Jared Kaltwasser

First-line bortezomib (Velcade) appears to be linked with a heightened risk of falls in elderly patients with 

, also suggested that patients who experience a fall within the first year on bortezomib face a higher risk of mortality. The investigators cautioned that further research is needed to confirm the findings.

Corresponding author Kelly L. Schoenbeck, MD, of the University of California San Francisco, and colleagues, explained that older patients have a higher risk of falls in general, and older adults with cancer have been shown to have a higher risk of falling than matched controls without cancer. The reasons for that risk include functional and cognitive impairment, depression, high-risk medications, frailty, and other factors. 

MM primarily impacts older adults, with a median age of 70 at diagnosis. It is often treated with the proteasome inhibitor bortezomib, a drug that has been linked with peripheral neuropathy. Schoenbeck and colleagues therefore hypothesized that patients taking the drug might face a higher risk of falls; however, that premise had not yet been tested in a scientific analysis.

Schoenbeck and colleagues decided to consult the Surveillance, Epidemiology, and End Results (SEER) Program-Medicare database to identify patients 65 years old and older who were diagnosed with MM between 2007 and 2013 and were enrolled in Medicare parts A, B, or D. All patients who met inclusion criteria and began therapy for MM within 6 months of diagnosis were included, and their records were analyzed through 2014 to find claims related to cancer treatment, falls, and certain covariates.

The investigators identified 4084 older adults who were diagnosed with MM and met inclusion criteria. Of those, 271 (6%) had fall-related claims in the year prior to initiation of treatment, and a similar number, 259 (6%), had falls in the first 12 months after treatment (the median time to fall was 129 days). Only a small minority of patients with a fall (8%) had falls in both the pre- and post-treatment-initiation periods.

Of the more than 4000 patients included in the study, half (2052 patients) received bortezomib as first-line therapy. Of those, 157 (8%) experienced a fall within 12 months of treatment, compared to just 192 (5%) patients who did not receive bortezomib. 

The investigators also found that diagnostic codes for peripheral neuropathy were more common in the bortezomib group (27.7% versus 14.8%), and those with peripheral neuropathy were more likely to experience falls, the data showed.

A multivariate analysis translated the findings into a 36% increased risk for falls among the patients receiving bortezomib. Further analysis revealed that, among patients who survived at least 12 months after initiation of treatment, the median overall survival of patients who experienced a fall was 35.7 months, compared to 49.1% for those patients who did not experience a fall. Thus, a first-year fall was associated with a 26% increased risk of death.

“We hypothesize the mechanism between bortezomib and falls among patients with multiple myeloma is treatment-related neuropathy,” Schoenbeck and colleagues wrote. “In support of this, we found that bortezomib, peripheral neuropathy, and falls are all associated.”

However, the authors also cautioned that it was not possible to conclusively draw a causal connection, in part because codes for symptoms like peripheral neuropathy may present themselves considerably earlier than they appear in Medicare claims, making it difficult to know the actual temporal relationship between the symptoms and the fall.

The investigators said further study is important, in part because if bortezomib increases the risk of falls, those falls appear to increase the risk of death.

“Given the preventable nature of falls, it will be imperative that future research focus on prospective fall-risk assessments and interventions that can mitigate fall risks in this patient population,” they concluded.

Schoenbeck KL, Fiala MA, Wildes TM. Bortezomib in first-line therapy is associated with falls in older adults with multiple myeloma [published online ahead of print, 2021 Mar 6]. 

. 2021;S1879-4068(21)00018-7. doi:10.1016/j.jgo.2021.02.009

Articles

Patients who experienced a fall within 12 months of multiple myeloma (MM) treatment initiation had a shorter median survival compared to those without falls.

Bortezomib Appears to Increase Fall Risk in Elderly Patients With MM, Study Suggests

 (MM) remains an incurable disease, but advances in our understanding of natural killer (NK) cells may provide new avenues by which to combat it.

The latest findings in NK cell research and their potential to be used in MM therapy were discussed in 

Corresponding author Tony Reiman, MD, of the University of New Brunswick, and colleagues, explained that a wide array of emerging therapies, such as proteasome inhibitors, immunomodulatory drugs, and novel combination therapies, have significantly improved outcomes in patients with MM, but that the high rate of eventual relapse and the heterogeneity of the disease among patients have made it a particularly difficult cancer to fight.

“Additionally, MM is considered a disease of the immune system,” the investigators wrote. “Gradual immune dysregulation and impairment of NK cells, T cells, B cells, and dendritic cells allow malignant plasma cells to escape immunosurveillance.”

Reiman and colleagues proposed that a better understanding of the immune environment of MM could lead to strategies to reengage the immune system to inhibit MM growth. This is where NK cells potentially come into play.

These cells are considered the most active subset of innate lymphoid cells. Their name comes from their ability to target infected and malignant cells without prior sensitization. They cells have both activating and inhibitory receptors (IRs), and their activity is controlled by signals between the receptors.

One strategy for leveraging NKs is to use monoclonal antibodies to target IRs. This approach has shown benefits in other types of cancers, the authors wrote, and there is emerging evidence suggesting it is a viable option in MM as well.

They advocated paying particular attention “to understanding the heterogeneity of ligand expression both within and across patients with MM, the interplay between NK and T cells in response to IR blockade therapy, and how NK-targeted therapy can be combined with existing therapeutic options in MM patients.”

The authors said notable research has been published suggesting a role for several other IRs in MM biology: KIRs, NKG2A, TIGIT, TIM-3, PD-1, and LAG-3.

Of those, Reiman and colleagues singled out KIRs as the “most promising” target.“Not only were anti-KIR antibodies shown to be well tolerated, but they were also shown to enhance NK cell function,” they wrote.

Some of those IRs are also expressed on T cells, meaning therapies that target those receptors might boost the anticancer effects of both types of cells; however, the authors said most studies into the IRs have focused almost exclusively on T cells while ignoring NK cells.

Early failure of some clinical trials of IR blockades is likely due to intra- and interpatient heterogeneity, the authors noted. Any kind of IR-blockade therapy would likely need to be tailored to each particular patient’s expression of receptors, the investigators said, similar to what is done in solid tumors.

The investigators closed with a list of key steps they believe will need to be undertaken to bring NK-based therapy for MM close to fruition. Among those steps:

Profile NK cell receptors, subpopulations, cell activity, and cell function in MM

Profile the expression of NK cell receptor cognate ligands

Explore the integration of NK cell–based therapies and traditional therapies preclinically in order to optimize clinical trial design.

Alfarra H, Weir J, Grieve S, Reiman T. Targeting NK cell inhibitory receptors for precision multiple myeloma immunotherapy. 

. Published online November 12, 2020. doi:10.3389/fimmu.2020.575609

Emerging research into natural killer cells has shown promise, but the findings are complicated by the heterogeneity of multiple myeloma (MM).

Natural Killer Cells Could Play Key Role in Fight Against MM

Patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA) experience equivalent declines in hand function, according to a new study, but investigators also found that psoriasis itself causes similar impairment of the hands.

, raises new questions about links between psoriasis and arthritis.

Both PsA and RA have well-documented impacts on patients’ physical functioning, but less has been published related to how the loss of hand function experienced by patients with RA compares with that of other diseases, according to corresponding Anna-Maria Liphardt, PhD, of the Friedrich-Alexander University Erlangen Nürnberg and University Clinic Erlangen, in Germany, and colleagues.

“The impact of inflammatory arthritis on hand function has mainly been studied in RA,” they said, “and studies comparing hand function in these diseases are sparse.”

Liphardt and colleagues therefore decided to comprehensively evaluate hand function in PsA and RA side by side, by looking at objective strength measures and also patient perceptions of hand function. In addition to comparing these measures in the 2 disease categories, the authors also compared them with healthy controls.

In the study, 299 subjects were enrolled, split nearly evenly between patients with RA (101 patients), patients with PsA (92 patients), and nonarthritic controls (106 patients). The nonarthritic patient arm was made up of 51 patients with psoriasis and 55 healthy controls.

The patients were assessed using a number of measures. A hand dynamometer was used to measure isometric grip strength. The Moberg-Picking-Up Test (MPUT) was used to assess fine-motor skills, and patients were also timed to see how long it took them to move 12 small items from a table into a box with their eyes opened. Lastly, patients were asked to rate their own hand function using the Michigan Hand Questionnaire (MHQ). Data were taken for both hands, but the investigators noted which hand was a patient’s dominant hand.

The investigators found that sex, age, disease group, and hand dominance all affected hand function. However, PsA and RA appeared to have similar influences on hand function, and in both cases the impact was greater for women than men. 

“We found that the impact of disease on hand function is particularly pronounced in older subjects, suggesting that younger individuals are better in functionally compensating their diseases,” they said. “This may be caused by generally better muscular performance and neuromuscular interaction in younger individuals, but also by disease management of RA and PsA in the last two decades.”

However, the authors also reported something they did not expect: Patients with psoriasis were experiencing significantly altered hand function.

“Although these patients did not show any clinical signs of PsA, hand function was clearly impaired and mirrored that in patients with RA and PsA but not in healthy controls,” they said.

Liphardt and colleagues said the finding suggests psoriasis patients “exhibit a functional arthritis-like phenotype.”

“Such observations back concepts that patients with psoriasis show an altered stress response not only in the skin but also in the musculoskeletal structures,” they said.

The investigators added that it is possible that functional changes in patients with psoriasis might be indicative of a more pronounced progression to PsA, but they said the question would need to be investigated with further studies.

Liphardt AM, Manger E, Liehr S, et al. Similar impact of psoriatic arthritis and rheumatoid arthritis on objective and subjective parameters of hand function. 

. 2020;2(12):734-740. doi:10.1002/acr2.11196

In an unexpected finding, patients with psoriasis showed similar hand impairment to patients with psoriatic arthritis and rheumatoid arthritis.

Psoriatic Arthritis, Rheumatoid Arthritis Cause Similar Hand Impairment, but So Does Psoriasis 

A new study suggests that ruxolitinib (Jakafi) may help mitigate steroid-refractory cytokine release syndrome (CRS) in children who receive chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphoblastic leukemia (B-ALL).

Journal of Cellular and Molecular Medicine

CAR T-cell therapy has been a promising advancement in a number of malignancies, including B-ALL, the most common type of cancer in children. However, the therapy has been associated with significant adverse effects, including CRS and immune effector cell–associated neurotoxicity syndrome (ICANS).

Investigators including corresponding author Xiaoming Feng, PhD, of the Chinese Academy of Medical Sciences and Peking Union Medical College, noted that the typical treatment for patients who suffer CRS or ICANS involves drugs like tocilizumab (Actemra) along with steroids. In cases of CRS grade 3 or higher, high-dose steroids are recommended, and high-dose methylprednisolone is recommended for refractory CRS. Unfortunately, those therapies do not always work, and their failure can pose a major barrier to patient survival.

“[L]ife-threatening consequences may occur if severe CRS cannot be controlled by current regimens,” the investigators said.

In hopes of providing another therapeutic avenue, Feng and colleagues turned to ruxolitinib, which is a Janus kinase 1 and 2 inhibitor. These kinases play a role in transmitting cytokine-induced signals and thus have become a target for a number of inflammatory diseases. The drug has already been approved for the treatment of steroid-refractory graft-vs-host disease, prompting hopes that it might be a meaningful intervention in other conditions, such as severe CRS.

The new study was a pilot study that involved just 14 patients, but the results were uniform.

Each patient in the study had received CD19 or CD22 CAR T-cell therapies, and 4 of those patients went on to develop grade 3 or higher CRS that could not be alleviated with high-dose steroids.

Each of those 4 patients was then administered oral ruxolitinib (5 mg twice daily). The results were rapid and convincing.

“CRS-related cytokines including IL-6, IL-10, sCD25, TNF‐γ, and SF quickly decreased in these four patients after ruxolitinib intervention, which implicates that ruxolitinib successfully stops these cytokines’ release,” the authors said.

In addition to the decrease in CRS symptoms, serum cytokines also decreased significantly.

At 30 days post CAR T-cell infusion, each patient had achieved complete remission, and the investigators were still able to detect CAR T expansion in vivo. No obvious adverse events were reported related to ruxolitinib.

There was, however, a caveat to the findings. Despite the positive in vivo results, in vitro assays suggested that ruxolitinib could dampen CAR T expansion and cytotoxicity.

“This discrepancy may be due to the presence of excretive systems or an intermediate cellular part in humans which await future clarification,” the authors said.

They added that their data also showed that ruxolitinib has a stronger impact on CAR T effector function than dexamethasone.

“Ruxolitinib mainly inhibits CAR T cell expansion and releasing of T cell cytotoxicity related cytokine (INF‐γ and Granzyme B) in vitro,” they said. “It would be interesting to measure INF‐γ and Granzyme B in patients with CAR T cell therapy in future study.”

In the meantime, the authors said physicians should carefully consider the timing and dosage of ruxolitinib in patients with steroid-refractory CRS in order to avoid dampening the anti-leukemia response.

Pan J, Deng B, Ling Z, et al. Ruxolitinib mitigates steroid-refractory CRS during CAR T therapy. 

. Published online December 12, 2020. doi:10.1111/jcmm.16176

A small pilot study could point the way to a new option for patients with B-cell acute lymphoblastic leukemia (B-ALL) who experience cytokine release syndrome (CRS) that cannot be cured with the standard therapy. 

Jared Kaltwasser

Articles

Bortezomib Appears to Increase Fall Risk in Elderly Patients With MM, Study Suggests

Natural Killer Cells Could Play Key Role in Fight Against MM

Psoriatic Arthritis, Rheumatoid Arthritis Cause Similar Hand Impairment, but So Does Psoriasis

Small Study Shows Ruxolitinib Helps Severe Steroid-Refractory CRS in Patients With B-ALL