy in Newly Diagnosed Multiple Myeloma: Findings from the MASTER and GRIFFIN Trials.

For eligible patients with newly diagnosed multiple myeloma (NDMM), standard of care includes induction therapy followed by autologous stem cell transplantation (ASCT). Daratumumab as monotherapy and in combination treatment is approved across multiple lines of therapy for multiple myeloma (MM), and lenalidomide is an effective and commonly used agent for induction and maintenance therapy in MM. However, there is concern that lenalidomide and daratumumab given as induction therapy might impair mobilization of stem cells for ASCT. Therefore, we assessed stem cell mobilization in patients following frontline induction therapy in the MASTER and GRIFFIN phase 2 clinical studies by examining stem cell mobilization yields, apheresis attempts, and engraftment outcomes for patients from each study. Adult transplantation-eligible patients with NDMM received induction therapy consisting of daratumumab plus carfilzomib/lenalidomide/dexamethasone (D-KRd) for four 28-day cycles in the single-arm MASTER trial or lenalidomide/bortezomib/dexamethasone (RVd) with or without daratumumab (D) for four 21-day cycles in the randomized GRIFFIN trial, followed by stem cell mobilization and ASCT in both studies. Institutional practice differed regarding plerixafor use for stem cell mobilization; the strategies were upfront (ie, planned plerixafor use) or rescue (ie, plerixafor use only after mobilization parameters indicated failure with granulocyte colony-stimulating factor [G-CSF] alone). Descriptive analyses were used to summarize patient characteristics, stem cell mobilization yields, and engraftment outcomes. In MASTER, 116 D-KRd recipients underwent stem cell mobilization and collection at a median of 24 days after completing induction therapy. In GRIFFIN, 175 patients (D-RVd, n = 95; RVd, n = 80) underwent mobilization at a median of 27 days after completing D-RVd induction therapy and 24 days after completing RVd induction therapy. Among those who underwent mobilization and collection, 7% (8 of 116) of D-KRd recipients, 2% (2 of 95) of D-RVd recipients, and 6% (5 of 80) of RVd recipients did not meet the center-specific minimally required CD34+ cell yield in the first mobilization attempt; however, nearly all collected sufficient stem cells for ASCT on remobilization. Among patients who underwent mobilization, plerixafor use, either upfront or as a rescue strategy, was higher in patients receiving D-KRd (97%; 112 of 116) and D-RVd (72%; 68 of 95) compared with those receiving RVd (55%; 44 of 80). The median total CD34+ cell collection was 6.0 × 106/kg (range, 2.2 to 13.9 × 106/kg) after D-KRd induction, 8.3 × 106/kg (range, 2.6 to 33.0 × 106/kg) after D-RVd induction, and 9.4 × 106/kg (range, 4.1 to 28.7 × 106/kg) after RVd induction; the median days for collection were 2, 2, and 1, respectively. Among patients who underwent mobilization, 98% (114 of 116) of D-KRd patients, 99% (94 of 95) of D-RVd patients, and 98% (78 of 80) of RVd patients underwent ASCT using median CD34+ cell doses of 3.2 × 106/kg, 4.2 × 106/kg, and 4.8 × 106/kg, respectively. The median time to neutrophil recovery was 12 days in all 3 treatment groups across the 2 trials. Because both trials used different criteria to define platelet recovery, data on platelet engraftment using the same criteria are not available. Four cycles of daratumumab- and lenalidomide-based quadruplet induction therapy had a minimal impact on stem cell mobilization and allowed predictable stem cell harvesting and engraftment in all patients who underwent ASCT. Upfront plerixafor strategy may be considered, but many patients were successfully collected with the use of G-CSF alone or rescue plerixafor.

Telehealth exercise to Improve Physical function and frailty in patients with multiple myeloma treated with autologous hematopoietic Stem cell transplantation (TIPS): protocol of a randomized controlled trial.

BACKGROUND: Advances in autologous hematopoietic stem cell transplantation (HSCT) and supportive care have led to marked improvements in survival for patients with multiple myeloma. Despite these improvements, patients with multiple myeloma remain at high risk of physical dysfunction and frailty due to HSCT and its associated exposures. Although traditional supervised exercise programs can improve frailty in cancer patients and survivors, rehabilitation facilities are typically far from a patient's residence, are offered on fixed days/hours, contain uniform activities for everyone, and carry a higher risk of contact cross-infection due to immunosuppression, which can be barriers to exercise participation. Innovative personalized interventions are needed to overcome the limitations of traditional exercise interventions. The purpose of this study is to determine the efficacy and sustainability of a telehealth exercise intervention on physical function and frailty in patients with multiple myeloma treated with HSCT. METHODS: This randomized controlled trial will assess the efficacy of an 8-week telehealth exercise intervention in 60 patients with multiple myeloma who underwent autologous HSCT (30-180 days post-transplant) and are pre-frail or frail. There will be 30 intervention participants and 30 delayed controls. We will administer remote baseline assessments (week 0), followed by an 8-week telehealth intervention (week 1-8), post assessment (week 9), and an additional follow-up assessment (week 17). Our primary endpoint will be improved physical function, as assessed by the Short Physical Performance Battery test. Our secondary endpoint will be a decrease in frailty characteristics such as gait speed, strength, and fatigue. We will also evaluate the sustainability of improved physical function and frailty at week 17. Participants randomized to the intervention group will perform at least 90 min of exercise per week throughout the 8 weeks. DISCUSSION: This study will help optimize the delivery of safe, low-cost, and scalable telehealth exercise interventions to improve health outcomes in patients with multiple myeloma, an understudied population at high risk for physical dysfunction and frailty. Our study may provide the foundation for sustainable telehealth exercise interventions to improve physical function and frailty for other hematologic cancer patients (e.g., acute leukemia, lymphoma) as well as any other cancer population of interest. TRIAL REGISTRATION: ClinicalTrials.gov NCT05142371 . This study was retrospectively registered on December 2nd, 2021, and is currently open to accrual.

Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma.

BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown. METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival. RESULTS: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P = 0.55); 42.0% and 46.8%, respectively, had a complete response or better (P = 0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65). CONCLUSIONS: Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.).

Patient perspectives on symptoms, health-related quality of life, and treatment experience associated with relapsed/refractory multiple myeloma.

PURPOSE: This study aimed to better understand the patient perspective and treatment experience of relapsed and/or refractory multiple myeloma (RRMM). METHODS: This qualitative study enrolled adult RRMM patients from 6 US clinics who had ≥ 3 months of life expectancy, ≤ 6 prior lines of therapy, and ≥ 1 treatment regimen with a proteasome inhibitor and immunomodulator, or a CD38 monoclonal antibody or an alkylating agent, and a steroid. In-person semi-structured qualitative interviews were conducted to capture concepts that were relevant and important to patients. Topics included RRMM symptoms and impacts and the mode of administration, frequency, duration, convenience, side effects, and overall experience with RRMM treatment. RESULTS: A total of 22 patients completed interviews. At enrollment, 59.1% of participants were using regimens containing dexamethasone, 36.4% daratumumab, 27.3% carfilzomib, and 18.2% lenalidomide. More participants had experience using intravenous or injectable therapy alone (40.9%) than oral therapy alone (18.2%). Back pain and fatigue were the most frequently reported symptoms (40.9% each); 27.3% reported no symptoms. Most participants reported physical function limitations (86.4%), emotional impacts (77.3%), MM-related activity limitations (72.7%), and sleep disturbances (63.6%). Most participants perceived treatment effectiveness based on physician-explained clinical signs (68.2%) and symptom relief (40.9%). Participants experienced gastrointestinal adverse events (59.1%), fatigue (59.1%), sleep disturbances (31.8%), and allergic reactions (31.8%) with treatment. Key elements of treatment burden included the duration of a typical treatment day (68.2%), treatment interfering with daily activities (54.5%), and infusion duration (50.0%). CONCLUSIONS: These results provide treatment experience-related data to further understand RRMM treatment burden and better inform treatment decision-making.

When and How to Treat Relapsed Multiple Myeloma.

The treatment landscape for relapsed multiple myeloma has expanded considerably in recent years, as numerous agents with new mechanisms of action have been introduced, increasing responses even in advanced disease and prolonging survival. The wealth of novel regimens comes with the challenges of balancing toxicities and aligning a regimen with the biology of the myeloma and the nature of the relapse in conjunction with patient treatment history and personal preference. Herein, we provide an overview of treatment options for both early and late relapsing disease as well as a discussion of the role of emerging immune-based therapies.

Daratumumab plus RVd for newly diagnosed multiple myeloma: final analysis of the safety run-in cohort of GRIFFIN.

The phase 2 GRIFFIN study of daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) for transplant-eligible, newly diagnosed multiple myeloma included a safety run-in phase followed by a randomized phase. The ongoing randomized phase has met its prespecified primary end point of an improved stringent complete response (sCR) rate after consolidation for D-RVd (reported elsewhere). Final analysis of the safety run-in cohort is reported herein and provides longer follow-up (median, 40.8 months) encompassing daratumumab plus lenalidomide (D-R) maintenance therapy. Patients in the safety run-in cohort (N = 16) received 4 induction cycles (D-RVd), high-dose melphalan supported by autologous stem cell transplant, 2 consolidation cycles (D-RVd), and 24 months of maintenance (D-R). By the end of consolidation, all patients had responded, with a best response of sCR in 9 (56.3%) patients; 8 (50.0%) patients were minimal residual disease (MRD) negative (10‒5 threshold). After maintenance, 15 (93.8%) patients had achieved a best response of sCR, and 13 (81.3%) patients were MRD (10‒5) negative. Estimated 36-month progression-free and overall survival rates were 78.1% and 93.8%, respectively. One death from progressive disease occurred in the patient who did not achieve sCR. Observed safety profiles were consistent with daratumumab and RVd. With >3 years of median follow-up, D-RVd achieved durable responses that deepened with D-R maintenance. This study was registered at www.clinicaltrials.gov as #NCT02874742.

Identifying CD38+ cells in patients with multiple myeloma: first-in-human imaging using copper-64-labeled daratumumab.

18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is one of the most widely used imaging techniques to detect multiple myeloma (MM). Intracellular FDG uptake depicts in vivo metabolic activity, which can be seen in both malignant and nonmalignant cells, resulting in limited sensitivity and specificity. Our group showed preclinically that tracing MM dissemination using a CD38-directed human antibody, daratumumab, that is radioconjugated with 64Cu via the chelator DOTA (64Cu-daratumumab), led to improved sensitivity and specificity over that of FDG. Here, we report the results of a phase 1 trial designed to (1) assess the safety and feasibility of 64Cu-daratumumab PET/CT and (2) preliminarily evaluate and characterize the ability of 64Cu-daratumumab to accurately detect or exclude MM lesions. A total of 12 daratumumab-naive patients were imaged. Prior to the injection of 15 mCi/5 mg of 64Cu-daratumumab, patients were treated with 0 (n = 3), 10 (n = 3), 45 (n = 3), or 95 mg (n = 3) of unlabeled daratumumab to assess its effect on image quality. No significant adverse events were observed from either unlabeled daratumumab or 64Cu-daratumumab. Of the dose levels tested, 45 mg unlabeled daratumumab was the most optimal in terms of removing background signal without saturating target sites. 64Cu-daratumumab PET/CT provided safe whole-body imaging of MM. A trial comparing the sensitivity and specificity of 64Cu-daratumumab PET/CT with that of FDG PET/CT is planned. This trial was registered at www.clinicaltrials.gov as #NCT03311828.

Repurposing leflunomide for relapsed/refractory multiple myeloma: a phase 1 study.

The inexpensive, well-tolerated, immunomodulatory agent leflunomide, used extensively for the treatment of rheumatoid arthritis, has been shown to produce significant activity against multiple myeloma (MM) in pre-clinical studies. We conducted a phase 1 study (clinicaltrials.gov: NCT02509052) of single agent leflunomide in patients with relapsed/refractory MM (≥3 prior therapies). At dose levels 1 and 2 (20 and 40 mg), no dose-limiting toxicities (DLTs) were observed. At dose level 3 (60 mg), one patient experienced elevated alanine aminotransferase; an additional three patients were enrolled at this dose level without further DLTs. Overall, toxicities were infrequent and manageable. Nine out of 11 patients achieved stable disease (SD), two subjects experiencing SD for nearly one year or longer. The tolerable safety profile of leflunomide, combined with a potential disease stabilization, is motivating future studies of leflunomide, in combination with other MM drugs, or as an approach to delay progression of smoldering MM.

Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial.

Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10-5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P < .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.

Integrating Touchscreen-Based Geriatric Assessment and Frailty Screening for Adults With Multiple Myeloma to Drive Personalized Treatment Decisions.

PURPOSE: Geriatric assessment (GA) results predict toxicity/survival in older adults, yet GA is not routinely used in care for patients with multiple myeloma (MM). We tested a tablet-based modified GA (mGA) providing real-time results to clinicians. METHODS: One hundred sixty-five patients with MM aged ≥ 65 years facing a treatment decision from 4 sites completed a tablet-based mGA with Katz Activities of Daily Living (ADL), Lawton Instrumental ADL, Charlson Comorbidity Index, and variables from the Cancer and Aging Research Group's Chemotherapy Toxicity Calculator. Providers reviewed the assessment results at the treatment visit. RESULTS: Patients were white (72%; n = 86), mean age was 72 years (range, 65-85 years), and averaged 7.71 minutes (range, 2-17 minutes) for survey completion. Providers averaged 3.2 minutes (range, 1-10 minutes) to review mGA results. Using International Myeloma Working Group frailty score, patients were fit (39%; n = 64), intermediate fit (33%; n = 55), or frail (28%; n = 46). Providers selected more aggressive treatments in 16.3% of patients and decreased treatment intensity in 34% of patients; treatment intensification was more common for fit patients and milder treatments for frail patients (χ2 = 20.02; P < .0001). Transplant eligibility significantly correlated with fit status and transplant ineligibility with frail status (P = .004). Outcomes on 144 patients 3 months post study visit showed 19.4% (n = 28) had grade ≥ 3 hematologic toxicities, 38.9% (n = 56) had dose modifications, and 18% (n = 26) had early therapy cessation. CONCLUSION: Limited patient time required for survey completion and provider time for results review show mGA can be easily incorporated into clinical workflow. Real-time mGA results indicating fit/frailty status influenced treatment decisions.

Understanding Caregiver Quality of Life in Caregivers of Hospitalized Older Adults With Cancer.

BACKGROUND/OBJECTIVES: Caregivers of older adults with cancer assist both with cancer care and other health issues, which may make them vulnerable to consequences of caregiving. Hospitalization may represent a time when a caregiver's ability to provide care at home is exceeded. We sought to characterize caregivers of hospitalized older adults with cancer, determine their quality of life (QOL), and identify factors associated with caregiver QOL. METHODS: Patients (n = 100), aged 65 years and older, with an unplanned hospitalization and their caregivers were included. Caregivers completed a questionnaire about their health, social support, caregiving relationship, QOL (Caregiver Quality of Life Index-Cancer [CQOLC] tool), and patient function. Patient medical history was obtained via chart review. The association between patient, caregiving, and caregiver factors and CQOLC was determined using multivariate linear regression. RESULTS: Most patients (73%) had metastatic/advanced disease, and 71% received treatment for their cancer within 30 days of hospitalization. Median Karnofsky Performance Status (KPS) was 60%, and 89% required help with instrumental activities of daily living, as reported by caregivers. Median caregiver age was 65 years (range = 29-84 years). The majority (60%) had no major comorbidities and rated their health as excellent/good (79%), though 22% reported worsening health due to caregiving. Caregivers had a median Mental Health Inventory-18 score of 70 (range = 0-97), a median Medical Outcomes Study (MOS)-social activity score of 56 (range = 0-87.5), and a median MOS-Social Support Survey score of 68 (range = 0-100). Caregivers provided a median of 35 hours of care per week (range = 0-168 hours of care per week). Mean CQOLC was 84.6 ± 23.5. Lower caregiver QOL was associated with poorer caregiver mental health, less social support, and poorer patient KPS (P < .05). CONCLUSION: Caregivers of hospitalized older adults with cancer are older but generally in good health. Those with poorer mental health, less social support, and caring for patients with poorer performance status are more likely to experience lower QOL. J Am Geriatr Soc 67:978-986, 2019.