Multiple Myeloma in Young Patients: A Scoping Review.

Data on the disease course, presenting features, outcomes, and prognosis of younger patients with multiple myeloma (MM) are lacking. Younger patients with MM have historically been considered to have better outcomes primarily based on better tolerance of treatment and lack of medical comorbidities, but the specific age range of this population has not been uniformly defined. Given the lack of consistent data reporting in patients considered to be young MM patients, we performed a scoping review to highlight the research currently available to start drawing conclusions about these patients and highlight unmet areas of need to focus on further investigation. We searched Embase, Cochrane Central Register of Controlled Trials, CINAHL Plus, Web of Science, and the OVID version of MEDLINE including broad terms that embody the concept of young patients with MM. Our final review included 201 studies which were then categorized according to age group, number of patients, outcomes, and comparators to older patients, along with location and database when available. We have chosen to categorize 3 age groupings: <50: young adults with MM (YA MM), 50 to 65: mid-life adults with multiple myeloma (ML MM) and 65+: older adults with multiple myeloma (OA MM). This review demonstrates the heterogeneity that exists in defining and describing young patients with MM, highlights the lack of studies specifically addressing the unique needs of younger patients, and emphasizes areas of future research unique to this population.

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.

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.

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.

Toxicity management strategies for next-generation novel therapeutics in multiple myeloma.

The therapeutic options available for patients with multiple myeloma have greatly expanded over the past decade and incorporating these novel agents into routine clinical practice has significantly improved outcomes. The next generation of therapeutics is available for relapsed and refractory patients either as standard of care or in clinical trial, and these drugs represent a generational paradigm shift. Patients now have access to a multitude of novel immunotherapeutics, including monoclonal antibodies, an antibody-drug conjugate, chimeric antigen receptor T-cells (CAR-T), and bispecific T-cell redirecting antibodies, and novel oral therapies including selinexor (selective inhibitor of nuclear export) and venetoclax (bcl-2 inhibitor). While these drugs have the potential to be highly efficacious in certain subsets of patients when used as single agents or in combination regimens, they are each associated with unique toxicity profiles. It is imperative to understand these potential adverse events to ensure patient safety. Appropriate supportive care management is paramount to maximize drug exposure and therapeutic efficacy. The following review focuses its discussion on drugs and combination regimens that are currently FDA-approved and those that continue to be investigated in clinical trials, highlights the clinically relevant toxicity profiles for each of the different agents, and provides practical considerations for the treatment team.

Financial toxicity in hematological malignancies: a systematic review.

Hematologic malignancy outcomes have remarkably improved in the past decade with further advancement expected in future years. However, the detrimental effects of financial toxicity (FT) on patients with hematologic malignancies, because of both diagnoses and subsequent treatments, have not been studied comprehensively. We performed a systematic review of all studies reporting FT as a primary or secondary outcome among adult or pediatric patients with hematological malignancies. A total of 55 studies met the inclusion criteria for analysis. Across studies, 20-50% of patients reported some form of FT, including loss of work productivity, food and transportation costs, and depletion of savings. Younger age, lower-income level, unemployment, and rural residence were the most commonly identified risk factors for FT. Two studies looked at survival outcomes, with one reporting improvement in survival with a decrease in financial toxicity. However, significant heterogeneity in FT definitions was found between countries and payor systems. Only half of the studies (51%, n = 28) used validated survey instruments such as the COST assessment. The present systematic review identified that FT is common in patients with hematological malignancies and may be associated with poorer outcomes. However, studies of FT generally use non-standardized methods with cross-sectional analyses rather than longitudinal, prospective assessments. Further work is needed to standardize FT reporting and investigate measures to alleviate FT among patients with hematologic malignancies.

Characteristics of clinical trials for haematological malignancies from 2015 to 2020: A systematic review.

BACKGROUND: As the landscape of haematological malignancies dramatically changes due to diagnostic and therapeutic advances, it is important to evaluate trends in clinical trial designs. The objective of our study was to describe the design of clinical trials for five common haematological malignancies with respect to randomisation and end-points. We also aimed to assess trends over time and examine the relationships of funding source and country of origin to proportions of randomisation and utilisation of clinical end-points. METHODS: This systematic review identified haematological malignancy clinical trials starting in 2015-2020 registered at ClinicalTrials.gov as of 20th February 2021. Trial-related variables including randomisation status, type of primary end-point, and both projected and actual enrolment numbers were captured. Clinical end-points were defined as overall survival and quality of life, while surrogate end-points included all other end-points. RESULTS: Of 2609 relevant trials included in this analysis, only one-fifth were randomised (538, 21%), with a significant decrease in the proportion of randomised clinical trials from 26% of trials in 2015 to 19% in 2020 (p < 0.00001). Between the years 2015 and 2020, the proportion of randomised trials for all haematological malignancies using primary surrogate end-points remained relatively consistent, ranging from 84% in 2015 to 78% in 2020 (p = 0.352). Overall, only 15% of trials utilised primary end-points of overall survival or quality of life in a randomised design. CONCLUSIONS: This systematic review of haematological malignancy trials found that the majority of trials are non-randomised and that there has been an increase in the ratio of non-randomised to randomised studies over time. The vast majority of randomised haematological malignancy trials use surrogate primary end-points.

Age Adjusted Comorbidity Risk Index Does Not Predict Outcomes in an Autologous Hematopoietic Stem Cell Transplant Population.

The hematopoietic comorbidity risk index (HCT-CI) is a pre-transplant risk assessment tool used to prognosticate morbidity and mortality of patients undergoing allogeneic hematopoietic stem cell transplantation. Recently, the HCT-CI was updated to include an age component (HCT-CI-age). Although other studies have validated this tool in allogeneic stem cell transplant recipients, it has never been studied in an autologous transplant patient population. We retrospectively reviewed 181 patients who underwent their first autologous hematopoietic stem cell transplant. We aimed (1) to assess whether an HCT-CI score of 3 or greater is associated with greater mean transplant hospital days, greater total hospital days, or greater risk of intensive care unit (ICU) utilization and (2) whether age influences any of these responses independent of HCT-CI. There were 136 patients with an HCT-CI score of 3 or higher and 45 with a score less than 3. The length of initial transplant hospitalization in days was not statistically significant (15.6 v 16.4 days, P = 0.38). Utilizing spline modeling prediction curves, transplant hospital days were estimated to increase from a mean of 15.5 days for a patient with 4 comorbidities to a mean of 22.7 days for a patient with 8 comorbidities. Age made no significant impact on any of the outcomes. The HCT-CI, with or without age, in an autologous stem cell transplantation did not predict length of hospitalization or utilization of the ICU. Patients with higher-HCT-CI scores at baseline may incrementally utilize more resources, and this should be explored in a larger cohort population.

Intention to treat versus modified intention-to-treat analysis in B-cell maturation antigen and CD19 chimeric antigen receptor trials: A systematic review and meta-analysis.

INTRODUCTION: Chimeric antigen receptor T-cell therapy (CART) has revolutionised treatment of haematological malignancies; however, current reporting uses a modified intention-to-treat analysis (mITT) which over-estimates efficacy. We assessed what proportion of CD19 and B-cell maturation antigen (BCMA) CART trials report the number of patients not receiving CART after being enrolled by performing meta-analysis of the mITT and intention-to-treat (iTT) overall response rate (ORR). METHODS: PubMed/MEDLINE, EMBASE and Cochrane databases were searched. All prospective clinical trials of CD19 and BCMA-targeting CART enrolling two or greater patients from 1st January 2013 to 1st November 2020 were included. RESULTS: A total of 28 BCMA CART and 74 CD19 CART trials were identified. These included 10 BCMA CART (35.7%) and 52 (70.2%) CD19 CART trials reporting total number of patients enrolled and number of patients treated with CART. For this cohort of trials, the mITT ORR for BCMA CART was 78.0% (95% confidence interval (CI) = 67.0-89.0%), and the iTT ORR was 70.0% (95% CI = 59.0-80.0%). For CD19 leukaemia CART, the mITT ORR was 87.2% (95% CI = 83.1-91.2), and the iTT ORR was 74.9 (95% CI = 64.8-85.0). For CD19 lymphoma CART, the mITT ORR was 70.7% (95% CI = 63.9-77.5), and the iTT ORR was 58.7% (95% CI = 49.7-67.7). CONCLUSION: Across BCMA and CD19 CART trials, there is a difference of up to 8-12% in the ORR between modified and iTT analyses and a paucity of information regarding reasons why patients did not receive the intended study treatment.

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.

A Systematic Review and Network Meta-analysis of Randomized Data on Efficacy of Novel Therapy Combinations in Patients with Lenalidomide-refractory Multiple Myeloma.

INTRODUCTION: Lenalidomide use in nearly all induction regimens for multiple myeloma (MM) has led to the treatment of lenalidomide-refractory disease becoming one of the most important clinical questions in its treatment. Given the lack of direct comparisons of treatment regimens for lenalidomide-refractory MM, we used a systematic review to identify randomized controlled trials (RCTs) that included lenalidomide-refractory subgroup analysis. METHODS: We performed a systematic review to identify RCTs for MM that enrolled patients with lenalidomide-refractory disease, then performed a network meta-analysis (NMA) using random effects model to compare regimens. RESULTS: We identified 123 discrete RCTs, of which 7 reported primary outcomes for lenalidomide-refractory MM. These were linked in 2 discrete networks totaling 1698 lenalidomide-refractory patients. Network 1 compared bortezomib (bort)/dexamethasone (dex) versus other treatments, and analysis showed triplet therapy with pomalidomide (pom)/bort/dex (hazard ratios [HR] 0.65, 95% confidence interval [CI], 0.50-0.84), daratumumab (dara)/bort/dex (HR 0.36, 95% CI, 0.21-0.63), and dara/carfilzomib (carf)/dex (HR 0.38, 95% CI, 0.21-0.69) as more effective than bort/dex. Network 2 compared dex versus other treatments, and analysis showed pom/dex (HR 0.50, 95% CI, 0.40-0.62), isatuximab (isa)/pom/dex (HR 0.30, 95% CI, 0.20-0.44), and elotuzumab (elo)/pom/dex (HR 0.27, 95% CI, 0.16-0.45) as more effective than dex. Within each network, monoclonal antibody (mAb)-containing regimens had lower HRs and higher P-scores than non-mAb regimens, indicating higher likelihood of these regimens being most efficacious. CONCLUSION: The results of our NMA demonstrated that for lenalidomide-refractory MM, triplet therapy containing mAbs are superior. There is need for further RCTs to better ascertain the best standard of care for these patients.

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.

Quality of control groups in randomised trials of multiple myeloma enrolling in the USA: a systematic review.

To our knowledge, no study has evaluated the quality of control groups in randomised controlled trials of multiple myeloma. We aimed to do a systematic review of randomised controlled trials of multiple myeloma to ascertain the quality of the control groups used. PubMed (MEDLINE), Embase, Cochrane Controlled Register of Trials, and CinicalTrials.gov were searched for articles of randomised controlled trials of multiple myeloma based in the USA that initiated participant enrolment between Jan 1, 2010, and June 30, 2020. A control group regimen was considered to be inferior if a previous randomised controlled trial had shown an improved progression-free survival versus the control group before enrolment. Of 49 identified randomised controlled trials, seven (14%) began enrolling patients into inferior control groups after an existing superior regimen to the control had already been published. Nine (18%) of the 49 trials continued enrolment on substandard control groups after data emerged during the study enrolment period. The median time that newer data emerged regarding inferiority of the control group from the time a trial first enrolled a patient was 13 months (IQR 8-29 months). 12 (75%) of these 16 randomised controlled trials are published, and nine (75%) of the 12 published trials had overlapping investigators with trials that had previously shown the inferiority of the control group being used. Greater scrutiny on the quality of control groups in randomised controlled trials of multiple myeloma is needed.

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.