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.

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.

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 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.

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.

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.

Efficacy of Intravenous Immunoglobulin for Preventing Infections in Patients with Multiple Myeloma.

INTRODUCTION: Despite many recent advances in the treatment of multiple myeloma (MM), infection remains a major cause of morbidity and mortality. Prior studies have shown mixed results using intravenous immunoglobulin (IVIG) to prevent infections in MM and were conducted prior to most modern MM therapies. PATIENTS AND METHODS: We retrospectively reviewed all patients with MM treated with IVIG at our institution from 2010 to 2017. The primary endpoint was the incidence rate ratio (IRR) of infectious events (IEs) per patient-year during IVIG versus observation. RESULTS: A total of 68 patients were included; 151 IEs occurred during 918 months of IVIG treatment, whereas 446 IEs occurred during 2484 months of observation. Although the annual rate of IEs was substantially higher during periods of progressive disease (PD) compared with non-PD (4.9 vs. 1.8; P < .001), most IEs occurred during periods of non-PD (75% vs. 25% during PD). There was no overall difference in the annual rate of IEs per patient between IVIG and observation (1.97 vs. 2.16; IRR, 0.92; 95% confidence interval [CI], 0.76-1.10; P = .376). The subgroup of patients with hypogammaglobulinemia and whose myeloma was in a non-PD phase had a significant reduction in all-grade IEs (1.20 vs. 1.92; IRR, 0.63; 95% CI, 0.45-0.88; P = .009) and ≥ grade 3 IEs (0.25 vs. 0.56; IRR, 0.45; 95% CI, 0.22-0.94; P = .041) with IVIG compared with observation. CONCLUSION: Although treatment with IVIG did not show benefit in the overall population, there may be subgroups of patients that derive significant benefit. Additional observational studies are needed to confirm these findings and further refine patient selection.

Bispecifics, trispecifics, and other novel immune treatments in myeloma.

Despite recent advances in treatment, relapses in multiple myeloma (MM) are inevitable. Off-the-shelf immunotherapeutics represent a promising avenue for research, with various classes of agents under development and several demonstrating deep and durable responses in patients who have exhausted all available therapies. Antibody-drug conjugates (ADCs) seek to improve on naked monoclonal antibodies by delivering a cytotoxic payload directly to tumor cells while largely limiting systemic effects. Belantamab mafodotin, a B-cell maturation antigen (BCMA)-targeted ADC, has shown response rates >30% in a phase 2 trial of highly refractory patients and is being investigated in a variety of settings and combinations. Several other ADCs are in earlier stages of development that target cell surface antigens that are internalized, including BCMA, CD38, CD46, CD56, CD74, and CD138. Bispecifics are designed to bring cytotoxic immune effector cells into proximity with tumor cells, and several agents have shown high response rates in early trials. Current targets include BCMA, CD38, GPRC5d, and FCRH5, and all of these seek to engage T cells through CD3. Bispecifics targeting natural killer (NK) cells through CD16 are still in preclinical development. Trispecific antibodies may represent an advance over bispecifics by providing a T-cell costimulatory signal such as CD28, or alternatively, dual MM antigens to increase specificity of NK or T-cell targeting. This is an area of active preclinical research at this time. Lastly, designed ankyrin repeat proteins, which are small antibody-mimetic proteins with high target-binding affinity, have the potential to block multiple pathways at once and provide stimulatory signals to the immune system.

Severe COVID-19 virus reactivation following treatment for B cell acute lymphoblastic leukemia.

SARS-CoV-2 has infected millions of people worldwide, but little is known at this time about second infections or reactivation. Here, we report a case of a 55-year-old female undergoing treatment for CD20+ B cell acute lymphoblastic leukemia who experienced a viral reactivation after receiving rituximab, cytarabine, and dasatinib. She was initially hospitalized with COVID-19 in April and developed a high antibody titer with two negative nasal polymerase chain reaction (PCR) swabs for SARS-CoV-2 on discharge. After recovery, she resumed treatment in June for her leukemia, which included rituximab, cytarabine, and dasatinib. She promptly lost her COVID-19 antibodies, and her nasal PCR turned positive in June. She developed a severe COVID-19 pneumonia with lymphopenia, high inflammatory markers, and characteristic bilateral ground-glass opacities on chest CT, requiring high-flow nasal cannula and transfer to the intensive care unit. She received steroids, anticoagulation, and convalescent plasma, and within 48 h she was off oxygen. She was discharged home in stable condition several days later. Given the short time frame from leukemia treatment to PCR positivity and the low case rate in mid-June in New York City, reinfection appears to have been unlikely and SARS-CoV-2 reactivation is a possible explanation. This case illustrates the risks of treating recently recovered COVID-19 patients with immunosuppressive therapy, particularly lymphocyte- and antibody-depleting therapy, and raises new questions about the potential of SARS-CoV-2 reactivation.

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy.

Multiple myeloma (MM) is an incurable malignancy of plasma cells with a clinical course characterized by multiple relapses and treatment refractoriness. While recent treatment advancements have extended overall survival (OS), refractory MM has a poor prognosis, with a median OS of between 4 and 6 months. Nuclear export inhibition, specifically inhibition of CRM1/XPO1, is an emerging novel treatment modality that has shown promise in treatment-refractory MM. Initially discovered in yeast in 1983, early clinical applications were met with significant toxicities that limited their utility. The creation of small molecule inhibitors of nuclear export (SINE) has improved on toxicity limitations and has led to investigation in a number of malignancies at the preclinical and clinical stages. Preclinical studies of SINEs in MM have shown that these molecules are cytotoxic to myeloma cells, play a role in therapy resensitization, and suggest a role in limiting bone disease progression. In July 2019, selinexor became the first nuclear export inhibitor approved for use in relapsed/refractory MM based on the STORM trial. As of May 2020, there were eight ongoing trials combining selinexor with standard treatment regimens in relapsed/refractory MM. Eltanexor, a second-generation SINE, is also under investigation and has shown preliminary signs of efficacy in an early clinical trial while potentially having an improved toxicity profile compared with selinexor. Results in ongoing trials will help further define the role of SINEs in MM.

Practicing Antimicrobial Stewardship: De-Escalating Antibiotics in Patients With Acute Myeloid Leukemia and Neutropenic Fever.

We compared risk of recurrent fever in patients with acute myeloid leukemia undergoing induction chemotherapy with febrile neutropenia without an infectious source in which antibacterials were de-escalated before neutrophil recovery versus continued. There was less recurrent fever when antibacterials were de-escalated early with no increased adverse events.

Romiplostim for thrombocytopenia following allogeneic stem cell transplantation: A case series.

Thrombocytopenia is a relatively common complication following allogeneic hematopoietic stem cell transplantation and is associated with increased bleeding, transfusion requirements, chronic graft-versus-host disease, and all-cause mortality. There are currently no approved treatments outside of supportive transfusions. We report on the outcomes of five patients at our institution who received romiplostim for either primary engraftment failure or secondary failure of platelet recovery following stem cell transplantation. In total, four out of the five patients demonstrated a response to romiplostim, which was defined as seven consecutive days of platelet count >50 × 109/L with transfusion independence, with two ongoing responses (>365 days each) at the conclusion of the study period. Responses to romiplostim were sustained in the absence of significant bone marrow disease, which was found to contribute to recurrent thrombocytopenia. Additionally, romiplostim was well-tolerated overall; one patient developed minimal fibrotic changes on bone marrow biopsy postromiplostim. Although these results are promising, data from randomized clinical trials are needed to fully understand the role of romiplostim after stem cell transplantation.

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.