Low booster uptake in cancer patients despite health benefits.

Patients with cancer are at increased risk of death from COVID-19 and have reduced immune responses to SARS-CoV2 vaccines, necessitating regular boosters. We performed comprehensive chart reviews, surveys of patients attitudes, serology for SARS-CoV-2 antibodies and T-cell receptor (TCR) ß sequencing for cellular responses on a cohort of 982 cancer patients receiving active cancer therapy accrued between November-3-2020 and Mar-31-2023. We found that 92·3% of patients received the primer vaccine, 70·8% received one monovalent booster, but only 30·1% received a bivalent booster. Booster uptake was lower under age 50, and among African American or Hispanic patients. Nearly all patients seroconverted after 2+ booster vaccinations (>99%) and improved cellular responses, demonstrating that repeated boosters could overcome poor response to vaccination. Receipt of booster vaccinations was associated with a lower risk of all-cause mortality (HR=0·61, P=0·024). Booster uptake in high-risk cancer patients remains low and strategies to encourage booster uptake are needed. Highlights: COVID-19 booster vaccinations increase antibody levels and maintain T-cell responses against SARS-CoV-2 in patients receiving various anti-cancer therapiesBooster vaccinations reduced all-cause mortality in patientsA significant proportion of patients remain unboosted and strategies are needed to encourage patients to be up-to-date with vaccinations.

A Phase I Study to Assess the Safety and Pharmacokinetics of Single-agent Lorvotuzumab Mertansine (IMGN901) in Patients with Relapsed and/or Refractory CD-56-positive Multiple Myeloma.

BACKGROUND: Despite therapeutic advancements that have significantly improved outcomes in multiple myeloma (MM), it remains an incurable disease. Patients with relapsed and/or refractory MM have an aggressive disease course, with inferior outcomes, necessitating the need for agents with novel therapeutic mechanisms. We present the results of a completed phase I trial of single-agent lorvotuzumab mertansine, a unique antibody-drug conjugate targeting CD56, which is frequently expressed in MM. PATIENTS AND METHODS: Thirty-seven patients with relapsed MM were enrolled in a dose-escalation phase I clinical trial to determine the maximum tolerated dose of lorvotuzumab mertansine (112 mg/m2), followed by an expansion phase at the maximum tolerated dose. RESULTS: Despite a high proportion of patients with relapsed and/or refractory MM (56.8%), stable disease or better was noted in 42.9% of patients, and these patients had a long duration of response (median, 15.5 months). The adverse event profile was favorable, with a low incidence of grade 3/4 adverse events and no infusion-related reactions. No humoral responses were detected against the study drug. CONCLUSION: This completed phase I trial of single-agent lorvotuzumab mertansine provides ample evidence of safety and signals of clinical activity for this agent, warranting its further clinical development as part of combination regimens for the management of MM.

Development of the Histoculture Drug Response Assay (HDRA).

The histoculture drug response assay (HDRA) was developed using Gelfoam® histoculture of all tumor types. Twenty tumor classes, including all the major ones, have been histocultured on Gelfoam® and tested for drug response. Quantitative and qualitative results show increasing cell kill with rising cytotoxic drug concentration, differential drug sensitivities of multiple cell types within individual cultured tumors, differential sensitivities to a single drug of a series of tumors of the same histopathological classification, differential sensitivities of individual tumors to a series of drugs, and sensitivity patterns of various tumor types similar to the sensitivities found in vivo. Therefore, the results indicated that precise therapeutic data can be obtained from tumor specimens growing in Gelfoam® histoculture in vitro for the individual cancer patient as well as for rational and relevant screening for novel agents active against human solid tumors.

Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial.

BACKGROUND: New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. METHODS: In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126. FINDINGS: The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months (95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. INTERPRETATION: Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. FUNDING: Janssen Research & Development.

Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis.

CAN2007 was a phase 1/2 study of once- and twice-weekly single-agent bortezomib in relapsed primary systemic amyloid light chain amyloidosis (AL) amyloidosis. Seventy patients were treated, including 18 and 34 patients at the maximum planned doses on the once- and twice-weekly schedules. This prespecified final analysis provides mature response and long-term outcomes data after 3-year additional follow-up since the last report. In the once-weekly 1.6 mg/m(2) and twice-weekly 1.3 mg/m(2) bortezomib groups, final hematologic response rates were 68.8% and 66.7%; 80% of patients in each group sustained their response for ≥1 year. One-year progression-free rates were 72.2% and 76.8%. Median overall survival (OS) was 62.1 months and not reached; 4-year OS rates were 75.0% and 63.0%. Low baseline difference in κ/λ free light-chain level was associated with higher hematologic complete response rates and longer OS. At data cutoff, 40 (57%) patients had received subsequent therapy, including 19 (27%) retreated with bortezomib, 11 (58%) of whom achieved complete or partial hematologic responses. Four patients received prolonged bortezomib for between 3.5 and 5.6 years, with no new safety concerns, highlighting the feasibility of long-term therapy. Single-agent bortezomib produced durable hematologic responses and promising long-term OS in relapsed AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT00298766.

Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival.

Although TNFRSF17 (also designated as B-cell maturation antigen (BCMA)) is expressed on tumour cells in B-cell malignancies, it has not been found in serum. The present study found that BCMA concentrations were higher in the supernatants of cultured bone marrow mononuclear cells from multiple myeloma (MM) patients than in healthy subjects. Serum BCMA levels were measured in samples from MM patients (n = 209), monoclonal gammopathy of undetermined significance (MGUS) individuals (n = 23) and age-matched controls (n = 40). BCMA was detected in the serum of untreated MM patients (n = 50) and levels were higher than in MGUS patients (P = 0·0157) and healthy subjects (P < 0·0001). Serum BCMA levels were higher among patients with progressive disease (n = 80) compared to those with responsive disease (n = 79; P = 0·0038). Among all MM patients, overall survival was shorter among patients whose serum BCMA levels were above the median (P = 0·001). We also demonstrated that sera from mice with human MM xenografts contained human BCMA, and levels correlated with the change in tumour volume in response to melphalan or cyclophosphamide with bortezomib. These results suggest that serum BCMA levels may be a new biomarker for monitoring disease status and overall survival of MM patients.

Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study.

This first prospective phase 2 study of single-agent bortezomib in relapsed primary systemic AL amyloidosis evaluated the recommended (maximum planned) doses identified in phase 1 testing (1.6 mg/m² once weekly [days 1, 8, 15, and 22; 35-day cycles]; 1.3 mg/m² twice weekly [days 1, 4, 8, and 11; 21-day cycles]). Among all 70 patients enrolled in the study, 44% had ≥ 3 organs involved, including 73% and 56% with renal and cardiac involvement. In the 1.6 mg/m² once-weekly and 1.3 mg/m² twice-weekly groups, the hematologic response rate was 68.8% and 66.7% (37.5% and 24.2% complete responses, respectively); median time to first/best response was 2.1/3.2 and 0.7/1.2 months, and 78.8% and 75.5% had response durations of ≥ 1 year, respectively. One-year hematologic progression-free rates were 72.2% and 74.6%, and 1-year survival rates were 93.8% and 84.0%, respectively. Outcomes appeared similar in patients with cardiac involvement. Among all 70 patients, organ responses included 29% renal and 13% cardiac responses. Rates of grade ≥ 3 toxicities (79% vs 50%) and discontinuations/dose reductions (38%/53% vs 28%/22%) resulting from toxicities appeared higher with 1.3 mg/m² twice-weekly versus 1.6 mg/m² once-weekly dosing. Both bortezomib dose schedules represent active, well-tolerated regimens in relapsed AL amyloidosis. This study was registered at www.clinicaltrials.gov as #NCT00298766.

Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study.

New treatment options are required for primary systemic AL amyloidosis (AL). This phase 1 dose-escalation component of a phase 1/2 study in relapsed AL aimed to determine the maximum tolerated dose (MTD) of bortezomib once weekly (0.7-1.6 mg/m(2); days 1, 8, 15, and 22; 35-day cycles) and twice weekly (0.7-1.3 mg/m(2); days 1, 4, 8, and 11; 21-day cycles) and assess preliminary hematologic responses. Thirty-one patients with relapsed AL were enrolled across 7 cohorts. Dose-limiting toxicity included grade 3 congestive heart failure in 2 patients (1 at once weekly, 1.6 mg/m(2), and 1 at twice weekly, 1.0 mg/m(2)). MTD was not defined for either schedule; the maximum doses of 1.6 mg/m(2) (once weekly) and 1.3 mg/m(2) (twice weekly) are being used in phase 2 evaluation. Most commonly reported toxicities on both schedules included gastrointestinal events, fatigue, and nervous system disorders. Discontinuations and dose reductions for toxicity were reported in 12 and 4 patients, respectively. No treatment-related deaths occurred. Hematologic responses occurred in 15 (50%) of 30 evaluable patients, including 6 (20%) complete responses. Median time to first response was 1.2 months. Once-weekly and twice-weekly bortezomib appear generally well tolerated in relapsed AL, with promising hematologic responses. This study is registered with http://ClinicalTrials.Gov under identifier NCT00298766.

Safety and efficacy of bortezomib and melphalan combination in patients with relapsed or refractory multiple myeloma: updated results of a phase 1/2 study after longer follow-up.

Bortezomib synergizes with melphalan in preclinical and early clinical studies. Updated data from our phase 1/2 study assessing the safety and efficacy of bortezomib plus melphalan in relapsed/refractory multiple myeloma (MM) are presented. Bortezomib (0.7, 1.0, or 1.3 mg/m(2)) on days 1, 4, 8, and 11 and oral melphalan (0.025-0.25 mg/kg) on days 1-4 of a 28-day cycle were administered. Hematologic toxicities defined the maximum tolerated dose as bortezomib 1.0 mg/m(2) and melphalan 0.10 mg/kg. Because dose-limiting toxicities were attributed to the more myelosuppressive melphalan, cohorts 9 and 10 with higher bortezomib (1.3 mg/m(2)) and lower melphalan (0.025 and 0.10 mg/kg) doses were added. Responses occurred in 32/46 (70%) evaluable patients: two complete (4%), five near-complete (11%), 16 partial (35%), and nine minimal (20%). Complete and near-complete responses were observed only with higher bortezomib doses. Response rates were similar in patients with prior melphalan or bortezomib. Median progression-free survival was 9 months (range, 1-24), and overall survival was 32 months (range, 1-54). The most common grade 3/4 hematologic adverse events (AEs) were neutropenia (31%/0%), thrombocytopenia (25%/2%), and anemia (13%/0%). Grade 4 tumor lysis syndrome was reported in one patient. Fewer grade 3/4 hematologic AEs were reported in cohorts 9 and 10 than in cohorts receiving lower bortezomib and higher melphalan doses. In conclusion, bortezomib plus melphalan is a steroid- and immunomodulatory drug-free regimen that may provide a treatment alternative for elderly patients and patients with significant comorbidity.

Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma.

PURPOSE: Bortezomib has shown synergy with melphalan in preclinical models. We assessed the safety, tolerability, and response rate in a dose-escalation study of this combination for relapsed or refractory multiple myeloma patients. METHODS: Bortezomib was administered from 0.7 to 1.0 mg/m(2) on days 1, 4, 8, and 11 of a 28-day cycle for up to eight cycles. Oral melphalan was administered in escalating doses from 0.025 to 0.25 mg/kg on days 1 to 4. RESULTS: Thirty-five patients with relapsed or refractory myeloma were enrolled, 34 of whom were assessable for response. Dose-limiting toxicity of grade 4 neutropenia in two of six patients in the highest dose cohort led to the assignment of bortezomib 1.0 mg/m2 and melphalan 0.10 mg/kg as the maximum-tolerated dose (MTD). Responses (minimal [MR], partial [PR], or complete [CR]) occurred in 23 of 34 patients (68%), including two CRs (6%), three immunofixation-positive CRs (9%), 11 PRs (32%), and seven MRs (21%). Responses were observed in five of six assessable patients (83%) at the MTD. Median progression-free survival for all patients was 8 months (range, 2 to 18 months). Grade > or = 3 toxicities were related mostly to myelosuppression. Among the 15 patients with grade 1/2 neuropathy at baseline, it resolved during treatment in one, worsened in four, and remained stable in 10 patients. Eight other patients developed grade 1/2 neuropathy during the study. CONCLUSION: Bortezomib plus melphalan given on a 28-day schedule showed encouraging activity with manageable toxicity and represents a promising treatment for myeloma patients.

Overcoming drug resistance in multiple myeloma: the emergence of therapeutic approaches to induce apoptosis.

Drug resistance remains a major clinical challenge for cancer treatment. Early studies suggested that overexpression of P-glycoprotein was a major contributor to the chemotherapy resistance of myeloma cells and other tumor cells. Attempts in several clinical studies to reverse multidrug resistance protein (MDR) by using MDR modulators have not yet generated promising results. Recently, the emerging knowledge about the importance of overcoming antiapoptosis and drug resistance in treating a variety of malignancies, including multiple myeloma (MM), raises new hope of improving the treatment outcome for patients with cancer. The therapeutic value of targeting therapies that aim to reverse the antiapoptotic process in MM cells has been explored in a number of experimental systems, and the results have been promising. The proteasome inhibitor PS-341 is a new specifically targeted proapoptotic therapy that has been tested in clinical studies. The results indicate that PS-341 alone is an effective therapy for patients with MM who experience disease relapse. Recent in vitro data also demonstrate that PS-341 can markedly sensitize chemotherapy-resistant MM cells to various chemotherapeutic agents. On the basis of these encouraging results, clinical studies are underway to test the efficacy of PS-341 and chemotherapeutic agents as combination therapy in treating patients with refractory and relapsed MM.

The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents.

Increased nuclear factor kappaB (NF-kappaB) activity is associated with increased tumor cell survival in multiple myeloma. The function of NF-kappaB is inhibited through binding to its inhibitor, IkappaB. Release of activated NF-kappaB follows proteasome-mediated degradation of IkappaB resulting from phosphorylation of the inhibitor and, finally, conjugation with ubiquitin. We report that myeloma cells have enhanced IkappaBalpha phosphorylation and increased NF-kappaB activity compared with normal hematopoietic cells. The proteasome inhibitor PS-341 blocked nuclear translocation of NF-kappaB, blocked NF-kappaB DNA binding, and demonstrated consistent antitumor activity against chemoresistant and chemosensitive myeloma cells. The sensitivity of chemoresistant myeloma cells to chemotherapeutic agents was markedly increased (100,000-1,000,000-fold) when combined with a noncytotoxic dose of PS-341 without affecting normal hematopoietic cells. Similar effects were observed using a dominant negative super-repressor for IkappaBalpha. Thus, these results suggest that inhibition of NF-kappaB with PS-341 may overcome chemoresistance and allow doses of chemotherapeutic agents to be markedly reduced with antitumor effects without significant toxicity.

Identification of polymorphisms of the IkappaBalpha gene associated with an increased risk of multiple myeloma.

When NF-kappaB proteins are bound to IkappaBalpha, they remain in the cytosol, and are unable to act as transcription factors. Phosphorylation of IkappaBalpha at Serine32 and Serine36 has been shown to stimulate ubiquitination followed by proteasome-mediated degradation of IkappaBalpha, resulting in the release of active NF-kappaB. NF-kappaB activity is associated with bone loss and B cell growth as well as chemotherapy resistance. Because previous studies have shown abnormalities of the IkappaBalpha gene in patients with lymphoma, we determined whether alterations of this gene also occur in multiple myeloma (MM). We determined the DNA sequence of the IkappaBalpha gene from bone marrow mononuclear cells from 18 MM patients and 24 healthy subjects as well as two MM cell-lines. We identified eight polymorphisms. Statistically, the prevalence of three polymorphisms, one in exon 1 and two in exon 6, were significantly higher in MM patients (alpha>1) compared with samples from control subjects. Six of eight polymorphisms in myeloma samples have also been identified in previous studies of IkappaBalpha sequences derived from lymphoma samples. In addition, we detected two polymorphisms in the IkappaBalpha gene that have not been previously reported. Together, these results provide the basis for future evaluation the IkappaBalpha/NF-kappaB pathway in MM patients.