Options at the time of relapse after anti-BCMA therapy.

B-cell maturation antigen (BCMA)-directed therapies, including antibody-drug conjugates, bispecific antibodies (BsAbs), and chimeric antigen receptor T cells (CARTs), have shown remarkable efficacy in patients with late-line myeloma with prior exposure to immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies. However, optimal sequencing of these agents remains to be determined, and management of these patients once they relapse has become a new unmet need. Fortunately, there are multiple options with demonstrated activity after anti-BCMA therapy, including a different BCMA-directed therapy, non-BCMA-directed CARTs and BsAbs, novel non-T-cell-engaging drugs, and standard triplet/quadruplet regimens or salvage stem cell transplant. Factors to consider when choosing a next therapy after anti-BCMA therapy include patient characteristics and preferences, prior therapies and toxicities, disease biology, timing from last anti-BCMA therapy, and, in the future, BCMA expression and immune profiling. While current data are limited to retrospective studies and small prospective cohorts, the serial use of T-cell-engaging therapies looks particularly promising, especially as BCMA-directed therapies move up earlier in the myeloma treatment course and additional CARTs and BsAbs against alternative targets (eg, G protein-coupled receptor, family C, group 5, member D and Fc receptor-homolog 5) become available. Going forward, ongoing prospective studies, large real-world data sets, and better tools to interrogate antigen expression and immune cell fitness hopefully will provide further insight into how to best individualize therapy for this difficult-to-treat population.

Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents.

B-cell maturation antigen (BCMA)-targeting therapies, including bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs), are promising treatments for multiple myeloma (MM), but disease may progress after their use. CARTITUDE-2 is a phase 2, multicohort study evaluating the safety and efficacy of cilta-cel, an anti-BCMA chimeric antigen receptor T therapy, in various myeloma patient populations. Patients in cohort C progressed despite treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and noncellular anti-BCMA immunotherapy. A single cilta-cel infusion was given after lymphodepletion. The primary end point was minimal residual disease (MRD) negativity at 10-5. Overall, 20 patients were treated (13 ADC exposed; 7 BsAb exposed; 1 in the ADC group also had prior BsAb exposure). Sixteen (80%) were refractory to prior anti-BCMA therapy. At a median follow-up of 11.3 months (range, 0.6-16.0), 7 of 20 (35%) patients were MRD negative (7 of 10 [70.0%] in the MRD-evaluable subset). Overall response rate (95% confidence interval [CI]) was 60.0% (36.1-80.9). Median duration of response and progression-free survival (95% CI) were 11.5 (7.9-not estimable) and 9.1 (1.5-not estimable) months, respectively. The most common adverse events were hematologic. Cytokine release syndrome occurred in 12 (60%) patients (all grade 1-2); 4 had immune effector cell-associated neurotoxicity syndrome (2 had grade 3-4); none had parkinsonism. Seven (35%) patients died (3 of progressive disease, 4 of adverse events [1 treatment related, 3 unrelated]). Cilta-cel induced favorable responses in patients with relapsed/refractory MM and prior exposure to anti-BCMA treatment who had exhausted other therapies. This trial was registered at www.clinicaltrials.gov as NCT04133636.

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.

Myeloma: next generation immunotherapy.

The course of multiple myeloma (MM) from initial diagnosis to a relapsed/refractory state is characterized by acquisition of drug resistance as well as progressive immunologic dysfunction. Despite this, however, a number of novel therapies that work in part or solely via immune stimulation are in development for MM, with promising early clinical results. Several new whole-cell or multiepitope vaccine approaches are demonstrating immunologic efficacy in smoldering MM or as posttherapy consolidation, with trials ongoing to see whether this translates into delayed progression or elimination of minimal residual disease. Programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibition in combination with immunomodulatory drugs demonstrated excessive toxicity in randomized trials; however, antibodies targeting PD-1/PD-L1 and other checkpoint molecules continue to be explored in combination with tumor-targeted antibodies and other T cell-directed therapies. B-cell maturation antigen (BCMA) has emerged as the next big antigen target, with multiple BCMA-specific antibody-drug conjugates (ADCs) and T cell-directed bispecific antibodies/bispecific therapeutic engagers (BiTEs) entering the clinic. In initial trials, the ADC GSK2857916 and the BiTE AMG 420 have demonstrated high response rates in relapsed/refractory patients, with depth and durability of responses that may end up rivaling chimeric antigen receptor T-cell therapies. These agents have unique toxicities that require close monitoring, but they are moving forward in larger registration studies and in combination with standard MM agents. Additional ADCs and bispecific antibodies targeting BCMA and other surface antigens (eg, CD38, CD46, CD48, FcRH5, and G protein-coupled receptor, class C group 5 member D) are moving forward in phase 1 trials and may provide even more options for MM patients.

CAR T Cells and Other Cellular Therapies for Multiple Myeloma: 2018 Update.

Cellular therapies are a rapidly evolving approach to myeloma treatment, which bring a unique mechanism of action with the potential to overcome drug resistance and induce long-term remissions. Two primary approaches are being studied: non-gene-modified strategies, which rely on the endogenous anti-myeloma T-cell repertoire, and gene-modified strategies, which introduce a new T-cell receptor (TCR) or a chimeric antigen receptor (CAR) to confer novel antigen specificity. CAR T cells show the greatest activity to date. Multiple antigen targets, including B-cell maturation antigen (BCMA), CD19, CD38, CD138, and SLAMF7, are being explored for myeloma, and BCMA has emerged as the most promising. Preliminary data from four phase I studies of BCMA CAR T cells, each using a different CAR construct, that involved 90 evaluable patients with relapsed/refractory disease have been reported. These data show response rates of 60% to 100%, including minimal residual disease (MRD)-negative complete remissions, at effective doses (> 108 CAR-positive cells) after lymphodepleting conditioning. Response durability has been more variable, likely related to differences in CAR T-cell products, lymphodepleting regimens, patient selection criteria, and/or underlying biology/prognostic factors. In the two most recent studies, however, most patients remained progression free with median follow-up time of 6 to 10 months; some ongoing remissions lasted more than 1 year. Toxicities are similar to those from CD19 CAR T cells and include cytokine release syndrome and neurotoxicity that is reversible but can be severe. Multiple BCMA CAR T-cell studies are ongoing. Future directions include combinations with immunomodulatory drugs, checkpoint inhibitors, or other CAR T cells, as well as use of gene-edited cellular products to enhance the safety and efficacy of this approach.

Hematologic Malignancies: Plasma Cell Disorders.

Multiple myeloma (MM) is a plasma cell malignancy characterized by the growth of tumor cells in the bone marrow. Properties of the tumor microenvironment provide both potential tumor-promoting and tumor-restricting properties. Targeting underlying immune triggers for evolution of tumors as well as direct attack of malignant plasma cells is an emerging focus of therapy for MM. The monoclonal antibodies daratumumab and elotuzumab, which target the plasma cell surface proteins CD38 and SLAMF7/CS1, respectively, particularly when used in combination with immunomodulatory agents and proteasome inhibitors, have resulted in high response rates and improved survival for patients with relapsed and refractory MM. A number of other monoclonal antibodies are in various stages of clinical development, including those targeting MM cell surface antigens, the bone marrow microenvironment, and immune effector T cells such as antiprogrammed cell death protein 1 antibodies. Bispecific preparations seek to simultaneously target MM cells and activate endogenous T cells to enhance efficacy. Cellular immunotherapy seeks to overcome the limitations of the endogenous antimyeloma immune response through adoptive transfer of immune effector cells with MM specificity. Allogeneic donor lymphocyte infusion can be effective but can cause graft-versus-host disease. The most promising approach appears to be genetically modified cellular therapy, in which T cells are given novel antigen specificity through expression of transgenic T-cell receptors (TCRs) or chimeric antigen receptors (CARs). CAR T cells against several different targets are under investigation in MM. Infusion of CD19-targeted CAR T cells following salvage autologous stem cell transplantation (SCT) was safe and extended remission duration in a subset of patients with relapsed/refractory MM. CAR T cells targeting B-cell maturation antigen (BCMA) appear most promising, with dramatic remissions seen in patients with highly refractory disease in three ongoing trials. Responses are associated with degree of CAR T-cell expansion/persistence and often toxicity, including cytokine release syndrome (CRS) and neurotoxicity. Ongoing and future studies are exploring correlates of response, ways to mitigate toxicity, and "universal" CAR T cells.

Outpatient Autologous Stem Cell Transplantation for Patients With Myeloma.

BACKGROUND: High-dose melphalan with autologous stem cell support improves survival for patients with myeloma. For selected patients, we have been using a protocol of short hospitalization, discharging patients to home with careful outpatient monitoring in the office, which we hypothesized would reduce complications and utilization of inpatient beds. METHODS: We reviewed 301 initial autologous transplants for myeloma, categorized as brief stay (≤ 4 days, 82 patients) or prolonged stay (≥ 5 days, 219 patients). Selection for a brief stay was determined by clinical characteristics, availability of caregivers at home, distance from our medical center, and patient preference. RESULTS: Within the brief stay population, 67% required readmission before day + 100, but this group still had fewer cumulative hospital days (9 vs. 18, P < .0001). There were fewer documented infections among brief stay patients (22% vs. 46% P < .001) and fewer admissions to intensive care units (0% vs. 5.9%, P = .02). The groups had similar rates of bleeding (1.2% vs. 1.4% P = 1.0) and thrombosis (3.7% vs. 4.6% P = 1.0). No patients in the brief stay group died within 100 days, compared with mortality of 1.8% (P = .6) in the prolonged stay group. CONCLUSION: Carefully selected patients receiving an autologous stem cell transplant for treatment of myeloma can be managed with a brief initial hospitalization and outpatient follow-up, with low morbidity and mortality.