This article explores the circumstances under which providers and patients should be able to attempt drugs or combinations for indications for which we still lack formal clinical trials.

The authors pay tribute to Dr. Susan Bates's and Dr. Antonio “Tito” Fojo's careers of more than 30 years with the National Cancer Institute.

BACKGROUND:In a 2003 paper in BMJ, the authors made the tongue-in-cheek observation that there are no randomized controlled trials (RCTs) of parachutes. This paper has been widely read, cited and used to argue that RCTs are impractical or unnecessary for some medical practices. We performed a study to identify and evaluate claims that a medical practice is akin to a parachute. METHODS:Using Google Scholar, we identified all citations to the 2003 paper. We searched for claims that a specific practice was akin to a parachute. For each practice, we identified the desired outcome of the practice, and searched Google Scholar and ClinicalTrials.gov for RCTs that were conducted, ongoing, halted, planned or unpublished. RESULTS:Of 822 articles citing the original paper, 35 (4.1%) argued that a medical practice was akin to a parachute. Eighteen of the 35 (51%) concerned mortality or live birth, and 17 (49%) concerned a lesser outcome. For 22 practices (63%), we identified 1 or more RCTs: in 6 cases (27%), the trials showed a statistically significant benefit of the practice; in 5 (23%), the trials rejected the practice; in 5 (23%), the trials had mixed results; in 2 (9%), the trials were halted; and in 4 (18%), the trials were ongoing. Effect size was calculated for 5 of the 6 practices for which RCTs gave positive results, and the absolute risk reduction ranged from 11% to 30.8%, corresponding to a number needed to treat of 3-9. INTERPRETATION:Although there is widespread interest regarding the BMJ paper arguing that randomized trials are not necessary for practices of clear benefit, there are few analogies in medicine. Most parachute analogies in medicine are inappropriate, incorrect or misused.

Chimeric antigen receptor T cell (CAR-T) therapies are Food and Drug Administration (FDA)-approved for patients with triple refractory multiple myeloma (MM). Real-world access to CAR-T therapy remains challenging owing to supply chain limitations impacting manufacturing. The goal of this study was to evaluate the extent of this issue and how major centers are handling the challenges of CAR-T manufacturing slot allocation. MM CAR-T physician leaders at each CAR-T treatment center across the United States were surveyed. We received responses from 17 of 20 centers. A median of 1 slot is allocated per month per center, and the median number of patients per center on the waitlist since the FDAs approval of idecabtagene vicleucel is 20 (range, 5 to 100). As a result, patients remain on the waitlist for a median of 6 months (range, 2 to 8 months) prior to leukapheresis. For patient selection, all centers reported using a committee of experienced CAR-T physicians to ensure consistency. To ensure transparency, 15 centers make selection criteria, selection timelines, and priority scores readily available for CAR-T providers. Centers also reported using ethical values for selection: (1) equal treatment: time spent on waiting list (n = 12); (2) priority to the worst-off: limited therapeutic options (n = 14), MM burden (n = 11), high Hematopoietic Cell Transplantation Comorbidity Index (n = 5); (3) maximize benefit: most likely to complete apheresis (n = 13) or infusion (n = 13) or to achieve response (n = 8); and (4) social value: younger patients (n = 3). Maximizing benefit was considered the most important criterion by 10 centers. This study is the first attempt to evaluate existing issues with CAR-T access for patients with MM and the variability and challenges in patient selection. Integrating ethical resource allocation strategies, similar to those described here, into formal institutional policies would help streamline access to CAR-T therapy and protect the needs of both current and future patients and physicians.

The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement. To date, we have found no evidence of RCR in 338 pre-treatment and 1,595 post-treatment blood samples from 737 patients associated with 60 clinical trials. Most samples (75%) were obtained within 1 year of treatment, and samples as far out as 9 years after treatment were analyzed. The majority of trials (93%) were cancer immunotherapy, and 90% of the trials used vector products produced with the PG13 packaging cell line. The data presented here provide further evidence that current manufacturing methods generate RCR-free products and support the overall safety profile of retroviral gene therapy.

Multiple myeloma (MM) is twice as common in Black individuals compared with in White individuals, and diabetes mellitus (DM) disproportionately affects Black patients. Although numerous studies have shown a correlation between DM and MM, this has not been studied in the context of race and in vivo mechanisms. We conducted a retrospective clinical study of 5383 patients with MM of which 15% had DM (White, 12% and Black, 25%). Multivariable Cox models showed reduced overall survival (OS) for patients with DM (hazard ratio, 1.27; 95% confidence interval, 1.11-1.47; P < .001). This appeared to be driven by a marked difference in OS between White patients with and without DM but not in Black patients. In contrast, obesity was associated with better OS in Black patients but not in White patients. To complement this analysis, we assessed MM growth in a genetically engineered immunocompromised nonobese diabetic (Rag1-/-/muscle creatinine kinase promoter expression of a human IGF1R [M] with a lysine [K] to arginine [R] point mutation) mouse model to evaluate the mechanisms linking DM and MM. MM.1S xenografts grew in more Rag1-/-/MKR mice and grew more rapidly in the Rag1-/-/MKR mice compared with in controls. Western blot analysis found that MM1.S xenografts from Rag1-/-/MKR mice had higher phosphorylated S6 ribosomal protein (Ser235/236) levels, indicating greater activation of the mammalian target of rapamycin pathway. Our study is, to our knowledge, the first to evaluate racial differences in DM prevalence and survival in MM, as well as the effect of DM on tumor growth in mouse models. Our results suggest that DM may contribute to the higher incidence of MM in Black patients; and to improve survival in MM, DM management cannot be ignored.

UNLABELLED: Patients with multiple myeloma have a compromised immune system, due to both the disease and antimyeloma therapies, and may therefore be particularly susceptible to COVID-19. Here, we report outcomes and risk factors for serious disease in patients with multiple myeloma treated at five large academic centers in New York City in the spring of 2020, during which it was a global epicenter of the SARS-CoV-2 pandemic. Of 100 patients with multiple myeloma (male 58%; median age 68) diagnosed with COVID-19, 75 were admitted; of these, 13 patients (17%) were placed on invasive mechanical ventilation, and 22 patients (29%) expired. Of the 25 nonadmitted patients, 4 were asymptomatic. There was a higher risk of adverse outcome (intensive care unit admission, mechanical ventilation, or death) in Hispanics/Latinos (n = 21), OR = 4.7 (95% confidence interval, 1.3-16.7), and African American Blacks (n = 33), OR = 3.5 (1.1-11.5), as compared with White patients (n = 36). Patients who met the adverse combined endpoint had overall higher levels of inflammatory markers and cytokine activation. None of the other studied risk factors were significantly associated (P > 0.05) with adverse outcome: hypertension (n = 56), OR = 2.2 (0.9-5.4); diabetes (n = 18), OR = 0.9 (0.3-2.9); age >65 years (n = 63), OR = 1.8 (0.7-4.6); high-dose melphalan with autologous stem cell transplant <12 months (n = 7), OR = 0.9 (0.2-5.4); and immunoglobulin G <650 mg/dL (n = 42), OR = 0.9 (0.3-2.2). In this largest cohort to date of patients with multiple myeloma and COVID-19, we found the case fatality rate to be 29% among hospitalized patients and that race/ethnicity was the most significant risk factor for adverse outcome. SIGNIFICANCE: Patients with multiple myeloma are immunocompromised, raising the question whether they are at higher risk of severe COVID-19 disease. In this large case series on COVID-19 in patients with multiple myeloma, we report 29% mortality rates among hospitalized patients and identify race/ethnicity as the most significant risk factor for severe outcome.See related commentary by Munshi and Anderson, p. 218. This article is highlighted in the In This Issue feature, p. 215.

[This corrects the article DOI: 10.1158/2643-3230.BCD-20-0102.].