Evaluating early intervention in smoldering myeloma clinical trials: a systematic review.

BACKGROUND: Smoldering multiple myeloma (SMM), an asymptomatic precursor of multiple myeloma (MM), carries a variable risk of progression to MM. There is little consensus on the efficacy or optimal timing of treatment in SMM. We systematically reviewed the landscape of all clinical trials in SMM. We compared the efficacy of treatment regimens studied in SMM to results from these regimens when used in newly diagnosed multiple myeloma (NDMM), to determine whether the data suggest deeper responses in SMM versus NDMM. METHODS: All prospective interventional clinical trials for SMM, including published studies, meeting abstracts, and unpublished trials listed on ClinicalTrials.gov up to April 1, 2023, were identified. Trial-related variables were captured, including treatment strategy and efficacy results. Relevant clinical endpoints were defined as overall survival (OS) and quality of life. RESULTS: Among 45 SMM trials identified, 38 (84.4%) assessed active myeloma drugs, while 7 (15.6%) studied bone-modifying agents alone. Of 18 randomized trials in SMM, only one (5.6%) had a primary endpoint of OS; the most common primary endpoint was progression-free survival (n = 7, 38.9%). Among 32 SMM trials with available results, 9 (28.1%) met their prespecified primary endpoint, of which 5 were single-arm studies. Six treatment regimens were tested in both SMM and NDMM; 5 regimens yielded a lower rate of very good partial response rate or better (≥VGPR) in SMM compared to the corresponding NDMM trial (32% vs 63%, 43% vs 53%, 40% vs 63%, 86% vs 89%, 92% vs 95%, and 94% vs 87%, respectively). CONCLUSION: In this systematic review of all prospective interventional clinical trials in SMM, we found significant variability in trial design, including randomization status, primary endpoints, and types of intervention used. Despite the statistical limitations, comparison of treatment regimens revealed no compelling evidence that the treatment is more effective when introduced early in SMM compared to NDMM.

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

Not available.

The promise and harms of screening for plasma cell dyscrasias.

In this perspective, we highlight both the promise and harms of screening for plasma cell dyscrasias, as well as the implications of the use of mass spectrometry for diagnosing monoclonal gammopathy of undetermined significance in routine practice.

Time-to-event surrogate end-points in multiple myeloma randomised trials from 2005 to 2019: A surrogacy analysis.

Use of surrogate end-points such as progression-free survival (PFS) and other time-to-event (TTE) end-points is common in multiple myeloma (MM) clinical trials. This systematic review characterises all published randomised controlled trials (RCTs) in MM using PFS or other TTE end-points between 2005 and 2019 and assesses strength of surrogacy of PFS for overall survival (OS). The association between OS hazard ratios (HRs) and PFS HRs was evaluated with linear regression, and the coefficient of determination with Pearson's correlation. We identified 88 RCTs of which 67 (76%) used PFS as the primary/co-primary end-point. One trial indicated whether progression was biochemical or clinical. Of the variance in OS, 39% was due to variance in PFS. Correlation between PFS and OS was weak (0.62, 95% confidence interval [CI] 0.38-0.78). In newly diagnosed MM, 43% of the variance in OS was due to changes in PFS. The correlation between PFS and OS was weak (0.65, 95% CI 0.30-0.84). In relapsed/refractory MM, 58% of the variance in OS was due to changes in PFS. Correlation between PFS and OS was medium (0.76, 95% CI 0.42-0.91). We demonstrate that PFS and progression characteristics are characterised poorly in MM trials and that PFS is a poor surrogate for OS in MM.

Cancer-specific mortality in multiple myeloma: a population-based retrospective cohort study.

Survival has improved in patients diagnosed with multiple myeloma (MM) over the last two decades; however, there remains a paucity of data on the causes of death in MM patients and whether causes of death change during the disease trajectory. We conducted a retrospective population-based study to evaluate the rates of MM-specific versus non-MM cause of death and to identify factors associated with cause-specific death in MM patients, stratified into autologous stem cell transplant (ASCT) and non-ASCT cohorts. A total of 6,677 patients were included, 2,576 in the ASCT group and 4,010 in the non-ASCT group. Eight hundred and seventy-three (34%) ASCT patients and 2,787 (68%) non-ASCT patients died during the follow-up period. MM was the most frequent causes of death, causing 74% of deaths in the ASCT group and 67% in the non-ASCT group. Other cancers were the second leading causes of death, followed by cardiac and infectious diseases. Multivariable analysis demonstrated that a more recent year of diagnosis and novel agent use within 1 year of diagnosis were associated with a decreased risk of MM-specific death, whereas a history of previous non-MM cancer, older age, and the presence of CRAB criteria at diagnosis increased the risk of non-MM death. Our data suggests that despite improvement in MM outcomes in recent years, MM remains the greatest threat to overall survival for patients. Further advances in the development of effective MM therapeutic agents in both ASCT and non-ASCT populations and patient access to them is needed to improve outcomes.

Attrition and withdrawal in multiple myeloma randomized controlled trials: A systematic review.

OBJECTIVES: Patients with multiple myeloma (MM) enrolled in randomized control trials (RCTs) discontinue treatment for various reasons; however, no prior study has analyzed reasons for discontinuation. We performed a systematic review of MM RCTs to investigate reasons for treatment discontinuation, imbalances between trial cohorts, and reporting practices. METHODS: A comprehensive search for RCTs in MM from 2015 to 2021 identified 45 studies meeting inclusion criteria. RESULTS: Of 21 236 randomized patients, 10 161 (47.8%) discontinued therapy by primary endpoint ascertainment. Causes of discontinuation included progression (n = 4790; 22.6% of randomized patients); toxicity (n = 2569; 12.1%); patient/physician withdrawal (n = 1200; 5.7%) and death (n = 495; 2.3%). Of randomized patients, 20 914 (98.5%) were included in the RCT analysis. Imbalances of attrition, defined as trials with greater than 5% absolute difference in discontinuation rate for reasons other than death, progression, and toxicity between intervention and control arms, were found in 11 (24.4%) studies. CONCLUSIONS: Although progression is the most common reason for RCT treatment discontinuation in patients with MM, over 10% discontinued due to toxicity. Furthermore, 24.4% of trials showed substantial imbalances between trial cohorts; raising concern for informative censoring and emphasizes the importance of detailed characterization of withdrawal in MM RCTs.

Clinical efficacy of retreatment of daratumumab-based therapy (D2) in daratumumab-refractory multiple myeloma.

Daratumumab demonstrates activity as a single agent and in combination with either immunomodulatory agents (IMiDs) or proteasome inhibitors (PIs) in relapsed refractory multiple myeloma (RRMM). However, little is known about the benefit of daratumumab retreatment in daratumumab-refractory MM. This study aimed to analyze the clinical efficacy of daratumumab-based retreatment (D2) in patients who are daratumumab refractory MM. Retrospectively, we identified 43 RRMM patients from a single-center database review. The median age was 65 years, 42% patients had high-risk cytogenetics, and 23% had an extramedullary disease, while the median time between D2 and prior daratumumab was 1 (0.25-39) month. All D2 patients received combination therapy with either pomalidomide, carfilzomib, bortezomib, or lenalidomide. The response rate, median progression-free, and overall survival were 49%, 7.97 and 32.6 months, respectively. Our study raises the possibility of re-utilizing daratumumab in combination with different classes of anti-myeloma drugs to generate responses in RRMM patients who are daratumumab-refractory.

Impact of academic medical center access on outcomes in multiple myeloma.

Treatment at academic cancer centers (ACs) is associated with improved survival across hematologic malignancies, though the benefit in multiple myeloma (MM) has not been examined. This study aims to evaluate survival outcomes at Commission on Cancer accredited ACs compared to non-academic centers (NACs) for patients receiving MM-directed therapy. The National Cancer Database (NCDB) was used to identify demographics and overall survival (OS) of MM patients diagnosed from 2004 to 2017 and to compare outcomes by facility type. Survival analysis was repeated in a propensity score matched cohort, with NACs matched 1:1 to ACs by age, race, comorbidity score, insurance, year of diagnosis, distance traveled, and income. Of 163 375 MM patients, 44.5% were treated at ACs. Patients at ACs were more likely to receive MM-directed therapy compared to NACs (81% vs. 73%, p < .001). For patients receiving treatment, median OS at ACs was 71.3 months versus 41.2 months at NACs (p < .001). When adjusted for baseline demographics, patients treated at ACs had reduced mortality; hazard ratio (HR) 0.79 (95% CI 0.78-0.81, p < .001). The propensity score matched cohort maintained this survival benefit with a median OS of 59.9 months at ACs versus 37.0 months at NACs (p < .001), HR of 0.66 (95% CI 0.64-0.67, p < .001). ACs treated younger patients with fewer comorbidities and were more likely to treat racial minorities and patients with Medicaid or private insurance, and the uninsured. In this analysis, MM patients treated at ACs have significantly improved survival. While potentially related to access to specialized care, socioeconomic factors that drive facility selection may also contribute.

Quality of end-of-life care in multiple myeloma: A 13-year analysis of a population-based cohort in Ontario, Canada.

Optimizing end-of-life (EOL) care for multiple myeloma (MM) represents an unmet need. An administrative cohort in Ontario, Canada was analysed between 2006 and 2018. Aggressive care was defined as two or more emergency-department visits in the last 30 days before death, or at least two new hospitalizations within 30 days of death, or an intensive care unit (ICU) admission within the last 30 days of life. Supportive care was defined as a physician house-call in the last two weeks before death, or a palliative nursing or personal support visit at home in the last 30 days before death. Among 5095 patients, 23.2% of patients received chemotherapy at EOL and 55.6% of patients died as inpatient. A minority received aggressive care at EOL [28.3%: autologous stem cell transplant (ASCT), 20.4%: non-ASCT], and a majority received supportive care at EOL (65.4%: ASCT, 61.5%: non-ASCT). Supportive care was less likely to be received by those aged over 80 years and in lower-income neighbourhoods. Supportive care at EOL increased from 56.0% in 2006 to 70.3% in 2018. Despite improvements, many patients with MM experience aggressive care at EOL. Even in a publicly funded health care system, disparities based on age, income and community size are present.

Palliative care utilization, transfusion burden, and end-of-life care for patients with multiple myeloma.

INTRODUCTION: Despite treatment advances, multiple myeloma (MM) remains a significant source of morbidity and mortality. We aimed to examine specialist palliative care (SPC) involvement and end-of-life care for patients with MM. METHODS: We assessed all deceased patients with a diagnosis of MM who received care at a single institution from January 2010 to December 2019 and assessed SPC involvement. RESULTS: We reviewed 456 deceased patients. Overall, 207 patients (45.4%) received SPC visits by clinicians during their disease, and 153 (33.5%) were on MM treatment in the month before death. Median time from SPC consultation to death was 1 month, with 42 (9.2%) of patients receiving SPC visits 6 or more months before death. Amongst the patients for which a place of death was reported (351), 117 (33.3%) died in the acute care setting. Outpatient SPC did not correlate with a reduction of death in the acute care setting. In the group of patients who received outpatient SPC, 22/84 (26.2%) died in an acute care setting, whereas 95/267 (35.5%) patients who did not receive outpatient SPC also died in an acute care setting, (p = .11). CONCLUSION: In our analysis of the entire trajectory of the MM patient experience from diagnosis to death, we found low rates of SPC involvement and a significant proportion of patients receiving aggressive care at end-of-life. While there is no clear correlation that SPC involvement impacted the rate of acute care deaths or decreased utilization of MM treatment in the last month of life, further prospective research on optimal utilization of SPC is required.

Hospitalization at the end of life in patients with multiple myeloma.

BACKGROUND: Despite advances in treatment, multiple myeloma (MM) remains incurable and results in significant morbidity and mortality. Further research investigating where MM patients die and characterization of end-of-life hospitalizations is needed. METHODS: We utilized the National Inpatient Sample (NIS) to explore the hospitalization burden of MM patients at the end of their lives. RESULTS: The percent of patients dying in the hospital as a percent of overall MM deaths ranged from 54% in 2002 to 41.4% in 2017 (p < 0.01). Blood transfusions were received in 32.7% of these hospitalizations and infections were present in 47.8% of patients. Palliative care and/or hospice consultations ranged from 5.3% in 2002 to 31.4% in 2017 (p < 0.01). CONCLUSION: Our study demonstrates that patients with MM dying in the hospital have a significant requirement for blood transfusions and have a high infection burden. We also show that palliative care and hospice involvement at the end of life has increased over time but remains low, and that ultimately, inpatient mortality has decreased over time, but MM patients die in the hospital at a higher rate than the general population.

Infection risks in multiple myeloma: a systematic review and meta-analysis of randomized trials from 2015 to 2019.

BACKGROUND: Patients with multiple myeloma (MM) remain at an increased risk of infection due to the disease process, as well as the ensuing treatments. METHODS: We performed a systematic review to evaluate the monthly risk of grade III/IV infection, pneumonia, and neutropenia in patients with myeloma enrolled in randomized clinical trials (RCTs). RESULTS: The risk of grade III or higher infection, pneumonia, and neutropenia persists among all phases of treatment. There was no statistical difference in grade III or higher infection, pneumonia, and neutropenia between frontline and relapsed/refractory setting. In the maintenance setting, the complications of infection, pneumonia, and neutropenia were low, but not negligible. Three-drug regimens were no more likely than two-drug regimens to have an increased risk of Grade III or higher infection. CONCLUSIONS: This is the first study to quantify the monthly risk of grade III or higher infection, pneumonia, and neutropenia across different treatment regimens in the frontline, maintenance, and relapsed/refractory settings. The results of our systematic review demonstrate a significant risk for severe infection, pneumonia, and neutropenia in patients with MM. Further studies are needed to determine the value of antibiotic prophylaxis in a broader myeloma patient population, as well as other approaches that will further mitigate the morbidity and mortality related to infection in this vulnerable patient population.

Carfilzomib, cyclophosphamide, and dexamethasone (KCd) for the treatment of triple-class relapsed/refractory multiple myeloma (RRMM).

BACKGROUND: Multiple myeloma (MM) is an incurable hematologic malignancy, and outcomes remain poor for patients with triple-class relapsed/refractory MM (RRMM). Descriptive analyses were performed on available data for patient characteristics, disease course, and outcomes of the KCd on triple-class RRMM patients at our institution. PATIENTS AND METHODS: Twenty-three patients with triple-class RRMM treated with KCd between June 2017 and October 2020 were included in our analysis. The regimen KCd consisted of 28 days cycles of carfilzomib 20/36 mg/m2 IV on days 1, 2, 8, 9, 15, and 16, cyclophosphamide 300 mg/m2 IV weekly, and dexamethasone (20-40) mg orally weekly. RESULTS: Patients received a median of 6 (3-10) prior regimens. The median number of cycles administered was 4 (1-11) cycles. Overall response rate was 52%, 6 patients (26%) achieved very good partial response (VGPR), 6 patients (26%) achieved partial response (PR), and 5 patients (22%) achieved stable disease (SD). Progression-free survival (PFS) and Overall-survival (OS) were 4 and 11.9 months, respectively. There was no reported treatment-related mortality. The most common grade ≥3 adverse events were neutropenia (26%), thrombocytopenia (56.5%), and anemia (56.5%). CONCLUSIONS: KCd showed clinically meaningful efficacy and manageable safety profile in patients with triple-class RRMM in real-world.

Use of endpoints in multiple myeloma randomized controlled trials over the last 15 years: A systematic review.

Surrogate endpoints are being used more frequently in randomized controlled trials, even though they do not consistently corelate with patient outcomes. We systemically evaluated the use of surrogate endpoints in multiple myeloma randomized controlled trials over the past 15 years. We searched three databases (Pubmed, Embase, Cochrane) for multiple myeloma randomized controlled trials from January 1, 2005 to December 30, 2019. The primary outcome of our study was the proportion of randomized controlled trials that used overall survival as their primary endpoint. Secondary outcomes included the use of surrogate endpoints, and trends over time, and whether they differed based on study sponsorship. We included 151 randomized controlled trials in our analysis. The primary endpoint was overall survival (OS) in 17 (11.3%) of studies, progression free survival (PFS) or event-defined endpoints in 91 studies (60.3%) and response-based endpoints in 44 studies (29.1%). Quality of life was a primary endpoint in only three studies (2%). The use of OS as a primary endpoint decreased from 28.5% of trials from 2005 to 2009 to 5.5% from 2015 to 2019. There has been a decrease in the clinically meaningful endpoint of OS over the past 15 years in multiple myeloma randomized controlled trials. Use of quality of life as a primary endpoint remains exceedingly low. It remains paramount to recognize that the use of surrogate endpoints is imperfect, and care based upon them requires constant physician and patient re-analysis.

A Critical Appraisal and Targeted Intervention of the Oncology Experience in an Internal Medicine Residency.

Most oncology education is provided to residents on an inpatient oncology service, with limited outpatient exposure. There exists considerable need to develop effective education strategies to teach resident physicians basic concepts in oncology. We created a 2-hour small-group interactive workshop, using interactive cases, followed by a number of questions regarding curability, survival, and possible treatment options. All residents were asked to fill out optional questionnaires before and after this workshop. A total of 64 residents participated in this study with an average of 16 residents per session. Significant deficits in knowledge were identified, and prognosis was estimated correctly by 40% of residents when presented with a variety of clinical scenarios. We demonstrated an increase in comfort level in basic oncology concerns, comfort level at estimating prognosis, and managing toxicity based on pre- and post-level testing. Our results confirm that the oncology inpatient rotation may not be adequate in educating residents. The format of our workshop demonstrates that it is possible to create and implement a focused intervention with fairly limited resources. This can serve as a platform for evaluation of oncology medical education of internal medicine residents at other institutions.

Similar response rates and survival with PARP inhibitors for patients with solid tumors harboring somatic versus Germline BRCA mutations: a Meta-analysis and systematic review.

BACKGROUND: PARP inhibitors (PARPi) have recently been approved for various malignancies based on the results of several clinical trials. However, these trials have mostly recruited patients with germline BRCA mutations, and it is unclear whether PARPi have similar efficacy in patients with somatic BRCA mutations. Our study aimed to determine the efficacy of PARPi in patients with somatic BRCA mutations. METHODS: We performed a meta-analysis comparing overall response rate to PARPi in patients harboring somatic versus germline BRCA mutations. We looked at studies including somatic and germline mutations in BRCA patients that received PARPi. RESULTS: After screening and removing duplicates, 18 studies met our criteria for including both somatic and germline BRCA mutations. Only 8 studies reported response rates for both somatic and germline BRCA mutations. In those studies, 24 out of 43 patients with somatic BRCA mutations (55.8%), and 69 out of 157 (43.9%) patients with germline BRCA patients had a response to therapy to PARPi. This difference was not statistically significant (p = 0.399). In all five studies that reported progression-free survival, there was no obvious difference in outcomes between somatic versus germline BRCA patients, however a precise statistical analysis could not be performed. CONCLUSION: Our meta-analysis and systematic review of the literature indicates similar response rates of PARPi therapy in patients with somatic and germline BRCA mutations. Investigation of use of PARPi therapy in a broader patient population, and the inclusion of somatic BRCA mutations in further clinical trials is paramount in improving therapeutic options for our patients.

Antibiotic prophylaxis for patients with newly diagnosed multiple myeloma: Systematic review and meta-analysis.

OBJECTIVE: Ascertain the benefit of prophylactic antibiotics for patients with newly diagnosed multiple myeloma (MM), given that clinical trials evaluating this have had conflicting results. METHODS: We performed a systematic review and meta-analysis evaluating the use of prophylactic antibiotics in patients with MM and its impact on infection risk and mortality. RESULTS: Across three included studies, a total of 664 patients received antibiotics and 650 patients received no antibiotics. The overall incidence of infection within 3 months was lower for antibiotic group compared to placebo (18.4% vs 23.4%, RR: 0.79, 95% CI 0.62-1.00, P = .05, I2  = 6.5%). There was no difference in mortality in the first 3 months (1.5% vs 3.5%, RR: 0.47, 95% CI 0.17-1.27, P = .60, I2  = 28.1%). CONCLUSION: Antibiotic prophylaxis for a finite duration can decrease the overall incidence of infection within the first 3 months following diagnosis. This does not lead to a decrease in mortality. Further data on antibiotic resistance patterns, toxicity, healthcare expenditures, and the impact of antibiotics on subsequent therapies can assist providers in helping make decisions on prophylactic antibiotics with their patients.

Inpatient mortality of patients with multiple myeloma and renal impairment undergoing autologous stem cell transplantation.

OBJECTIVES: Further data are needed on the safety of high-dose melphalan and autologous stem cell transplant (HDM-ASCT) in patients with multiple myeloma (MM) and renal impairment. The objective of our study was to use the National Inpatient Sample (NIS) to determine inpatient mortality for patients with MM and renal impairment undergoing HDM-ASCT, as well as trends over time. METHODS: Using the NIS, we tracked hospital admissions for MM patients from 2002 to 2014 who underwent HDM-ASCT, using ICD 9 coding. RESULTS: The total weighted estimate of inpatient admissions for HDM-ASCT among MM patients was 47,253 from 2002 to 2014. A weighted total of 45 and 1709 patients with MM received peritoneal dialysis (PD) and hemodialysis (HD) during HDM-ASCT for MM, respectively. There was a markedly increased risk of inpatient mortality in patients on dialysis undergoing transplant (20.5% for PD patients, 13.8% for HD patients), even after accounting for other comorbidities (odds ratio of inpatient mortality of 6.193 [CI 3.585-10.701]). A significant decrease was noted in inpatient mortality for patients with ESRD undergoing HDM-ASCT over time from 15.6% in 2009 to 5% in 2014 (P < .001). CONCLUSION: Patients with MM on dialysis undergoing HDM-ASCT are at significantly increased risk of inpatient mortality.