Impact of Black Race on Peripheral Neuropathy in Patients With Newly Diagnosed Multiple Myeloma Receiving Bortezomib Induction.

PURPOSE: The incidence of multiple myeloma (MM) is two to three times higher in Black patients compared with other races, making it the most common hematologic malignancy in this patient population. Current treatment guidelines recommend the combination of a proteasome inhibitor, an immunomodulatory agent, and a corticosteroid as preferred induction therapy. Bortezomib use comes with the risk of peripheral neuropathy (PN) and potential need for dose reduction, therapy interruption, and additional supportive medications. Known risk factors for bortezomib-induced peripheral neuropathy (BIPN) include diabetes mellitus, previous thalidomide, advanced age, and obesity. We aimed to determine the potential association between Black race and incidence of BIPN. PATIENTS AND METHODS: We identified a cohort of 748 patients with newly diagnosed MM who received induction with bortezomib, lenalidomide, and dexamethasone from 2007 to 2016. One hundred forty Black patients were matched with 140 non-Black patients on age, sex, BMI, and route of bortezomib administration. Incidence of BIPN was a binary event defined as new use of a neuropathy medication, bortezomib dose reduction, dose omission, or discontinuation because of PN. RESULTS: The incidence of BIPN was higher in Black patients (46%) compared with non-Black patients (34%; P = .05) in both univariate (odds ratio [OR], 1.61; 95% CI, 1.00 to 2.61; P = .052) and multivariable analyses (OR, 1.64; 95% CI, 1.01 to 2.67; P = .047). No significant differences in BIPN were seen when stratified by route of administration. CONCLUSION: These data indicate that Black race is an independent risk factor for the development of BIPN. Additional prevention strategies, close monitoring, and appropriate supportive care measures are warranted for these patients.

Novel approaches to the treatment of multiple myeloma.

The treatment landscape for multiple myeloma (MM) has evolved significantly over the last decade with the approval of novel therapies and combinations in the newly diagnosed and relapsed/refractory settings. There has also been a shift toward a risk-adapted approach to induction and maintenance regimens, with the goal of achieving better response rates for those with high-risk disease. The incorporation of anti-CD38 monoclonal antibodies into induction regimens has led to longer progression-free survival and higher rates of measurable residual disease negativity. In the relapsed setting, the emergence of B-cell maturation antigen-directed therapy, including antibody-drug conjugates, chimeric antigen receptor T-cell therapy, and more recently, bispecific antibodies, has produced deep and durable responses in heavily pretreated patients. This review article describes novel approaches to the treatment of MM in both the newly diagnosed and the relapsed/refractory setting.

Impaired SARS-CoV-2 Variant Neutralization and CD8+ T-cell Responses Following 3 Doses of mRNA Vaccines in Myeloma: Correlation with Breakthrough Infections.

Patients with multiple myeloma (MM) mount suboptimal neutralizing antibodies (nAb) following 2 doses of SARS-CoV-2 mRNA vaccines. Currently, circulating SARS-CoV-2 variants of concern (VOC) carry the risk of breakthrough infections. We evaluated immune recognition of current VOC including BA.1, BA.2, and BA.5 in 331 racially representative patients with MM following 2 or 3 doses of mRNA vaccines. The third dose increased nAbs against WA1 in 82%, but against BA variants in only 33% to 44% of patients. Vaccine-induced nAbs correlated with receptor-binding domain (RBD)-specific class-switched memory B cells. Vaccine-induced spike-specific T cells were detected in patients without seroconversion and cross-recognized variant-specific peptides but were predominantly CD4+ T cells. Detailed clinical/immunophenotypic analysis identified features correlating with nAb/B/T-cell responses. Patients who developed breakthrough infections following 3 vaccine doses had lower live-virus nAbs, including against VOC. Patients with MM remain susceptible to SARS-CoV-2 variants following 3 vaccine doses and should be prioritized for emerging approaches to elicit variant-nAb and CD8+ T cells. SIGNIFICANCE: Three doses of SARS-CoV-2 mRNA vaccines fail to yield detectable VOC nAbs in nearly 60% and spike-specific CD8+ T cells in >80% of myeloma patients. Patients who develop breakthrough infections following vaccination have low levels of live-virus nAb. This article is highlighted in the In This Issue feature, p. 101.

Impact of concurrent gabapentin or pregabalin with high-dose melphalan in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplant.

BACKGROUND: Melphalan is an alkylating agent used in both autologous (ASCT) and allogeneic stem cell transplantation. It is a substrate of L-type amino acid transporter-1 (LAT-1) and LAT-2, which are involved in its tissue penetration and elimination. Gabapentin and pregabalin, common concomitant medications in patients with multiple myeloma undergoing ASCT, are also substrates of LAT transporters, raising concern for potential competitive inhibition of melphalan transport. We evaluated whether concurrent use of gabapentin or pregabalin in patients receiving high-dose melphalan (≥140 mg/m2 ) prior to ASCT impacted frequency and severity of melphalan-related adverse events. OBJECTIVE: We aimed to determine if concurrent administration of gabapentin or pregabalin and melphalan increased melphalan toxicity. METHODS: This was a single-center, retrospective evaluation including patients ≥18 years of age who received high-dose melphalan as part of a conditioning regimen at the Winship Cancer Institute of Emory University between August 1, 2010 and April 1, 2020 and were followed through their transplant admission. After identification and inclusion of patients who received melphalan in combination with gabapentin or pregabalin, patient matching based on age (±5 years), sex, and melphalan dose (140 mg/m2 or 200 mg/m2 ) was utilized to generate a comparable cohort of patients who received melphalan alone. The primary outcome was hospital length of stay (LOS); secondary outcomes included supportive care requirements between days +4 and day +14 and time to neutrophil and platelet-20 engraftment. RESULTS: Among 176 patients evaluated in each group, median hospital LOS was 16 days, median time to neutrophil engraftment was 14 days, and median time to platelet-20 engraftment was 16 days in both groups. In addition, there were no significant differences in supportive care requirements between groups. CONCLUSION: In this study, use of gabapentin or pregabalin in combination with melphalan did not impact safety of the conditioning regimen in patients undergoing ASCT.

Daratumumab for the Treatment of Multiple Myeloma: A Review of Clinical Applicability and Operational Considerations.

OBJECTIVE: To review the available data for the efficacy and safety of daratumumab in the treatment of multiple myeloma (MM), both in the newly diagnosed and relapsed/refractory settings, as well as provide additional guidance to clinicians on operational, safety, and supportive care considerations. DATA SOURCES: A literature search of PubMed (1966 to October 2021) was conducted using the keywords daratumumab, Darzalex, and myeloma. Data were also obtained from prescribing information and unpublished abstracts from meetings. STUDY SELECTION AND DATA EXTRACTION: All relevant published articles, prescribing information, and unpublished meeting abstracts on daratumumab for the treatment of MM were reviewed. DATA SYNTHESIS: Daratumumab is an anti-CD38 monoclonal antibody indicated for the treatment of MM. The addition of daratumumab to proteasome inhibitor and immunomodulatory drug-based regimens has led to a consistent improvement in progression-free survival and response rates in relapsed/refractory MM as per the POLLUX, CASTOR, APOLLO, and CANDOR trials. The ALCYONE and MAIA phase III trials have demonstrated an overall survival benefit when adding daratumumab to frontline regimens for transplant-ineligible patients with newly diagnosed MM. In transplant-eligible patients, daratumumab-based quadruplet regimens have improved depth of response in the CASSIOPIEA and GRIFFIN trials. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Operational and safety considerations that clinicians need to account for do exist, including different administration and infusion strategies, infusion-related reactions, increased risk for infectious complications, and interference with blood transfusion management. CONCLUSIONS: Daratumumab has led to a shift in the treatment paradigm of both newly diagnosed and relapsed/refractory MM, leading to improvements in outcomes such as response rates, depth of response, and progression-free survival.

Antibody treatment in multiple myeloma.

Antibody therapy, which has become a critical option in the treatment of multiple myeloma (MM), includes monoclonal antibodies, antibody-drug conjugates, and bispecific antibodies. Anti-CD38 and anti-SLAMF7 monoclonal antibodies were the first to enter the MM portfolio as treatment options for relapsed/ refractory MM. More recently, daratumumab has become important in the treatment of newly diagnosed MM, and a subcutaneous formulation has been approved. BCMA-targeted antibody-drug conjugates and bispecific antibodies, which are the newest antibody therapies to be investigated, provide additional therapeutic options for patients with heavily pretreated MM. This article reviews how antibody therapy has influenced the treatment of MM, describes the unique adverse event profiles of each relevant drug class, and explains how to incorporate antibody therapy into practice.

Current developments in the combination therapy of relapsed/refractory multiple myeloma.

INTRODUCTION: Therapy for patients with multiple myeloma has improved dramatically over the past decade following the introduction of novel agents and combinations across the disease spectrum. When relapse or refractory disease develops, non-cross-resistant drugs, most often used in multidrug regimens, have provided significant improvements in patient outcomes. Despite these advances, myeloma remains incurable and additional therapeutic approaches, based on emerging molecular and cellular biology, are moving rapidly through development phases. Approaches new to myeloma, including antibody-drug conjugates, T-cell-directed therapies, and novel small molecules, are poised to bring in the next wave of treatment. AREAS COVERED: This review addresses recent data for the management of relapsed/refractory disease, rationale for agent and regimen selection and combinations, and options showing early promise in trials. Literature and abstracts pertaining to trial data published or presented up to 2019 are included. EXPERT OPINION: Therapeutic strategies continue to evolve in myeloma, with the application of existing platforms (e.g., antibody-drug conjugates) to target relevant biology (e.g., B cell maturation antigen). Within the next year, there will be additional agents approved for those with advanced disease, and combinations as well as placement in sequencing will deepen responses and improve outcomes for patients.

Management of Mantle Cell Lymphoma in the Era of Novel Oral Agents.

Objectives: To discuss (1) recent and emerging data for pharmacological management of untreated and relapsed/refractory (R/R) mantle cell lymphoma (MCL) with agents approved in the United States, (2) important considerations for toxicity monitoring and management, and (3) preliminary data and ongoing studies for agents in MCL-specific clinical trials. Data Sources: PubMed/MEDLINE, EMBASE, Google Scholar, product labeling, National Comprehensive Cancer Network, American Cancer Society, and ClinicalTrials.gov were searched for studies published between January 1, 2017, and January 31, 2020, and key historical trials. Study Selection and Data Extraction: Relevant studies conducted in humans and selected supporting preclinical data were reviewed. Data Synthesis: MCL is a rare but usually aggressive non-Hodgkin lymphoma that most commonly affects the older population. Traditionally, the treatment of MCL has been determined based on transplant eligibility. Newer data suggest that more tolerable frontline therapy may produce outcomes similar to intensive historical induction regimens, possibly precluding fewer patients from autologous stem cell transplant and producing better long-term outcomes in transplant-ineligible patients. In the R/R setting, novel regimens are improving outcomes and changing the landscape of treatment. Relevance to Patient Care and Clinical Practice: This review summarizes and discusses recent and emerging data for management of newly diagnosed and R/R MCL; key supportive care considerations for agents are also discussed. Conclusions: Recent study results are changing management of MCL. Although these data have complicated the picture of regimen selection, increasingly effective and tolerable therapy and additional anticipated data point to a brighter future for patients with MCL.

Current and Investigational Agents Targeting the Phosphoinositide 3-Kinase Pathway.

Prevalent molecular alterations of the phosphoinositide 3-kinase (PI3K) pathway are found on solid tumors and are expressed in leukocytes, making it a desirable target in both solid and hematologic malignancies. In recent years, two agents targeting this pathway have been approved by the United States Food and Drug Administration, idelalisib and copanlisib, with many others under investigation. Due to the off-target effects seen with these agents, those under development have varying isoform specificity that mitigates toxicity. In this review, we attempt to illustrate the varying differences among these agents, both mechanistically as well as highlight differences in their respective adverse effect profiles.

Maintenance azacitidine after myeloablative allogeneic hematopoietic cell transplantation for myeloid malignancies.

Allogeneic hematopoietic cell transplantation (HCT) is a curative option for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but carries a high risk of relapse. This retrospective review evaluates the effectiveness of maintenance azacitidine in high-risk AML and MDS patients to reduce the probability of relapse. Twenty-five patients who received maintenance azacitidine were matched to historical controls in a two-to-one ratio based on diagnosis, donor type, conditioning regimen intensity, and age. Over 90% of patients received myeloablative conditioning. There was no difference in time to hematologic relapse, overall survival, or non-relapse mortality. Maintenance therapy was stopped early in 72% of patients due to graft-versus-host-disease, relapse, infection, and intolerance (13 of 25 patients received less than 4 cycles). There was a trend towards higher toxicity in the azacitidine group. The use of prophylactic azacitidine following myeloablative allogeneic HCT outside a clinical trial cannot be recommended at this time.

Dinutuximab: An Anti-GD2 Monoclonal Antibody for High-Risk Neuroblastoma.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, and formulary considerations for dinutuximab. DATA SOURCES: MEDLINE was searched (1964 to January 2016) using the terms ch14.18, dinutuximab, immunotherapy, and neuroblastoma. Other information was identified from package insert, Biologics License Application, abstracts, news releases, and ClinicalTrials.gov. STUDY SELECTION AND DATA EXTRACTION: Identified English-language articles were reviewed. Selected studies included phase I through III. DATA SYNTHESIS: High-risk neuroblastoma is primarily a childhood cancer with 5-year survival rates of 40% to 50%. Treatment for high-risk neuroblastoma includes induction chemotherapy, surgery, myeloablative chemotherapy with autologous hematopoietic stem cell transplant, and radiation therapy. For patients achieving clinical remission, limited treatments exist for preventing relapse. Dinutuximab is a chimeric, human-murine, anti-GD2 monoclonal antibody approved in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), aldesleukin (interleukin-2 [IL-2]), and isotretinoin (13-cis-retinoic acid [RA]) for maintenance treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to first-line multiagent, multimodality therapy. In phase III trials, dinutuximab increased 2-year event-free survival and overall survival when compared to standard treatment. Severe adverse effects of dinutuximab include pain, hypersensitivity reactions, capillary leak syndrome, and hypotension. CONCLUSIONS: Dinutuximab is the first anti-GD2 monoclonal antibody approved in combination with GM-CSF, IL-2, and RA for maintenance treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to first-line multiagent, multimodality therapy. Ongoing research will determine if dinutuximab could be used earlier in treatment, in nonresponders to initial therapies, in combination with chemotherapy, or in other cancers.