Music-listening interventions (MLIs) are a form of complementary and integrative treatment that medical professionals may be unaware of. However, my colleagues at the Michigan State University College of Nursing and I are tackling research that suggests music—a fixture in many people’s daily lives—may possess a nausea-reducing capability.

MLIs have already shown considerable effectiveness in managing other symptoms. For example, the National Comprehensive Cancer Network has labeled music as an acceptable treatment modality to treat anticipatory nausea and vomiting related to chemotherapy, so long as the music is prescribed in conjunction with typical pharmaceuticals.

Furthermore, the American Pain Society and the American Society of Regional Anesthesia and Pain Medicine have both endorsed music for its mitigating effects in the setting of postoperative pain.

 In addition, the c linical practice guidelines provided by the Society for Integrative Oncology also endorse music for patients with breast cancer in the setting of anxiety, mood disturbances, and pain.

In all cases, these endorsements came as a result of careful review of the evidence base for MLIs. If pain, anxiety, and mood all can be positively impacted through the incorporation of an MLI—why not chemotherapy-induced nausea?

This research began with a systematic review of the available literature, scouring databases for all prior studies that examined an MLI as treatment for chemotherapy-induced nausea.

This search identified 10 relevant studies across the past 30 years. However, they had a variety of designs, making comparisons between them difficult. Some studies paired music with other interventions, which made it difficult to discriminate what percentage each intervention was contributing to nausea reduction. Variations in timing (when the MLI was delivered and when the effect on nausea was measured) also raised questions.

Moreover, in the world of pharmaceuticals, a drug’s half-life determines how quickly its effects fade. However, variations in how MLIs were timed to intervene on nausea illuminated the fact that MLI’s half-lives are not well understood. It remains unclear whether half-lives even exist for MLIs. Overall, the overarching body of existing literature highlighted a need for more nuanced research.

The greatest uncertainty that remains with MLIs has to do with mechanism of action. Although MLIs have previously demonstrated the potential to relieve nausea, investigators do not yet understand how the brain physiology permits this.

One possible answer to this question comes from surprising research unrelated to chemotherapy-induced nausea. In 2000, Evers and Suhr

 published a study in which healthy participants listened to music that participants rated as “pleasant” and music that participants identified as “unpleasant.” In this study, the concentration of serotonin in blood platelets was measured at baseline (before any music), after the unpleasant music, then after the pleasant music. The release of serotonin from platelets was significantly less after the pleasant music intervention than what was measured after the unpleasant music. These findings connected to chemotherapy-induced nausea by way of its serotonin effects. After chemotherapy, this neurotransmitter becomes a major contributor to the sensation of nausea. This also explains the pharmacologic rationale for prescribing drugs that antagonize serotonin’s ability to bind to receptors at the postsynapse of neurons in the central nervous system.

This interesting physiologic possibility initiated a pilot study that yielded encouraging results. Twelve patients were asked to engage in a 30-minute MLI whenever they felt the need to take their antiemetic medication as needed, beginning on the day of chemotherapy administration and continuing through day 5. Participants used ordinal scales to rate their nausea severity and their distress level before the MLI and again immediately upon completion. Platelet serotonin levels were not drawn due to cost. In total, 66 MLIs were engaged at various points within the 5-day nausea window. The analysis showed a significant reduction in both nausea severity and patient distress, which is an encouraging finding in a pilot study and worth replicating in a larger randomized control trial.

This larger trial will have several refinements. First, a control group using a nonmusic intervention will reveal what percentage of the antinausea effect was attributable to the MLI and what percentage was attributable to medication alone. Creating study groups by time (5-minute MLI and 10-minute MLI) will allow subgroup analysis by dose, which is something not often done in MLI research. Finally, strict attention to competing auditory stimuli (other sounds in the room) through noise-cancelling headphones will help participants more fully engage with the MLI. 

Strategically using music listening to produce improved physiologic states is not new, but its scientific activity is gaining momentum. Work in chemotherapy-related nausea may inspire other investigators to think about MLIs in the setting of other nausea forms, such as pregnancy-induced nausea or postoperative/postanesthesia nausea. As the research builds, the day may come when the oncology nurse delivers acetaminophen alongside 20 mg of Mozart.

NCCN. Clinical Practice Guidelines in Oncology. Antiemesis, version 2.2022. Accessed April 23, 2022.

 https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf

Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. 

. 2016;17(2):131-157. Published correction appears in 

Lyman GH, Greenlee H, Bohlke K, et al. Integrative therapies during and after breast cancer treatment: ASCO endorsement of the SIO clinical practice guideline. 

. 2018;36(25):2647-2655. doi:10.1200/JCO.2018.79.2721

Evers S, Suhr B. Changes of the neurotransmitter serotonin but not of hormones during short time music perception. 

. 2000;250(3):144-147. doi:10.1007/s004060070031

Kottschade L, Novotny P, Lyss A, Mazurczak M, Loprinzi C, Barton D. Chemotherapy-induced nausea and vomiting: incidence and characteristics of persistent symptoms and future directions NCCTG N08C3 (Alliance). 

. 2016;24(6):2661-2667. doi:10.1007/s00520-016-3080-y

Articles

A Michigan State University investigator is preparing to expand on an encouraging pilot study that used a music-listening intervention to influence chemotherapy-induced nausea.

Prescribing 20 mg of Mozart for Chemotherapy-Induced Nausea

Findings from a subgroup analysis of the phase 2 MAIA trial (NCT02252172) demonstrated that daratumumab (Darzalex) plus lenalidomide (Revlimid) and dexamethasone (D-Rd) yielded superior responses over Rd alone in transplant-ineligible patients with newly diagnosed multiple myeloma–regardless of renal function or cytogenetic risk.

The findings, which were presented at the 

, found that, at the median fol­low-up of 56.2 months, the median time to a very good partial response (VGPR) or better in the intention-to-treat population was 3.8 months in the D-Rd group vs 9.4 months in the Rd group (HR, 2.08; 95% CI, 1.73-2.49; 

Stratifying outcomes by renal function, those with baseline creatine clearance (CrCl) at or below 60 mL/min had median time to VGPR of 3.8 months with D-Rd vs 12.5 months with Rd (HR, 2.26; 95% CI, 1.69-3.02; 

 < .0001). In those with CrCl 60 mL/min or more, median time to VGPR was 3.8 months with D-Rd vs 8.5 months with Rd (HR, 1.82; 95% CI, 1.45-2.28; 

Those with high cytogenic risk status with a VGPR or better had a median time to response of 4.7 months with D-Rd vs 14.1 months with Rd (HR, 2.50; 95% CI, 1.44-4.36; 

 = .0008). Those with standard-risk status had a median time to VGPR or better of 3.8 months in the D-Rd group vs 9.3 months in the Rd group (HR, 1.96; 95% CI, 1.59-2.40; 

The MAIA trial was designed to compare D-Rd vs Rd alone for patients with transplant-ineligible newly diagnosed multiple myeloma. Investigators found that the D-Rd regimen resulted in improved progression-free survival (PFS) as well as depth and duration of response. Patients were given 25 mg of oral lenalidomide on days 1 to 21; 40 mg or oral dexamethasone once a week; and 16 mg/kg of intravenous daratumumab once weekly for cycles 1 and 2, every 2 weeks for cycles 3 to 6, and every 4 weeks following.

For the current analysis, patients were divided into subgroups based on renal impairment, at CrCl 60 mL/min or less, and cytogenetic risk, with deletion 17p (del17[p]) or t(14;16) abnormality denoting high-risk status. The primary end point was PFS with secondary end points of time to response and duration of response. Investigators also measured patient-reported outcomes (PROs) using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item.

In the subgroup, a total of 368 patients were randomized to the D-Rd group and 369 in the Rd group. Baseline CrCl above 60 mL/min was reported for 56.0% and 61.5% of the D-Rd and Rd groups, respectively. Standard cytogenetic risk was noted for 85.0% of the D-Rd group and 86.4% of the Rd group.

Median time to complete response (CR) or better in the overall population was 20.8 months in the D-Rd group vs 47.9 months in the Rd group (HR, 1.72; 95% CI, 1.36-2.18; 

 < .0001). The median time to a CR or better for those with CrCl greater than 60 mL/min was 17.6 months for the D-Rd group vs 43.8 months for the Rd group (HR, 1.80; 95% CI, 1.34-2.41; 

 <.0001); corresponding medians for those with CrCl of 60 mL/min or less was 23.3 months vs 54.6 months (HR, 1.58; 95% CI, 1.07-2.23; 

 = .0197). Those with the standard cytogenetic risk status had a median time to CR of 20.8 months in the D-Rd group vs 42.6 months in the Rd group (HR, 1.69; 95% CI, 1.29-2.21; 

 <.0001). Those with high-risk disease had a median time to CR of 15.7 months vs 47.9 months with D-Rd and Rd, respectively (HR, 1.74; 95% CI, 0.83-3.63; 

At 48 months, the estimated event-free survival (EFS) rate for those with a complete response was 81.8% in the D-Rd group vs 57.8% in the Rd group (HR, 0.38; 95% CI, 0.23-0.65; 

Duration of CR or better was improved in the D-Rd group compared with the Rd group in patients with CrCl greater than 60 mL/min (HR, 0.41; 95% CI, 0.22-0.77; 

 = .0043), CrCl 60 mL/min or less (HR, 0.45; 95% CI, 0.20-1.04; 

 = .0551), standard cytogenic risk status (HR, 0.42; 95% CI, 0.24-0.73; 

 = .0015), and high-risk status (HR, 0.32; 95% CI, 0.09-1.16; 

 = .0694). The estimated 48-month EFS rates for D-Rd vs RD were 82.2% vs 55.3%, respectively, for those with CrCl greater than 60 mL/min; 81.0% vs 61.5% for CrCl 60 mL/min or less; 80.0% vs 55.1%, with standard-risk cytogenetics; and 74.7% vs not estimable for high-risk features.

In the overall study population, improvement in the duration of partial response or better was observed in the D-Rd group vs the Rd group (HR, 0.50; 95% CI, 0.39-0.64; P <.0001). By subgroups, the response was similar in those with renal function of CrCl greater than 60 mL/min (HR, 0.50; 95% CI, 0.36-0.70; 

 <.0001), CrCl 60 mL/min or less (HR, 0.50; 95% CI, 0.34-0.74; 

 = .0003), cytogenic standard risk status (HR, 0.43; 95% CI, 0.32-0.57; 

 < .0001), and high risk status (HR, 0.65; 95% CI, 0.35-1.19; 

 = .1560). Additionally, the 48-month EFS rates for each subgroup treated with D-Rd vs Rd was 69.8% vs 48.9%, respectively, for CrCl greater than 60 mL/min; 67.2% vs 44.4% for CrCl 60 mL/min or less; 72.3% vs 45.7% for standard cytogenic risk status; and 48.8% vs 29.9% for high-risk status.

PROs showed a reduction in patient symptom scores for the D-Rd group compared with the Rd group during cycle 6, day 1 for those with renal impairment (least squares [LS] mean change from baseline, –14.9 vs –7.0, respectively; 

 = .0241). Improvement in pain scores was also observed for patients treated in the D-Rd group across most time points, and this was consistent across cytogenetic risk group.

At cycle 24, day 1, patients in the D-Rd group had a reduction in fatigue symptom scores compared with the Rd group (LS mean change from baseline, –2.9 vs 8.1, respectively; 

 = .0018). Similar results were observed at cycle 30, day 1 of (–3.7 vs 4.4; 

 = .0258) and cycle 36, day 1 (–2.6 vs 6.5; 

 = .0183). Additionally, investigators noticed a reduction in nausea and vomiting scores with D-Rd vs RD at cycle 36, day 1 (LS mean change from baseline, –3.7 vs 3.3; 

Facon T, Kumar S, Plesner T, et al. Time to response, duration of response, and patient-reported outcomes (PROs) with daratumumab (DARA) plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): Subgroup analysis of the phase 3 MAIA study. 

. 2022;40(suppl 16):8044. doi:10.1200/JCO.2022.40.16_suppl.8044

Facon T, Kumar SK, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. 

. 2021;22(11):1582-1596. doi:10.1016/S1470-2045(21)00466-6

Daratumumab plus lenalidomide and dexamethasone bested standard therapy in producing rapid, deep, and durable responses across subgroups of patients with newly diagnosed multiple myeloma. 

DRd Outperforms Rd in Newly Diagnosed Multiple Myeloma 

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for patients with hematologic malignancies. Many researchers eagerly anticipate the advent of allogeneic CAR T cells, which would help alleviate the long engineering process associated with autologous therapy. 

Before CAR T-cell therapy entered the oncology treatment arena, there were patients with hematologic malignancies (ie, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, and mantle cell lymphomas) for whom traditional chemotherapy and immunotherapy were unsuccessful. These patients were often told not much more could be done. However, CAR T-cell therapy has dramatically shifted that narrative to one of possibility and promise.

Growth in CAR T-cell research is inspiring. In 2017, the FDA approved 2 autologous CAR T-cell therapies. Since then, 3 autologous therapies have been approved and clinical trials for allogeneic CAR T-cell therapies are back on track, offering more hope to patients. 

To learn more about these therapies and their impact on patient outcomes, Oncology Nursing News® interviewed Brittney Baer, BSN, RN, patient nurse care coordinator for patients undergoing immune effector cell therapies, at Vanderbilt University Medical Center in Nashville, Tennessee; and Kelly Garvin, BSN, RN, OCN, a lymphoma specialist and primary nurse for Bijal Shah, MD, in the Department of Malignant Hematology, Moffitt Cancer Center in Tampa, Florida. Baer and Garvin are enthusiastic about the trajectory of CAR T-cell therapy and excited about future possibilities. “CAR T-cell therapy has given relapsed/ refractory patients another chance,” Baer said. “Before this treatment was available, they might find themselves running out of options. CAR T-cell therapy allows us to harness their immune system and use it to their advantage.” 

Baer said patients are thrilled with the treatment. “It’s a 1-and-done dose unlike chemotherapy and radiation, which require multiple treatment sessions. In addition, the adverse effects are much easier on patients and more transitory than those accompanying traditional therapy. Patients are grateful, even when treatment is not successful, because it provided them with 1 more option.” 

“CAR T-cell therapy is a targeted treatment,” Garvin noted. “Unlike traditional treatment—which kills anything dividing, including hair, nail, [gastrointestinal], and bone marrow cells—this therapy is designed to enhance the efficiency of the immune system to kill only the targeted malignancy.” 

The CAR T-cell process begins with collection of the patient’s T cells, known as leukapheresis; they are then sent to a manufacturing facility where they go through transduction.

 Transduction allows the expression of receptors on the T cell, which in turn target antigens on malignant cells. The cells are then rigorously checked for quality and purity. The engineering process for autologous CAR T cells can take from 1 to 3 weeks before they are ready to be shipped back to the treatment facility for infusion. “The biggest challenge with autologous therapy is time,” Baer said. “Our patients are quite sick and may not have the time needed to prepare the treatment cells.” 

Allogeneic CAR T cells undergo an engineering process like that of autologous therapy. However, because donor cells are used rather than the patient’s cells, allogeneic treatments can be prepared ahead of time and quickly made available. Of primary concern to nurses administering donor cell therapy is monitoring patients for graft-vs-host disease, which is not an issue with autologous therapy. 

Although these “off-the-shelf” donor CAR T cells are ready for quick shipment, which is an advantage, patients receiving allogeneic therapy may have significant travel times if they live outside major metropolitan areas where clinical trials are offered. Baer is anxiously awaiting FDA approval for allogeneic CAR T-cell therapy as clinical trials move into phase 2. “Approval would provide greater accessibility and benefit many more patients,” she stated. “Travel concerns and limited access also add to health disparity, which is always concerning.” 

Price is another discrepancy between autologous and allogeneic CAR T cells. “Autologous treatment is very expensive, whereas the pharmaceutical company covers the cost of allogeneic cells used in clinical trials,” Baer noted. 

Treatment efficacy for both autologous and allogeneic therapy has been described as “dramatic,” with “high rates of complete remission.” Baer and Garvin concur, each having witnessed similar results in their respective clinical settings. Both are hopeful CAR T-cell therapies will expand to include solid tumors and other cancers. 

Baer and Garvin would like to see these therapies move into a frontline treatment option. “It would be great if we could also predict which patients will get cytokine release syndrome and other toxicities and intervene quicker,” Garvin added. 

CAR T-cell therapy has opened an exciting new door in how we treat cancer, the experts concluded. It continues to signify a big step forward in the fight against this disease.  

1. Muthineni S, Zink K, Kambhampati S. A primer on chimera associated receptor T-cells. 

2. Baer B. CAR T-cell therapy: updates in nursing management. 

2021;25(3):255-258. doi:10.1188/21.CJON.255-258

Approval of off-the-shelf CAR T-Cell therapy options would provide greater accessibility and benefit to patients, say experts.

The Future of CAR T-Cell Therapy: Will Off-the-Shelf Options Soon Enter the Playing Field? 

The risk factors associated with venetoclax (Venclexta) differ for patients with acute myeloid leukemia (AML) compared with other hematologic malignancies, such as chronic lymphocytic leukemia and multiple myeloma, explains Ilene Galinsky, BSN, MSN, ANP-C.

Galinsky, who is the senior leukemia protocol research nurse practitioner, at Dana-Farber Cancer Institute, presented on the efficacy and practical treatment considerations with BCL2 inhibitors at the 47th Annual Oncology Nursing Society Congress. In an interview with 

 she highlights optimal dosing strategies with venetoclax.

Important factors to consider include a patient’s disease burden and concomitant medications, Galinsky said. Venetoclax should not be initiated if a patient has a high white blood count and hydroxyurea should be used to achieve counts below 25,000 cells/μL. Further, tumor lysis syndrome, though rare, has been observed with venetoclax, and providers should closely monitor patients’ hydration levels during ramp up to reduce that risk of occurrence.

CYP3A4 inhibitors can also affect the pharmacokinetics of venetoclax, she said. If a patient is receiving one of those drugs, dose modifications may be necessary to get the patient to their target venetoclax dose.

Another important consideration is the likelihood of myelosuppression, she added. A mid-cycle bone marrow biopsy is recommended between days 21 to 28 to dictate if–and when–the second 28-day cycle can begin.

If a patient is not in remission after 1 cycle, treatment should be continued despite low blood counts, and a second barrow biopsy should be repeated, she said. If a patient is in remission, and has neutropenia, providers should wait until the patient has recovered to grade 1 or 2 neutropenia before initiating a second dose. If, following a second dose, neutropenia is persisting, providers should hold the dose and, upon resuming, prescribe a 21-day cycle instead of a 28-day cycle.

Videos

Ilene Galinsky, BSN, MSN, ANP-C, senior leukemia protocol research nurse practitioner at Dana-Farber Cancer Institute, underscores key prescribing considerations with venetoclax. 

Ilene Galinsky Highlights Optimal Venetoclax Dosing Strategies in AML

Findings from the phase 3 DETERMINATION trial (NCT01208662) showed that patients with newly diagnosed multiple myeloma derived clinical benefit from a combination of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) plus autologous stem cell transplant (ASCT) as initial therapy, followed by lenalidomide maintenance, compared with RVd alone.

The results, which were presented at the 

, revealed a significant improvement in progression-free survival (PFS) in this population.

 At a median follow-up of 76 months, the median PFS was 46.2 months in the nontransplant arm vs 67.6 months in the transplant arm (HR 1.53; 95% CI, 1.23-1.91; 

 < .0001). The estimated 5-year PFS rates were 41.5% and 55.6%, respectively.

“What we were able to demonstrate was that there was a highly significant improvement in PFS with the use of early ASCT,” said lead author Paul G. Richardson, MD, clinical program leader and director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.

Additional findings illustrated no difference in OS between arms; the estimated 5-year OS rates were 79.2% and 80.7% in the in the non-transplant and transplant arms, respectively.

“Our results provide support for personalized treatment approaches,” Richardson noted. “What I mean by that is if we do not see a benefit in OS and you can delay transplant to use it in a tailored fashion you can have an equally efficacious outcome in OS. We can give patients that option.”

High-dose melphalan plus ASCT is the standard of care in transplant-eligible myeloma, and triplet regimens are associated with high rates of deep response and prolonged clinical benefit, which is often maintained with lenalidomide maintenance.

As such, investigators conducted the DETERIMINATION trial to understand whether these approaches can be used collectively up front to improve outcomes.

In the trial, patients with newly diagnosed multiple myeloma between the ages of 18 and 65 years received 3 cycles of RVd followed by stem cell mobilization, and were randomized to either 5 more cycles of RVd (n = 357; arm A) or 200 mg/m

of intravenous (IV) melphalan plus ASCT and 2 cycles of RVd (n = 365; arm B).

Each 21-day cycle of RVd comprised 25 mg of oral lenalidomide on days 1 through 14, 1.3 mg/m

 of IV or subcutaneous bortezomib on days 1, 4, 8, and 11, and 20 mg of oral dexamethasone in cycles 1 through 3 and then 10 mg thereafter on days 1, 2, 4, 5, 8, 9, 11, and 12.

Patients in both arms received between 10 mg of lenalidomide maintenance daily for the first 3 months followed by a dose of 15 mg daily thereafter until progression or intolerance.

The primary end point was PFS and had 90% power to detect a PFS HR of 1.43 for arm A vs B with an α = 0.05 on stratified 2-sided log-rank test. Secondary end points included response rates, duration of response (DOR), time to progression, overall survival (OS), quality of life, and safety. Data cut-off was December 10, 2021.

The median age was 57 years in arm A and 55 years in arm B; 14% and 13% had International Staging System stage III disease, and 18% each had high-risk cytogenetics including t(4;14), t(14;16), and del17p. In the nontransplant and transplant arms, 291 and 289 patients received lenalidomide maintenance; 79 and 81 patients are still receiving lenalidomide maintenance.

With regard to responses, 46.9% of patients in the transplant arm achieved a complete response or better vs 42% of patients in the nontransplant arm. The very good partial response or better rate was 82.7% vs 79.6%, respectively. The partial response or better rate was 97.5% vs 95%, respectively.

Moreover, the DOR was longer in the transplant arm at 56.4 months vs 38.9 months with RVd alone.

“The prognosis for patients with multiple myeloma has improved substantially over the last 10 years,” said ASCO chief medical officer and executive vice president Julie R. Gralow, MD, FACP, FASCO, said during a press briefing. “This trial gives very important information on the benefit and toxicity [of the RVd regimen] so we can have informed discussions with patients. I think duration of response matters to a lot of patients, some [of whom] would rather go a long time others would rather put off a very toxic treatment [such as] ASCT until they might need it later. These data off information that informs a discussion with the patient and helps patients make informed decision.”

The rate of minimal residual disease MRD negativity at a sensitivity of 10-5 was 39.8% without transplant vs 54.4% with transplant. However, Richardson noted that patients who achieved MRD negativity had comparable PFS regardless of treatment.

Notably, only 28% of patients treated with RVd alone underwent delayed transplant; others received next-generation novel agents and monoclonal antibodies.

Grade 3 or greater treatment-related adverse effects including mucositis, fatigue, and infections were less common without transplant than with at 78.2% vs 94.2%.

Regarding quality of life, patients in the transplant arm experienced a temporary but clinically meaningful decrease in during transplant, which improved from baseline throughout maintenance.

The difference in mean change from baseline in the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire QLQ-C30 global health status score was fewer than 10 points throughout treatment except at cycle 5 of RVd vs post-ASCT where the mean change was plus 3.0 vs minus 11.1, respectively (

The 5-year cumulative rate of any secondary cancers was 10.8% with transplant vs 9.7% without. Invasive cancers were reported in 6.5% and 4.9% of patients, respectively. Hematologic cancers developed in 3.5% and 1.6% of patients in each respective arm.

“This was a key toxicity outcome that we monitored carefully,” Richardson said. “We were able to show that there was no difference in the rate of secondary cancers between the arms; however, we did see a higher instance of acute myeloid leukemia and myelodysplastic syndrome was seen with the use of transplant.”

Richardson noted that since this trial was initiated in 2010, triplet therapies have been leveraged as the backbone for quadruplet therapies incorporating monoclonal antibodies and next-generation novel therapies for patients with multiple myeloma. “[Results from studies evaluating quadruplet therapies] are extremely exciting and promising…and by virtue of that this informs our decision-making even more and there are certain research tools such as [minimal residual disease] that can guide us to the best choices for our patients.”

Richardson PG, Jacobus SJ, Weller E, et al. Lenalidomide, bortezomib, and dexamethasone (RVd) ± autologous stem cell transplantation (ASCT) and R maintenance to progression for newly diagnosed multiple myeloma (NDMM): the phase 3 DETERMINATION trial. 

. 2022;40(suppl 17):LBA4. doi:10.1200/JCO.2022.40.17_suppl.LBA4

Autologous stem cell transplant as part of initial therapy showed improved progression-free survival in newly diagnosed multiple myeloma patients. News release. ASCO. June 3, 2022. Accessed June 3, 2022. https://bit.ly/3x8Igbq

Patients with multiple myeloma who received initial combination therapy with lenalidomide, bortezomib, and dexamethasone, plus autologous stem cell transplant, followed by lenalidomide maintenance, experienced improved progression-free survival. 

RVd Plus ACST and Lenalidomide Maintenance Promote Efficacy in Newly Diagnosed Multiple Myeloma 

As biosimilars continue to be approved for cancer-specific agents, the role of the oncology nurse in implementing and educating patients about their use becomes more pronounced, according to Kellie Zeichner, RN, BSN, OCN.

“[The Biologics Price Competition and Innovation Act of 2009] generated a licensure pathway for biologic products which [have been] proven to be biosimilar to or interchangeable with FDA[-approved] biologic products,” Zeichner, an oncology nurse with the Rutgers Cancer Institute of New Jersey who has experience working with biosimilars, said in an interview with 

Frequently used agents in oncology care—trastuzumab (Herceptin), rituximab (Rituxan), and pegfilgrastim—all have approved interchangeable products. Most recently, bevacizumab (Avastin) added a third FDA-approval biosimilar, bevacizumab-maly (Alymsys) in April 2022.

In the discussion, Zeichner highlighted the vital components of the development of biosimilars and interchangeable products that oncology nurses need to know.

 Please contextualize how biosimilars compare with their reference products.

[Biosimilars] are large, complex molecules made from living sources that are not identical but very similar to approved reference or brand drugs [with slight alterations and inactive components]. There are no clinically meaningful variants in safety, purity, or strength.

Biosimilars differ from generic drugs in their complexity and the manner [in] which they are manufactured. The cell lines that are processed [for reference products] are proprietary for biologics; therefore, the original product can never be duplicated precisely, and an exact copy of a biologic cannot be made. This is different from a small molecule drug, which can be copied with insignificant or no variable change from the original. The process of biosimilar manufacturing is rigorous [and is conducted] in a highly controlled environment.

The products are tested on several levels, which include preclinical, structural, and operational levels for safety, efficacy, and immunogenicity. [The biosimilars] must meet FDA standards—they have to be manufactured in an FDA-licensed facility, and they must be tracked as part of post marketing surveillance to ensure continued safety, which is of the utmost importance.

What is the approval process for a biosimilar?

Following the approval of [an] original brand drug, there is a period of market protection. For [approximately] 10 years there is an order to safeguard the reimbursement of research and developmental costs—which are quite high—for [the reference] biological agents.

Once this period has expired, biosimilars are legally allowed to be created. At this point, submission can be placed for a licensed application of biosimilar or an interchangeable [biosimilar product]. Then, through analytical data, animal testing, and clinical studies, an applicant must prove that there is no clinically meaningful difference in safety, purity, and strength between the biosimilar and the reference drug. Biosimilars can be approved as interchangeable either at initial approval, or at supplemental approval, if switching studies are conducted.

Please expand on the differences of an interchangeable biosimilar.

What is an interchangeable? This is a biosimilar product that can be substituted for a brand product without the intervention of the health care provider who prescribed it.

 To demonstrate interchangeability, [the FDA] requires that the biosimilar will produce the same clinical result as a brand product for any given patient and that it presents no additional risk to the patient if a switch between a product had occurred.

All biosimilars have a nonproprietary name and a suffix that is attached to the [reference product name], [this] always has a hyphen at the end [followed by 4 lowercase letters, of which 3 are distinct. They don’t carry any meaning at all, [but are there to ensure] that the biosimilar cannot be capable of being mistaken for the name of a current drug that is marketed already.

The intent for this is 2-fold. [One purpose] is patient safety, [specifically] to prevent patients from receiving medication that was not the intended biologic product prescribed and to avoid switching [to] biologics that are not deemed interchangeable. [The hyphen also serves] for tracking. It allows manufacturers specific tracking and most importantly, the remediation of adverse events should one occur.

Why is immunogenicity important when discussing a biosimilar?

Immunogenicity is an immune response [triggered by] a host against the therapeutic protein or the drug. It is an important concern regarding the efficacy and safety of biologics.

Biologics are more structurally complex than chemical drugs, and even a small variation in their manufacturing can cause undetected changes in [the] biologic composition of the product. These minor differences between a biosimilar and a reference biologic product could lead to the development of an anti-drug antibody.

At least 1 comparative parallel arm clinical trial must be done to assess the potential difference in immune response between the reference product and the biosimilar. Most importantly, the biosimilar approval process should prove that the biosimilar does not present a greater risk than the [reference] or the brand drug does. This is done through a highly complex and fully validated approach for detecting anti-drug antibodies and a head-to-head comparison of immunogenicity testing between the biosimilar and the reference product.

Implementation of the biologics price competition and innovation act of 2009. FDA. Updated Feburary12, 2016. Accessed June 2, 2022. 

FDA approves Alymsys (bevacizumab-maly), a biosimilar of bevacizumab by Amneal Pharmaceuticals, Inc., developed by mAbxience. News release. Brand Institute, Inc. April 18, 2022. Accessed June 2, 2022. https://prn.to/3k7MGt7

Biosimilar and interchangeable biologics: more treatment choices. FDA. Updated October 12, 2021. Accessed June 2, 2022. 

Kellie Zeichner, RN, BSN, OCN, discusses the production of biosimilars, their approval and naming processes, and why immunogenicity is important when discussing these agents. 

The Basics of Biosimilars for Oncology Nurses

Data from the phase 3 Children’s Oncology Group (COG) Protocol AAML1031 (NCT01371981) demonstrated that sorafenib (Nexavar) when added to conventional chemotherapy offers a safe and effective strategy for pediatric patients with 

-ITD–positive acute myeloid leukemia (AML), according to findings published in the 

Treatment with sorafenib was associated with improved event-free survival (EFS) from study entry (

 = .001) as well as disease-free survival (DFS; 

 = .032) and relapse risk from complete remission (CR; 

 = .012) but not overall survival (OS; 

The median follow-up time for patients alive at last contact was 5.3 years (range, 0.3-13.1). There were 32 EFS events among patients who received sorafenib (n = 72) and 35 events among patients who did not (n = 76).

“These data demonstrate that sorafenib dosing of 200 mg/m2 [per] day was tolerable in conjunction with conventional chemotherapy, significantly improved EFS, relapse risk, and DFS, and provided potent FLT3 inhibition,” lead study author Jessica A. Pollard, MD, a physician at Dana-Farber Cancer Institute, and coauthors wrote in the publication. “For treatment of pediatric 

-ITD–positive AML outside of a study context, these data provide compelling support for sorafenib combined with conventional chemotherapy.”

-ITD mutations are associated with poor prognosis in pediatric AML, but chemotherapy remains the standard of care. Prior studies have shown sorafenib is safe in adults with 

-mutant AML. Following documentation of sorafenib’s ease of administration in the pediatric population, investigators sought to examine its use in combination with chemotherapy.

The study enrolled 1645 patients with newly diagnosed, 

-ITD–mutant AML, of which 1609 were eligible. Patients were randomized to 1 of 4 arms: standard chemotherapy consisting of asparaginase, cytarabine, daunorubicin, and etoposide (arm A); asparaginase, bortezomib (Velcade), cytarabine, daunorubicin, and etoposide (arm B); asparaginase, cytarabine, daunorubicin, etoposide, and sorafenib (arm C); or cytarabine, daunorubicin, and etoposide (arm D).

At enrollment, patients were randomized to arm A or arm B and underwent centralized 

-ITD mutation testing. Patients with a high 

-ITD allelic ratio (> 0.4) were eligible for enrollment on arm C, which was split into 3 cohorts. If consented, patients initially randomized to arm A continued standard chemotherapy with sorafenib, and patients in arm B discontinued bortezomib when consenting to arm C. After arms A and B closed, 19 patients were enrolled on arm D until 

-ITD results returned; if positive, patients were eligible for arm C.

Of the 1609 patients enrolled, 8.5% (n = 136) had high allelic ratio 

-ITD–positive AML and were eligible for enrollment in arm C, of which 68% (n = 92) of patients consented. Another 42 patients with high allelic ratio enrolled on arm A or B did not participate in arm C.

During the safety phase, sorafenib was given at a dose of 200 mg/m2 once daily; this dose was determined to be the recommended dosing for sorafenib given the absence of protocol defined dose-limiting toxicities requiring treatment de-escalation. Following completion of the first cohort, the study was amended such that cohort 2 started sorafenib on day 11 of induction 1 and received the agent concomitantly with chemotherapy thereafter.

A preliminary signal of increased cardiac toxicity was reported in 22% (n = 7) of patients in cohort 2 of arm C as defined by grade 3 ejection fraction decline (n = 3), grade 2 ejection fraction decline (n = 2), grade 3 left-ventricular systolic dysfunction (n = 1), grade 2 cardiac other (shortening fraction decline, n = 1), and grade 1 cardiac other (shortening fraction decline, n = 1).

Two patients met the criteria for permanent discontinuation of sorafenib and both tolerated restart. The remaining five discontinued treatment before retreatment was possible. This safety signal led investigators to start sorafenib after completion of standard chemotherapy in each cycle.

A year of sorafenib maintenance, administered after hematopoietic stem cell transplant (HSCT) or completion of chemotherapy was added for patients enrolled in cohort 2 given early evidence of the activity of maintenance therapy. Maintenance dosing was 100 mg/m2 daily with a potential for escalation to a maximum dose of 150 mg/m2 twice daily.

Only 80 patients received sorafenib maintenance in cohorts 2 and 3 of arm C; 38% (n = 30) received at least 1 cycle and 25% (n = 20) completed all maintenance treatment. Maintenance toxicity rates were comparable to those of earlier treatment cycles.

Additional findings from secondary analyses, in which patients who were sorafenib-treated and -naïve were censored at the date of last contact, demonstrated similar outcomes as did censoring of both groups at the time of elective withdrawal.

-positive tumors treated with sorafenib did not show a statistically significant improvement in outcomes vs those who did not receive sorafenib (EFS: 

Although outcomes appeared better overall for children with 

-ITD–positive AML who received sorafenib, they also underwent HSCT more frequently than the comparator population (64% vs 25%, respectively; 

 status and HSCT as a time-varying covariate, significantly worse EFS, DFS, and relapse risk was seen in patients who did not receive sorafenib vs those who did (EFS from study entry: HR, 2.37; 95% CI, 1.45-3.88;

 < .001; DFS from CR: HR, 2.28; 95% CI, 1.08-4.82; 

 = .032; relapse risk from CR: HR, 3.03; 95% CI, 1.31-7.04; 

In terms of safety, dose-limiting toxicities reported in cohort 1 of arm C included rash (grade 2, n = 1; grade 3, n = 1), grade 2 hand-foot syndrome (n = 1), and grade 3 fever (n = 1). The incidence of targeted toxicities was comparable between all 3 cohorts of arm C.

Patients initially enrolled on arm A before switching to arm C (n = 53) were compared with patients who remained on arm A (n = 34). Targeted toxicities were comparable overall as well as across cohorts and treatment phases for patients in arm C who initially were treated on arm A. Additionally, the incidence of chemotherapy-related dose reduction and intensive care unit admission were similar. Notably, patients in arm C were more likely to receive dexrazoxane as a cardioprotectant with anthracycline therapy during induction (

 = .006). No significant unanticipated toxicities were reported in the sorafenib cohort.

Ultimately, the cardiac toxicity reported in arm C was similar to that of arm A. Differences in median ejection fraction were also similar between arms C and A and across arm C cohorts.

“These data are the largest analysis of sorafenib efficacy in pediatric 

-ITD–positive AML. The presently open COG phase 3 study, AAML1831 [NCT04293562], builds on our sorafenib experience by testing gilteritinib in both 

-ITD–positive AML and children with clinically relevant 

-activating mutations,” the study authors concluded.

Pollard JA, Alonzo TA, Gerbing R, et al. Sorafenib in combination with standard chemotherapy for children with high allelic ratio FLT3/ITD+ acute myeloid leukemia: a report from the Children's Oncology Group Protocol AAML1031. 

. Published online March 29, 2022. doi:10.1200/JCO.21.01612

Bortezomib and sorafenib tosylate in treating patients with newly diagnosed acute myeloid leukemia. ClinicalTrials.gov. Updated April 29, 2022. Accessed June 1, 2022. https://clinicaltrials.gov/ct2/show/NCT01371981

This article was originally published on 

® as “Sorafenib Plus Standard Chemotherapy Provides Clinical Benefit in Pediatric 

Standard chemotherapy plus sorafenib achieved clinical benefit in pediatric patients with FLT3-ITD–positive acute myeloid leukemia.

Addition of Sorafenib to Chemotherapy Found to be Safe, Effective in Pediatric FLT3-ITD+ AML

Edema and effusion are generally manageable with dose delays and modifications in patients receiving loncastuximab tesirine-lpyl (Zynlonta) for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in the phase 2 LOTIS 2 study (NCT03589469), according to results of a poster presentation at the 47th Annual Oncology Nursing Society Congress.

 Furthermore, the median onset time for any-grade edema and effusion was approximately 2 or 3 treatment cycles, while grade 3 or higher edema and effusion, while less common, had a median onset time of about 6 treatment cycles.

Loncastuximab tesirine is an FDA-approved antibody-drug conjugate made up of a CD19-targeted antibody coupled with a pyrrolobenzodiazepine (PBD) dimer cytotoxin, which is used to treat patients with relapsed/refractory DLBCL following 2 or more prior lines of systemic therapies.

Nurse investigators characterized the onset and management of edema and effusion with loncastuximab tesirine in the pivotal LOTIS-2 trial.

Hematology