Interventions and outcomes of patients with multiple myeloma receiving salvage therapy after BCMA-directed CAR T therapy.

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR T) therapy has demonstrated remarkable efficacy in patients with relapsed/refractory multiple myeloma, and now there are two US Food and Drug Administration-approved BCMA-directed CAR T products. However, despite high initial response rates, most patients eventually relapse. The outcomes of patients with disease recurrence after BCMA-directed CAR T have not been comprehensively studied, and such an analysis would help define optimal treatment strategies. We analyzed the salvage treatments and outcomes of 79 patients with multiple myeloma from two academic institutions, who had progression of disease after treatment with BCMA-directed CAR T. A total of 237 post-CAR T salvage treatment lines were used, and patients received a median of 2 (range, 1-10) treatment lines. The median overall survival from the date of relapse post-CAR T therapy was 17.9 months (95% confidence interval [CI], 14.0 non-estimable). The overall response rate to the first salvage regimen was 43.4%, with a median progression-free survival of 3.5 months (CI, 2.5-4.6). Thirty-five patients (44.3%) received a T-cell-engaging therapy (bispecific antibody or subsequent CAR T) as salvage treatment. The overall survival in patients who received subsequent T-cell-engaging therapy was not reached after a median follow up of 21.3 months. Patients with multiple myeloma who relapse after BCMA-directed CAR T have a limited prognosis but can be potentially treated with multiple lines of salvage therapy. T-cell-engaging therapies appear to maintain pronounced clinical activity in this setting.

Trial designs and endpoints for immune therapies in multiple myeloma.

Immune therapies, including CAR-T cells, bispecific antibodies, and antibody-drug conjugates, are revolutionizing the treatment of multiple myeloma. In this review, we discuss clinical trial design considerations relevant to immune therapies. We first examine issues pertinent to specific populations, including elderly, patients with renal impairment, high-risk/extramedullary disease, and prior immune therapies. We then highlight trial designs to optimize the selection of dose and schedule, explore rational combination therapies based on preclinical data, and evaluate the nuances of commonly used endpoints. By exploiting their pharmacokinetic/pharmacodynamic profiles and utilizing novel translational insights, we can optimize the use of immune therapies in multiple myeloma.

Phase 1b trial of isatuximab, an anti-CD38 monoclonal antibody, in combination with carfilzomib as treatment of relapsed/refractory multiple myeloma.

BACKGROUND: Isatuximab (Isa), an anti-CD38 monoclonal antibody, and carfilzomib (K), a next-generation proteasome inhibitor (PI), both have potent single-agent activity in relapsed and refractory multiple myeloma (RRMM). METHODS: This phase 1b study evaluated the combination of Isa and K in 33 patients with RRMM. Isa was administered by intravenous infusion in 3 dosing cohorts: dose level 1 (Isa at 10 mg/kg biweekly), dose level 2 (DL2; Isa at 10 mg/kg weekly for 4 doses and then biweekly), and dose level 3 (Isa at 20 mg/kg weekly for 4 doses and then biweekly) and all patients received K (20 mg/m2 intravenously for cycle 1, days 1 and 2, and then 27 mg/m2 for all subsequent doses). A standard 3+3 dose-escalation design was used, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. An expansion cohort of 18 patients was enrolled at DL2 to further evaluate safety and efficacy. Responses were assessed with the International Myeloma Working Group response criteria, and patients continued treatment until disease progression or unacceptable toxicity. RESULTS: With a median follow-up of 26.7 months, in this heavily pretreated population with a median of 3 prior lines (refractory to PIs and immunomodulatory drugs, 76%; refractory to K, 27%), the overall response rate was 70% (stringent complete response/complete response, 4; very good partial response, 8; partial response, 11). The median progression-free survival was 10.1 months, and the 2-year survival probability was 76%. The most common treatment-related adverse events (grade 2 or higher) were anemia, leukopenia, neutropenia, thrombocytopenia, hypertension, and infection. Infusion reactions were common (55%) but did not limit dosing. CONCLUSIONS: Treatment with Isa plus K was well tolerated with no unexpected toxicity. The combination was effective despite the enrollment of heavily pretreated patients with RRMM. LAY SUMMARY: This phase 1b study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of isatuximab and carfilzomib in patients with relapsed and refractory multiple myeloma. Thirty-three patients were treated: 15 in dose escalation and 18 in dose expansion. Patients received an average of 10 cycles. The treatment was safe and effective. No unexpected toxicity or drug-drug interactions were noted. Seventy percent of the subjects responded to therapy, and the progression-free survival was 10.1 months.

Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma.

Pomalidomide and low-dose dexamethasone (PomDex) is standard treatment of lenalidomide refractory myeloma patients who have received >2 prior therapies. We aimed to assess the safety and efficacy of the addition of oral weekly cyclophosphamide to standard PomDex. We first performed a dose escalation phase 1 study to determine the recommended phase 2 dose of cyclophosphamide in combination with PomDex (arm A). A randomized, multicenter phase 2 study followed, enrolling patients with lenalidomide refractory myeloma. Patients were randomized (1:1) to receive pomalidomide 4 mg on days 1 to 21 of a 28-day cycle in combination with weekly dexamethasone (arm B) or pomalidomide, dexamethasone, and cyclophosphamide (PomCyDex) 400 mg orally on days 1, 8, and 15 (arm C). The primary end point was overall response rate (ORR). Eighty patients were enrolled (10 in phase 1 and 70 randomized in phase 2: 36 to arm B and 34 to arm C). The ORR was 38.9% (95% confidence interval [CI], 23-54.8%) and 64.7% (95% CI, 48.6-80.8%) for arms B and C, respectively (P = .035). As of June 2015, 62 of the 70 randomized patients had progressed. The median progression-free survival (PFS) was 4.4 (95% CI, 2.3-5.7) and 9.5 months (95% CI, 4.6-14) for arms B and C, respectively (P = .106). Toxicity was predominantly hematologic in nature but was not statistically higher in arm C. The combination of PomCyDex results in a superior ORR and PFS compared with PomDex in patients with lenalidomide refractory multiple myeloma. The trial was registered at www.clinicaltrials.gov as #NCT01432600.

Methods for determining key components in a mathematical model for tumor-immune dynamics in multiple myeloma.

In this work, we analyze a mathematical model we introduced previously for the dynamics of multiple myeloma and the immune system. We focus on four main aspects: (1) obtaining and justifying ranges and values for all parameters in the model; (2) determining a subset of parameters to which the model is most sensitive; (3) determining which parameters in this subset can be uniquely estimated given certain types of data; and (4) exploring the model numerically. Using global sensitivity analysis techniques, we found that the model is most sensitive to certain growth, loss, and efficacy parameters. This analysis provides the foundation for a future application of the model: prediction of optimal combination regimens in patients with multiple myeloma.

The effect of novel therapies in high-molecular-risk multiple myeloma.

Multiple myeloma is a heterogeneous disease with a prognosis that varies with patient factors, disease burden, tumor biology, and treatments. Certain molecular abnormalities confer a worse prognosis and thus are considered high-risk. These include t(4;14), del(17p), t(14;16), t(14;20), hypodiploidy, and gain(1q)/del(1p). In our previous review in 2013, we discussed the effect of available therapies on prognosis in these high-risk patients. Since then, seven phase 3 clinical trials in relapsed myeloma with 1 to 3 lines of therapy have been conducted, resulting in the approval of panobinostat, ixazomib, daratumumab, and elotuzumab, as well as additional data on carfilzomib. In our current review of these studies, all the novel therapies resulted in an improvement in progression-free survival for high-risk patients, but none of the trials provided clear statistical evidence that they overcame high-risk status. Moreover, there are several limitations in the currently available data. For example, the patient's Revised International Staging System score is generally not reported, and even when it is reported, it is usually at the time of initial diagnosis rather than at the time of study entry. Furthermore, the methodology used to determine risk suffers from technologic issues. Finally, the clonal and allele burden and concurrent molecular abnormalities can affect risk status and prognosis. To determine the optimal therapy for high-risk patients, future clinical trials should provide standardized risk assessments for all patients in addition to hazard ratios for Kaplan-Meier survival curves of high-risk patients vs those of standard-risk patients to determine if high-risk status has truly been overcome by a novel agent.

Patients with newly diagnosed multiple myeloma and chromosome 1 amplification have poor outcomes despite the use of novel triplet regimens.

The prognostic impact of amplification of chromosome 1(C1A) in newly diagnosed multiple myeloma (nMM) patients treated with the most commonly used bortezomib-based triplet regimens is unclear. In this study, we analyzed the outcome of novel triplet therapies in a series of unselected patients with C1A detected by FISH. We identified 28 unselected nMM patients with C1A who had a gain of 1q21 locus. Despite 50% of patients being diagnosed at ISS stage 1 or 2 and 93% having no other high-risk molecular findings, the median overall survival of all patients was only 37 months, with 8 deaths (29%) occurring 8-37 months after diagnosis. Those who died had a median of four lines (range was 1-8) of therapy. Moreover, 71% of patients were non-Caucasian. Extra-osseous and CNS involvement occurred in 36 and 11% of patients respectively. Gain of the long arm of chromosome 1 detected by FISH remains a high-risk prognostic marker even in the setting of novel triplet therapies.

Creating Equitable and Inclusive Clinical Trials for Multiple Myeloma.

Black and Latino/Hispanic populations are disproportionately impacted by multiple myeloma (MM) in the United States and are underrepresented in many clinical trials. The Multiple Myeloma Research Foundation sponsored a 1-day workshop of 46 experts spanning the ecosystem of MM research and care, including government, academia, nonprofits, pharma/biotech, community partners, and retail pharmacy. Specific, tangible steps to overcome the well-documented barriers to improving the diversity and inclusivity of clinical trials were discussed, including broadening inclusion/exclusion criteria, reducing the financial and other burdens of trial participants, selecting diverse study sites, including implicit bias training, and taking steps to empower patients.

Phase 1 study combining elotuzumab with autologous stem cell transplant and lenalidomide for multiple myeloma.

BACKGROUND: Autologous stem cell transplantation (ASCT) after induction therapy improves disease-free survival for patients with multiple myeloma (MM). While the goal of ASCT is to render a minimal disease state, it is also associated with eradication of immunosuppressive cells, and we hypothesize that early introduction of immunotherapy post-ASCT may provide a window of opportunity to boost treatment efficacy. METHODS: We conducted a phase 1 clinical trial to investigate the application of autologous lymphocyte infusion and anti-SLAMF7 monoclonal antibody, elotuzumab, after ASCT in patients with newly diagnosed MM previously treated with induction therapy. In addition to CD34+ stem cells, peripheral blood mononuclear cells were harvested prior to transplant and infused on day 3 after stem cell infusion to accelerate immune reconstitution and provide autologous natural killer (NK) cells that are essential to the mechanism of elotuzumab. Elotuzumab was administered starting on day 4 and then every 28 days after until 1 year post-ASCT. Cycles 4-12 were administered with standard-of-care lenalidomide maintenance. RESULTS: All subjects were evaluated for safety, and 13 of 15 subjects completed the treatment protocol. At 1 year post-ASCT, the disease status of enrolled subjects was as follows: five stringent complete responses, one complete response, six very good partial responses, one partial response, and two progressive diseases. The treatment plan was well tolerated, with most grade 3 and 4 AEs being expected hematologic toxicities associated with ASCT. Correlative analysis of the immune microenvironment demonstrated a trend toward reduced regulatory T cells during the first 3 months post-transplant followed by an increase in NK cells and monocytes in patients achieving a complete remission. CONCLUSIONS: This phase 1 clinical trial demonstrates that early introduction of immunotherapy after ASCT is well tolerated and shows promising disease control in patients with MM, accompanied by favorable changes in the immune microenvironment. TRIAL REGISTRATION NUMBER: NCT02655458.

Prevalence and impact of diabetes on survival of patients with multiple myeloma in different racial groups.

ABSTRACT: Multiple myeloma (MM) is twice as common in Black individuals compared with in White individuals, and diabetes mellitus (DM) disproportionately affects Black patients. Although numerous studies have shown a correlation between DM and MM, this has not been studied in the context of race and in vivo mechanisms. We conducted a retrospective clinical study of 5383 patients with MM of which 15% had DM (White, 12% and Black, 25%). Multivariable Cox models showed reduced overall survival (OS) for patients with DM (hazard ratio, 1.27; 95% confidence interval, 1.11-1.47; P < .001). This appeared to be driven by a marked difference in OS between White patients with and without DM but not in Black patients. In contrast, obesity was associated with better OS in Black patients but not in White patients. To complement this analysis, we assessed MM growth in a genetically engineered immunocompromised nonobese diabetic (Rag1-/-/muscle creatinine kinase promoter expression of a human IGF1R [M] with a lysine [K] to arginine [R] point mutation) mouse model to evaluate the mechanisms linking DM and MM. MM.1S xenografts grew in more Rag1-/-/MKR mice and grew more rapidly in the Rag1-/-/MKR mice compared with in controls. Western blot analysis found that MM1.S xenografts from Rag1-/-/MKR mice had higher phosphorylated S6 ribosomal protein (Ser235/236) levels, indicating greater activation of the mammalian target of rapamycin pathway. Our study is, to our knowledge, the first to evaluate racial differences in DM prevalence and survival in MM, as well as the effect of DM on tumor growth in mouse models. Our results suggest that DM may contribute to the higher incidence of MM in Black patients; and to improve survival in MM, DM management cannot be ignored.

Determining optimal combination regimens for patients with multiple myeloma.

While many novel therapies have been approved in recent years for treating patients with multiple myeloma, there is still no established curative regimen, especially for patients with high-risk disease. In this work, we use a mathematical modeling approach to determine combination therapy regimens that maximize healthy lifespan for patients with multiple myeloma. We start with a mathematical model for the underlying disease and immune dynamics, which was presented and analyzed previously. We add the effects of three therapies to the model: pomalidomide, dexamethasone, and elotuzumab. We consider multiple approaches to optimizing combinations of these therapies. We find that optimal control combined with approximation outperforms other methods, in that it can quickly produce a combination regimen that is clinically-feasible and near-optimal. Implications of this work can be used to optimize doses and advance the scheduling of drugs.

Bortezomib-Induced Reticular Eruption in Patient with Multiple Myeloma.

Bortezomib is the first proteasome inhibitor to treat a variety of malignancies and is currently part of the standard of care regimen for the initial treatment of patients with newly diagnosed multiple myeloma. While bortezomib is generally well tolerated, it has been associated with various side effects, which have limited its use in some patients. Here, we describe a unique case with histological confirmation of a reticular eruption that appeared at the site of a subcutaneous administration of bortezomib in a 62-year-old male who was newly diagnosed with IgG kappa multiple myeloma. A skin biopsy was performed, which revealed superficial perivascular dermatitis predominantly composed of lymphocytes with rare eosinophils. The patient was successfully treated with betamethasone dipropionate 0.05% cream. When consulted, dermatologists should advise the oncology team of multiple myeloma patients treated with bortezomib to maintain a high threshold before discontinuing the drug when a patient experiences an atypical, reticular rash following subcutaneous administration. Additionally, potent topical corticosteroids, such as betamethasone dipropionate 0.05% cream, should be considered in managing the cutaneous reticular eruptions related to bortezomib administration, in order to maintain an optimal treatment regimen for patients with multiple myeloma.

Multi-omic analysis of the tumor microenvironment shows clinical correlations in Ph1 study of atezolizumab +/- SoC in MM.

Multiple myeloma (MM) remains incurable, and treatment of relapsed/refractory (R/R) disease is challenging. There is an unmet need for more targeted therapies in this setting; deep cellular and molecular phenotyping of the tumor and microenvironment in MM could help guide such therapies. This phase 1b study (NCT02431208) evaluated the safety and efficacy of the anti-programmed death-ligand 1 monoclonal antibody atezolizumab (Atezo) alone or in combination with the standard of care (SoC) treatments lenalidomide (Len) or pomalidomide (Pom) and/or daratumumab (Dara) in patients with R/R MM. Study endpoints included incidence of adverse events (AEs) and overall response rate (ORR). A novel unsupervised integrative multi-omic analysis was performed using RNA sequencing, mass cytometry immunophenotyping, and proteomic profiling of baseline and on-treatment bone marrow samples from patients receiving Atezo monotherapy or Atezo+Dara. A similarity network fusion (SNF) algorithm was applied to preprocessed data. Eighty-five patients were enrolled. Treatment-emergent deaths occurred in 2 patients; both deaths were considered unrelated to study treatment. ORRs ranged from 11.1% (Atezo+Len cohorts, n=18) to 83.3% (Atezo+Dara+Pom cohort, n=6). High-dimensional multi-omic profiling of the tumor microenvironment and integrative SNF analysis revealed novel correlations between cellular and molecular features of the tumor and immune microenvironment, patient selection criteria, and clinical outcome. Atezo monotherapy and SoC combinations were safe in this patient population and demonstrated some evidence of clinical efficacy. Integrative analysis of high dimensional genomics and immune data identified novel clinical correlations that may inform patient selection criteria and outcome assessment in future immunotherapy studies for myeloma.

Bridging advanced myeloma patients to subsequent treatments and clinical trials with classical chemotherapy and stem cell support.

Rapidly progressing relapsed/refractory multiple myeloma (RRMM) patients with compromised marrow have limited treatment options. Thus, non-myeloablative chemotherapy with a stem cell boost (SCB) may provide disease control and hematopoietic improvement as bridge to subsequent therapies. We identified 96 patients who received a SCB between January 2011 and December 2019 at the Mount Sinai Hospital. Patients had a median age of 64 years, received a median of 7 prior lines of therapy and 68 and 42% were triple-class and penta-drug refractory, respectively. Chemotherapy included melphalan (MEL) (n = 16), melphalan + carmustine (BCNU/MEL) (n = 52) or a variant of DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin) (n = 28). Median time to neutrophil recovery was 10 days and was significantly lower with DCEP (8 days) compared to MEL and BCNU/MEL (10-11 days) (p = 0.0047). Time to progression, progression-free survival and overall survival were 3.19, 2.7 and 8.38 months, respectively. The BCNU/MEL group had the highest response rate of 85% (p = 0.05), clinical benefit rate of 94% (p = 0.0014), progression-free survival of 3.3 months (p = 0.4) and overall survival of 8.7 months (p = 0.5). Sixty-six patients (69%) were bridged to new lines of therapy, including clinical trials. Non-myeloablative chemotherapy with SCB provides rapid disease control and marrow recovery with potential to receive further therapy.

IVIg Use Associated with Ten-Fold Reduction of Serious Infections in Multiple Myeloma Patients Treated with Anti-BCMA Bispecific Antibodies.

BCMA-targeted bispecific antibodies (BiAb) are efficacious in relapsed/refractory multiple myeloma; however, serious infections have emerged as important toxicities. In this retrospective study, we characterized all infections and their risk factors, and evaluated the impact of infection prophylaxis in patients treated with BCMA-targeted BiAbs. Among 37 patients, 15 (41%) experienced a grade 3-5 infection, with two infection-related deaths during deep remissions. Most (84%) infections occurred during disease remissions. The cumulative probability of grade 3-5 infection increased over time with no plateau. Among responders (n = 26), profound hypogammaglobulinemia occurred in 100% and continued throughout the entire duration of treatment. During periods when patients were receiving intravenous immunoglobulin (IVIg), the rate of grade 3-5 infections was 90% lower than during observation (incidence rate ratio, 0.10; 95% confidence interval, 0.01-0.80; P = 0.0307). No other risk factors for infection were identified. This study demonstrates that profound hypogammaglobulinemia is universal with BCMA-targeted BiAbs, with intravenous immunoglobulin potentially abrogating most of the infection risk. SIGNIFICANCE: To the best of our knowledge, this is the first study to comprehensively analyze risk factors and mitigation strategies to prevent infections in myeloma patients receiving anti-BCMA bispecific antibodies. Profound and prolonged hypogammaglobulinemia was universal among responders, while immunoglobulin replacement was associated with 90% lower rates of grade 3-5 infections. See related commentary by Garfall and Stadtmauer, p. 427 . This article is featured in Selected Articles from This Issue, p. 419.

Sequencing T-cell redirection therapies leads to deep and durable responses in patients with relapsed/refractory myeloma.

T-cell redirection therapy using chimeric antigen receptor (CAR) T cells and bispecific antibodies (BiAbs) has shown promising efficacy in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), leading to the approval of 2 CAR T-cell products and numerous BiAb trials. Data on the outcomes after relapse following BiAbs are urgently required to develop strategies for sequencing salvage therapies. We identified 58 patients progressing after a BiAb trial at Mount Sinai Hospital. Progression-free survival (PFS) to the first salvage (PFS1), second salvage therapy (PFS2), and overall survival (OS) were estimated using the Kaplan-Meier method. The median age of the patients was 67 years, and 78% had high-risk cytogenetics. They had a median of 6 prior therapy lines, 89% were triple-class refractory, and 44% were penta-drug refractory. After the BiAb trial, patients were followed for a median of 30.5 months and received a median of 2 additional salvage therapies (range, 1-9). The most common first salvage was T-cell redirection in 19 patients (10 BiAb and 9 CAR T cells). Ten patients underwent T-cell redirection as a second salvage treatment. T-cell redirection therapy as first or second salvage was feasible and associated with a median PFS1 of 28.9 months, PFS2 of 30.9 months, and an OS of 62% at 2 years. The sequential use of different T-cell redirection therapies is possible and may lead to deep and durable responses following the relapse after BiAb therapy in RRMM.

Immunophenotypic correlates of sustained MRD negativity in patients with multiple myeloma.

The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. In this study, we comprehensively profile the immune system in patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of discovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor ß sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterize the immune landscape in 23 patients before and one year after lenalidomide exposure. We compare patients achieving sustained minimal residual disease (MRD) negativity to patients who never achieved or were unable to maintain MRD negativity. We observe that the composition of the immune microenvironment in both the blood and the marrow varied substantially according to both MRD negative status and history of autologous stem cell transplant, supporting the hypothesis that the immune microenvironment influences the depth and duration of treatment response.

Cross center single-cell RNA sequencing study of the immune microenvironment in rapid progressing multiple myeloma.

Despite advancements in understanding the pathophysiology of Multiple Myeloma (MM), the cause of rapid progressing disease in a subset of patients is still unclear. MM's progression is facilitated by complex interactions with the surrounding bone marrow (BM) cells, forming a microenvironment that supports tumor growth and drug resistance. Understanding the immune microenvironment is key to identifying factors that promote rapid progression of MM. To accomplish this, we performed a multi-center single-cell RNA sequencing (scRNA-seq) study on 102,207 cells from 48 CD138- BM samples collected at the time of disease diagnosis from 18 patients with either rapid progressing (progression-free survival (PFS) < 18 months) or non-progressing (PFS > 4 years) disease. Comparative analysis of data from three centers demonstrated similar transcriptome profiles and cell type distributions, indicating subtle technical variation in scRNA-seq, opening avenues for an expanded multicenter trial. Rapid progressors depicted significantly higher enrichment of GZMK+ and TIGIT+ exhausted CD8+ T-cells (P = 0.022) along with decreased expression of cytolytic markers (PRF1, GZMB, GNLY). We also observed a significantly higher enrichment of M2 tolerogenic macrophages in rapid progressors and activation of pro-proliferative signaling pathways, such as BAFF, CCL, and IL16. On the other hand, non-progressive patients depicted higher enrichment for immature B Cells (i.e., Pre/Pro B cells), with elevated expression for markers of B cell development (IGLL1, SOX4, DNTT). This multi-center study identifies the enrichment of various pro-tumorigenic cell populations and pathways in those with rapid progressing disease and further validates the robustness of scRNA-seq data generated at different study centers.