Comparing the clinical trial efficacy versus real-world effectiveness of treatments for multiple myeloma: a population-based study.

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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.

Impact of rituximab on COVID-19 outcomes.

Rituximab is associated with prolonged B-cell depletion and secondary hypogammaglobulinemia and is associated with a dampened humoral response and increased infectious complications. To describe the potential impact of prior rituximab therapy on clinical outcomes from SARS-CoV-2 infection and development of COVID-19 antibodies, we conducted a retrospective study of adults across the Mount Sinai Health System diagnosed with COVID-19 who received rituximab for any indication from February 2019 to October 2020. Patients' baseline characteristics, markers of disease severity, clinical outcomes, and antibody development were examined. Of the 49 patients included in the analysis, 63.2% required hospitalization for COVID-19, 24.5% required an ICU admission, and 32.7% died. Proximity of last rituximab infusion and COVID-19 diagnosis did not affect rates of hospitalization, admission to intensive care units or death. Over half (51.7%) of those whose antibodies were checked developed neutralizing anti-spike protein antibodies. The median time between rituximab administration and COVID-19 diagnosis was not significantly different between those who developed antibodies and those who did not (p = .323). Of the 14 patients with documented negative COVID-19 antibody titers, 11 of them survived SARS-CoV-2 infection, indicating that development of neutralizing antibodies may not be necessary for recovery from COVID-19.

Comparing the epidemiology, clinical characteristics and prognostic factors of acute myeloid leukemia with and without acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a particularly aggressive subtype of acute myeloid leukemia (AML), with high rates of early death. It is important to examine how epidemiological characteristics, clinical and treatment factors, cytogenetic and genetic data affect survival and differ between APL and non-APL AML patients. We analyzed population data from the New York State Cancer Registry to characterize AML including APL incidence rates by demographics. APL incidence rates were higher among Hispanics than non-Hispanics [incidence rate ratio = 1.22; 95% confidence interval (CI) = 1.02-1.43]; and among foreign-born than USA-born persons. APL incidence rates increased more rapidly through 1995-2014 than non-APL AML; and its frequency increased faster among foreign-born persons. In a hospital cohort of 390 AML patients, the risk of death was significantly higher among APL patients with FLT3-internal tandem duplications than those without [hazard ratio (HR) = 11.74; 95% CI = 1.03-134.5]; and among APL patients with secondary versus de novo disease (HR = 17.32; 95% CI = 1.56-192.1). Among non-APL AML patients, risk of death was significantly associated with prior chemotherapy with antitubulin agents after adjusting for age, gender and ethnicity (adjusted HR = 3.30; 95% CI = 1.49-7.32); and separately with older age, unfavorable cytogenetics and complex karyotype. This study highlights FLT3-internal tandem duplications as a prognostic factor in APL and proposes consideration of prior antitubulin therapy as a prognostic factor in non-APL AML.

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.

Management of Newly Diagnosed Multiple Myeloma Today, and in the Future.

Treatment options have expanded rapidly and widely in the past two decades for patients with multiple myeloma. Triplet novel agent-based induction regimens have been accepted as the standard practice wordwide over the last decade both for transplant-eligible and non-eligible patients. The addition of anti-CD38 monoclonal antibodies as part of quadruplet regimens has led to even deeper and longer-lasting responses. The impressive results shown by the quadruplets havebeen practice-changing where accessible in recent years. Chimeric antigen receptor T cell therapy and bispecific antibodies are being tested in the upfront setting and have the potential to once again shift the paradigm of treatment of newly diagnosed MM.

Bispecific antibodies in the treatment of multiple myeloma.

The treatment paradigm in myeloma is constantly changing. Upfront use of monoclonal antibodies like daratumumab along with proteasome inhibitors (PI)s, and immune modulators (IMiD)s have significantly improved survival and outcomes, but also cause unique challenges at the time of relapse. Engaging immune T cells for tumour cell kill with chimeric antigenic T-cell (CAR T-cell) therapy and bispecific antibodies have become important therapeutic options in relapsed multiple myeloma. Bispecific antibodies are dual antigen targeting constructs that engage the T cells to plasma cells through various target antigens like B-cell membrane antigen (BCMA), G-protein-coupled receptor family C group 5 member D (GPRC5D), and Fc receptor-homolog 5 (FcRH5). These agents have proven to induce deep and durable responses in heavily pre-treated myeloma patients with a predictable safety profile and the ease of off-the-shelf availability. Significant research is ongoing to overcome resistance mechanisms like T cell exhaustion, target antigen mutation or loss and high disease burden. Various trials are also studying these agents as first line options in the newly diagnosed setting. These agents play an important role in the relapsed setting, and efforts are underway to optimize their sequencing in the myeloma treatment algorithm.

A Landmark Paper That Introduced Proteasome Inhibition in Myeloma.

The ongoing therapeutic revolution in multiple myeloma care can be traced to the turn of the millennium with the unanticipated discovery in 1999 that the cereblon binding small molecule thalidomide had profound clinical effectiveness and, simultaneously, the emergence of a new class of targeted therapies inhibiting the proteasome, both of which ultimately target ubiquitinated protein degradation. These contemporaneous discoveries forever changed the landscape of multiple myeloma care, substantially extending survival. Foreshadowing this seismic change, Nobel Prize winning work on the proteasome ubiquitin pathway had stimulated the development of highly specific proteasome inhibitor small molecules, particularly PS-341 (later named bortezomib). An abundance of the proteasome in hematologic malignancies had been recognized and thus PS-341 was logically being explored in relevant preclinical models. Concurrent with phase I trials, which were soon to prove the significant clinical relevance of preclinical models, the laboratory of Dr. Kenneth Anderson and colleagues at Dana-Farber, in partnership with Dr. Julian Adams and scientists at ProScript (later Millennium Pharmaceuticals) first demonstrated that the proteasome inhibitor PS-341 inhibited growth, induced apoptosis, and overcame drug resistance in human multiple myeloma cells. This landmark paper in Cancer Research set the stage for a paradigm shift in how multiple myeloma was managed across all stages of the disease, which changed the lives of patients worldwide. See related article by Hideshima and colleagues, Cancer Res 2001;61:3071-6.

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.

Depression symptoms as a function of duration of intractable or controlled epilepsy.

We examined if depression symptoms in patients with intractable (IE) or controlled epilepsy (CE) differ and how long after onset of epilepsy these effects would be most pronounced. The NDDI-E was administered to all outpatients (n=358) seen in a comprehensive epilepsy program clinic over a two-year period. Patients who met inclusion criteria (n=223) completed a total of 431 NDDI-E surveys over this time. Patients with a diagnosis of IE (n=72) or CE (n=151) were compared as a function of time since their epilepsy onset, segmented into 10-year epochs. Depression symptoms were higher in patients with IE compared to CE at 10-<20 years and did not differ at other time points. This study reveals differences in depression symptoms as a function of duration of epilepsy. Attending to the dynamic nature of depression symptoms in different epochs of epilepsy may be an important treatment target in patients with epilepsy.

Predictive value of Spanish neuropsychological testing for laterality in patients with epilepsy.

In presurgical treatment planning for patients with epilepsy, neuropsychological testing assists in lateralization of the seizure focus. Previous research with English speakers has shown that patients with left hemisphere (LH) onsets versus right hemisphere (RH) onsets perform worse on naming and other verbal skills tests, but similar findings with Hispanic patients are limited. Thirty-nine Spanish-speaking patients were administered a comprehensive battery of neuropsychological tests in Spanish. LH-onset patients performed significantly worse than RH-onset patients on verbal comprehension (P=0.006), visual matching (P=0.047), the Ponton-Satz Boston Naming Test (P=0.001), and the dominant hand trial of the Grooved Pegboard Test (P=0.012). A stepwise regression model to predict seizure laterality from these tests was significant (F=12.10, P=0.001), but only the Ponton-Satz Boston Naming Test was retained. This comprehensive battery of neuropsychological tests in Spanish proved useful in predicting lateralization in patients with partial epilepsy.

Impact of Fluoroquinolone Prophylaxis on Neutropenic Fever, Infections, and Antimicrobial Resistance in Newly Diagnosed AML Patients.

INTRODUCTION: Fluoroquinolone prophylaxis is recommended during induction chemotherapy for patients with acute myeloid leukemia (AML) to reduce risk of neutropenic fever and systemic bacterial infections. We evaluated the effectiveness of primary fluoroquinolone prophylaxis in an area with high fluoroquinolone resistance. MATERIALS AND METHODS: We performed a retrospective chart review of newly diagnosed adult AML patients who received frontline therapy at Mount Sinai Hospital in New York, NY, between 2012 and 2019. Primary outcome was development of neutropenic fever. Secondary outcomes were development of systemic bacterial infections and infections with multidrug-resistant organisms and Clostridioides difficile. Infectious outcomes were collected through 6 months after therapy initiation. We estimated the effect of fluoroquinolone prophylaxis with a time-dependent Cox proportional hazards model. RESULTS: Of 121 included patients, 87 received antibiotic prophylaxis and 34 did not. There was no difference in baseline characteristics, although the prophylaxis group had longer neutropenia duration (median 30 vs. 23 days, P = .013). The prophylaxis group had a reduced risk of neutropenic fever (hazard ratio 0.59, P = .039). The prophylaxis group had fewer gram-positive (P = .043) and gram-negative (P = .049) bloodstream infections and fewer clinically documented infections during frontline therapy (P = .005) and follow-up (P = .026). There was no difference in incidence of C. difficile or infection with fluoroquinolone-resistant or multidrug-resistant organisms. There was no mortality difference between groups. CONCLUSION: In an area with high fluoroquinolone resistance, primary fluoroquinolone prophylaxis in newly diagnosed AML patients reduced the risk of neutropenic fever and systemic bacterial infections without increased antimicrobial resistance. Prospective, randomized studies are needed to confirm these observations.

The value of intraoperative electrocorticography in surgical decision making for temporal lobe epilepsy with normal MRI.

PURPOSE: We hypothesized that acute intraoperative electrocorticography (ECoG) might identify a subset of patients with magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE) who could proceed directly to standard anteromesial resection (SAMR), obviating the need for chronic electrode implantation to guide resection. METHODS: Patients with TLE and a normal MRI who underwent acute ECoG prior to chronic electrode recording of ictal onsets were evaluated. Intraoperative interictal spikes were classified as mesial (M), lateral (L), or mesial/lateral (ML). Results of the acute ECoG were correlated with the ictal-onset zone following chronic ECoG. Onsets were also classified as "M,""L," or "ML." Positron emission tomography (PET), scalp-EEG (electroencephalography), and Wada were evaluated as adjuncts. KEY FINDINGS: Sixteen patients fit criteria for inclusion. Outcomes were Engel class I in nine patients, Engel II in two, Engel III in four, and Engel IV in one. Mean postoperative follow-up was 45.2 months. Scalp EEG and PET correlated with ictal onsets in 69% and 64% of patients, respectively. Wada correlated with onsets in 47% of patients. Acute intraoperative ECoG correlated with seizure onsets on chronic ECoG in all 16 patients. All eight patients with "M" pattern ECoG underwent SAMR, and six (75%) experienced Engel class I outcomes. Three of eight patients with "L" or "ML" onsets (38%) had Engel class I outcomes. SIGNIFICANCE: Intraoperative ECoG may be useful in identifying a subset of patients with MRI-negative TLE who will benefit from SAMR without chronic implantation of electrodes. These patients have uniquely mesial interictal spikes and can go on to have improved postoperative seizure-free outcomes.

Use of a side-cutting aspiration device for resection of tumors during endoscopic endonasal approaches.

OBJECT: Accessing intra- and extradural tumors via an endonasal approach requires working safely in a relatively narrow area with unobstructed visibility. The authors describe their experience to highlight the utility of a side-cutting aspiration device for endoscopic endonasal resection of skull base tumors. METHODS: The authors used this device in 13 nonconsecutive endoscopic endonasal procedures for different skull base tumors (8 pituitary macroadenomas, 2 craniopharyngiomas, 1 chordoma, 1 recurrent ependymoma, and 1 lymphoma). Illustrative cases and video are presented to demonstrate its use. RESULTS: The instrument was easy to use and effective in the removal of the lesions presented in this series. In 10 patients (77%), gross-total resection was possible; in the other 3 patients (23%), more than 80% of the tumor was resected. No collateral tissue damage or any other complication resulted from device-related debulking or aspiration. CONCLUSIONS: The side-cutting tissue resector is a safe, easy to use, and effective tool for internal debulking and extracapsular dissection of nonvascularized tumors that are too firm for bimanual suction or blunt ring curette dissection. It is particularly useful when working through a deep and narrow corridor such as is encountered in endoscopic endonasal skull base surgery.

Bispecific Antibodies in Multiple Myeloma: Present and Future.

Despite many recent advances in therapy, there is still no plateau in overall survival curves in multiple myeloma. Bispecific antibodies are a novel immunotherapeutic approach designed to bind antigens on malignant plasma cells and cytotoxic immune effector cells. Early-phase clinical trials targeting B-cell maturation antigen (BCMA), GPRC5D, and FcRH5 have demonstrated a favorable safety profile, with mainly low-grade cytokine release syndrome, cytopenias, and infections. Although dose escalation is ongoing in several studies, early efficacy data show response rates in the most active dose cohorts between 61% and 83% with many deep responses; however, durability remains to be established. Further clinical trial data are eagerly anticipated. SIGNIFICANCE: Overall survival of triple-class refractory multiple myeloma remains poor. Bispecific antibodies are a novel immunotherapeutic modality with a favorable safety profile and impressive preliminary efficacy in heavily treated patients. Although more data are needed, bispecifics will likely become an integral part of the multiple myeloma treatment paradigm in the near future. Studies in earlier lines of therapy and in combination with other active anti-multiple myeloma agents will help further define the role of bispecifics in multiple myeloma.