Medical World News: Clinical Updates

Study Identifies High Rates of Adherence to IMiDs Among Patients With Multiple Myeloma

A new study has found that adherence to immunomodulatory drugs (IMiDs) is high among patients with multiple myeloma. Even more encouraging is the finding that this high adherence was observed regardless of the drug.

IMiDs represent a significant proportion of treatment regimens for patients with multiple myeloma. In addition to being used as monotherapy in the frontline setting, the most widely used IMiD, lenalidomide (Revlimid), is being assessed as up-front therapy in combination with the proteasome inhibitor carfilzomib (Kyprolis) and dexamethasone. The class of drugs has demonstrated high efficacy, but it also comes with a high cost: Poor adherence not only affects patients’ health but also puts a financial strain on the healthcare system.

“To date, very few data are available about IMID adherence in multiple myeloma patients,” wrote the researchers. “For different reasons such as cost, adverse events, long-term intake, or health status improvement, adherence to IMIDs may not be optimal.”

Based on these factors, the findings of the study were a welcome surprise and represent the first prospective study to evaluate adherence to these drugs among patients with the disease in a real-world setting.

The study followed 63 patients who had at least 2 consecutive prescriptions of lenalidomide, thalidomide, or pomalidomide between March 1, 2016, and May 15, 2016. Using 2 methods, the researchers disseminated cancer-specific questionnaires to the participants, which included 10 questions and had a 10-point scale. A score lower than 8 was considered nonadherence. The mean score of the questionnaire was 8.2, with the highest score shown for lenalidomide (8.3), followed by thalidomide (Thalomid; 8.2) and pomalidomide (Pomalyst; 7.9).

The researchers also utilized the medication possession ratio (MPR) reports from hospital dispensing data. This measure is calculated as the total days’ supply of IMiDs dispensed divided by days between the first dispensation and the end of the last. With an MPR cut-off point of 90%, nonadherence was considered under 90%. Data from these reports found that the mean MPR was 0.97, with the highest levels seen among thalidomide (1.01), followed by lenalidomide (0.97) and pomalidomide (0.96).

Although 76% of patients were considered adherent according to the questionnaire, 94% were considered adherent according to the MPR. Using the questionnaire and hospital data together, there was an adherence rate of 70%.

“The high adherence in our study may be explained by intensive medical follow-up with scheduled visits every 4 weeks,” explained the researchers. “Furthermore, the daily presence of a clinical pharmacist in the ward may contribute to this elevated adherence.”

REFERENCE:

Dim Light at Night May Help Spread Breast Cancer to Bones

Cransac A, Aho S, Chretien ML, Giroud M, Caillot D, Boulin M. Adherence to immunomodulatory drugs in patients with multiple myeloma. PLoS one. 2019;27(14):e0214446. doi: 10.1371/journal.pone.0214446. When breast cancer spreads, it often goes to the bones, and new research¹ has found that exposure to dim light at night may contribute to this spread by disrupting the melatonin circadian signal. Results from an animal study were presented at ENDO 2019, the annual meeting of the Endocrine Society.

Breast cancer that has spread to the bones is a major source of morbidity and mortality. Cancer that spreads to the bones can cause severe pain and fragile bones, and it cannot be surgically removed—it can only be treated with chemotherapy and/or radiation.

The investigators injected estrogen receptor—positive human breast cancer cells into the shinbone of female mice who had a strong nighttime circadian melatonin signal. The mice were divided into 2 groups and examined over a 24-hour period. First, both groups were kept in the light for 12 hours. Then, 1 group was in the dark for the remaining 12 hours, while the second group spent the remaining 12 hours in dim light. The study found the group kept in the dim light had suppressed nocturnal melatonin production. This group developed breast cancer tumors in their bones (P <.05) that were highly osteolytic (P <.05).

“To date, no one has reported that exposure to dim light at night induces circadian disruption, which then increases the formation of bone metastatic breast cancer,” Muralidharan Anbalagan, PhD, assistant professor, Tulane University School of Medicine, said in a statement.² “This is important, as many patients with breast cancer are likely exposed to light at night as a result of lack of sleep, stress, excess light in the bedroom from mobile devices and other sources, or night shift work.”

The researchers showed that chronotherapeutic use of doxorubicin (Dox) in circadian alignment with melatonin reduced tumor growth and bone erosion.

“Successful chronotherapeutic use of Dox and [melatonin] in clinical trials, increasing efficacy in preventing or suppressing breast cancer metastasis to bone while decreasing toxic side effects of doxorubicin, would provide a revolutionary advancement in the treatment of bone metastatic breast cancer and decrease the morbidity and mortality associated with breast cancer metastasis to bone,” the authors concluded.

REFERENCES:

1. Anbalagan M, Dauchy RT, Xiang S, et al. Disruption of the circadian melatonin signal by dim light at night promotes bone-lytic breast cancer metastases. Presented at: ENDO 2019; March 23-26, 2019; New Orleans, LA. Abstract SAT-337. academic.oup.com/jes/article/3/Supplement_1/SAT-337/5482922.
2. Breast cancer may be likelier to spread to bone with nighttime dim-light exposure [press release]. Washington, DC: Endocrine Society; March 23, 2019. endocrine.org/news-room/2019/endo-2019---breast-cancer-may-be-likelier-to-spread-to-bone-with-nighttime-dim-light-exposure. Accessed April 18, 2019.

A Slower, Gentler CAR T-Cell Therapy? USC Says Results From Small Study Show It Could Work

For patients with certain forms of lymphoma and leukemia who have run out of treatment options, chimeric antigen receptor (CAR) T-cell therapy has been described as a miracle. Emily Dumler who was treated at The University of Texas MD Anderson Cancer Center1 says CAR T-cell therapy “gave me my life back” after 6 rounds of chemotherapy failed.

But even when it works, the treatment that harvests a patient’s T cells and engineers them to attack cancer is far from benign. It’s been described as a bomb going off in the body, or “the worst flu you could get.”¹ The cognitive effects² and the symptoms of cytokine release syndrome (CRS) can be severe and life-threatening. Adverse events are one reason that the treatment cost, either $373,000 or $495,000, depending on the indication, can jump to $800,000 to $1.5 million once all the administrative costs are added.

However, researchers at the University of Southern California (USC) say they’ve come up with a slower-moving and significantly less toxic version of an anti-CD19 CAR T-cell treatment that brought complete remission in 6 of 11 patients with lymphoma who received the same dose in the phase 1 trial, which tested several different doses in 25 patients. According to the report³ in the journal Nature Medicine, there was no neurological toxicity or CRS greater than grade 1 in 25 patients who received the new version of the anti-CD19 therapy, known as CD19-BBz(86).

“This is a major improvement,” senior author Siyi Chen, MD, PhD, of the USC Norris Comprehensive Cancer Center and a professor in the Keck School of Medicine, said in a statement.⁴ “We’ve made a new CAR molecule that’s just as efficient at killing cancer cells, but it works more slowly and with less toxicity.”

CRS occurs when the CAR T cells rapidly proliferate and release a flood of cytokines into a patient’s bloodstream, causing a host of reactions from nausea to fever to rash. The USC team adjusted the sequence and shape of the CAR molecules. These modified T cells can still hunt down and kill cancer cells, but with fewer cytokines that are produced more slowly so the patient’s body can clear them before they build up in the bloodstream. Thus, the treatment produces long-lasting benefits without the toxic effects.

“Toxicities are currently the biggest barrier to the use of CAR T-cell therapy,” Chen said. “My hope is that this safer version of CAR T-cell therapy could someday be administered in outpatient settings.”

The adverse events associated with CAR T-cell therapy have been of great concern to CMS, which just finished taking public comments5 on a proposal that would require Medicare patients receiving the treatment to be enrolled in clinical studies or registries before cancer centers could get reimbursement. Payment would come with strings attached: extensive data-reporting duties that would include collection of patient-reported outcomes for up to 2 years.

Major cancer centers have said that this requirement could prove untenable; some will not administer the treatment to Medicare patients. Meanwhile, community oncology clinics have asked if the proposal is worded in a way that excludes them. But a less toxic version of CAR T-cell therapy suitable for outpatient administration could make the life-saving treatment accessible to a wider range of patients; advocacy groups have cited the need for travel as a barrier to treatment.

The next step for the USC team is to perform a multicenter phase 2 study to test safety and efficacy in a larger group of patients, according to Chen.

REFERENCES:

1. Dumler E. Non-Hodgkin’s lymphoma survivor: a CAR T-cell therapy clinical trial gave me my life back. The University of Texas MD Anderson Cancer Center website. mdanderson.org/publications/cancerwise/non-hodgkins-lymphoma-survivor--car-t-cell--therapy-immunotherapy-clinical-trial-put-me-in-remission.h00-159220989. html. Published January 10, 2018. Accessed April 24, 2019.
2. Mattina C, Caffrey M. Therapeutics. The American Journal of Managed Care website. ajmc.com/journals/evidencebased-oncology/2019/pcoc-2018/therapeutics. Published February 26, 2019. Accessed April 24, 2019.
3. Ying Z, Huang XF, Xiang X, et al. A safe and potent anti-CD19 CAR T cell therapy [published online April 22, 2019]. Nature Med. doi: 10.1038/s41591-019-0421-7.
4. Hopper L. USC-led advance in groundbreaking cancer treatment eliminates severe side effects. USC News website. news.usc.edu/156066/car-t-cell-therapy-side-effects/. Published April 22, 2019. Accessed April 24, 2019.
5. Caffrey M. Providers, industry raise concerns about CMS plan for CAR T-cell reimbursement, reporting on PROs. The American Journal of Managed Care website. ajmc.com/journals/evidence-based-oncology/2019/ april-2019/providers-industry-raise-concerns-about-cms-plan-for-car-tcell-reimbursement-reporting-on-pros. Published April 15, 2019. Accessed April 24, 2019.