Targeted Therapies Continue to Shift Treatment Armamentarium in Multiple Myeloma

Patient outcomes across the multiple myeloma landscape have vastly improved with the approval of multiple agents in the treatment armementarium, such as belantamab mafodotin-blmf (Blenrep), selinexor (Xpovio), and ciltacabtagene autoleucel (Carvytkti; cilta-cel), according to a presentation by Daniel J. Verina, DNP, RN, MSN, ACNP-BC, at the 19th International Myeloma Society Annual Meeting.

“We are in the renaissance of myeloma with the new birth of therapies [and more] are coming,” Verina, a nurse practitioner with the myeloma team at Mount Sinai Medical Center said in a presentation at the International Myeloma Society’s 6th Annual Nursing Symposium.

Part of the progress we are experiencing according to Verina, is the growing number of sequential therapies available for this patient population.

“As each patient moves through this [treatment] marathon, each remission gets shorter and their options [become] fewer. That is what we have been used to,” he said. “We have a lot up front. And then as these patients relapse each time they relapse, besides the shortness of their progression-free survival time, their options become [fewer].”

The landscape has expanded to include CD38- and SLAM-F7-directed monoclonal antibodies, XPO-1 inhibitors, and CAR T-cell therapies which are revolutionizing outcomes in multiple myeloma. However, as more options are approved, best nursing practices must become nuanced and adapt to the needs posed by these different classes of agents.

In his presentation, Verina discussed these newer additions to the treatment paradigm, underscored their safety profiles and elaborated on best nursing practices regarding targeted therapies. 

Monoclonal Antibodies in Multiple Myeloma

Daratumumab (Darzalex) is a human CD38-directed monoclonal antibody that has been approved for numerous indications, including for newly diagnosed and relapsed or refractory disease. Elotuzumab (Empliciti) is approved in combination with pomalidomide/ dexamethasone, and in combination with lenalidomide (Revlimid)/dexamethasonefor relapsed or refractory disease. This agent functions by targeting SLAM-F7.^2-3

Isatuximab-irfc (Sarclisa), another human CD38-directed monoclonal antibody which was approved in March 2020 in combination with pomalidomide and dexamethasone following a relapse with carfilzomib (Kyprolis).4

The agents mentioned above are administered twice weekly for 8 weeks, and then once or twice monthly until either disease progression or unacceptable toxicity. When administering monoclonal antibodies, there is a risk of an infusion reactions. To combat these reactions, nurses may also administer dexamethasone, H1 or H2 blockers, and acetaminophen. They may also slow the infusion rate with elotuzumab to 0.5 mL/min—eventually escalating to 5 mL/min as the patient is able to tolerate it.^2-4

There is also an increased risk of venous thromboembolism with monoclonal antibodies and prophylaxis is advised.

When prescribing a monoclonal antibody with bortezomib (Velcade), nurses should monitor for neuropathy and hypotension. Doses may be held or adjusted as needed. Other key things to be monitoring for include complete blood count, glucose, renal and hepatic function, and any potential transfusion issues.

Belantamab Mafodotin Adverse Event Management

Belantamab mafodotin is approved in the United States to treat patients with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.⁵

In DREAMM-2 (NCT03525678), the most frequently reported treatment-emergent adverse events (AEs) were ocular toxicities, including keratopathy, decreased visual acuity, blurred vision, and dry eyes. Among 95 patients who received a 2.5 mg/kg dose of belantamab mafodotin, 71% developed keratopathy, 53% developed decreased visual acuity, 22% developed blurred vision, and 14% developed dry eyes. In terms of grade 3 or 4 severity, the percentage of cases with keratopathy, decreased visual acuity, blurred vision, and dry eye were 44%, 28%, 4%, and 1%, respectively.⁵

Investigators have proposed that belantamab mafodotin is able to penetrate the cornea and is internalized by the basal corneal epithelial cells–where it induces apoptosis, and that some agent-containing cells might travel near the visual axis and induce vision changes. Eventually, new epithelial cells are created which replace the belantamab mafodotin–containing cells that have undergone apoptosis.

Regardless of cause, vision changes must be monitored, Verina noted. Ophthalmic exams, using visual acuity and slit lamps, are required prior to each dose of belantamab mafodotin.

Belantamab mafodotin is administered once every 3 weeks. A baseline ocular assessment should take place within 3 weeks of the first dose. Follow-up examination should occur at least 1 week after the previous dose and within 2 weeks prior to the next dose. Examinations must continue until disease progression or unacceptable toxicity.⁵

In the event of a grade 2 or higher corneal toxicity per the keratopathy and visual acuity scale, belantamab mafodotin should be withheld until the patient improves. The dose may be resumed at either the same or reduced scale. If toxicity is severe, the agent may be permanently discontinued.

Clinical pearls for AE management with belantamab mafodotin include administering preservative-free lubricant eye drops at least 4 times a day. Eyedrop treatments should begin with the first infusion and continue until the end of treatment.

Patients should avoid wearing contact lenses unless specifically instructed to do so by their eye care specialist. Moreover, patients should use caution if operating machinery or driving a vehicle as changes in visual acuity may become more severe than they have realized.

XPO-1 Inhibitors

Selinexor AE Management

Thrombocytopenia

Patients receiving selinexor should be monitored for complete blood counts at baseline and throughout treatment.⁶

For a grade 1 hematologic event, other causes should be ruled out and dose should be maintained. For a grade 2 event, selinexor should be reduced by 1 dose. A grade 3 event without bleeding demands a dose reduction by 1 level, and consideration of concomitant antiplatelet agent therapy or bone marrow stimulants such as romiplostim (Nplate), or eltrombopag (Promacta).

A grade 3 event with bleeding, or a grade 4 event, signifies that a patient may need a transfusion and should be followed per institutional guidelines. Doses delayed until platelets recover to grade 2. Providers should consider concomitant antiplatelet agent therapy or bone marrow stimulants.

Examples of effective supportive care in this setting may include low-dose olanzapine (2.5 to 5.0 mg), and NK1 receptor antagonists, such as rolapitant (Varubi), aprepitant/fosaprepitant (Akynzeo), or netupitant/palonosetron (Akynzeo).

Benzodiazepines, such as lorazepam, and cannabinoid-receptor agonists, such as dronabinol at 2.5 to 5 mg twice daily, may also be effective.

Neutropenia

Patients receiving selinexor should be monitored for complete blood counts at baseline and throughout treatment. No intervention is needed for a grade 1 or 2 event, but if a grade 3 event occurs, a dose reduction should be considered and a granulocyte colony-stimulating factor

(G-CSF) should be administered, per institutional guidelines.⁶

In the event of a grade 4 incident, or febrile neutropenia, selinexor should be interrupted, neutrophil counts should be monitored until they return to 1.0 × 109/L or higher, and treatment should be restarted at 1 dose level lower. Growth-colony stimulating factor (G-CSF) should be administered per institutional guidelines.

Weight Loss and Anorexia

Nutritional counseling prior to treatment is encouraged to reduce the risk of weight loss. If a grade 1 or 2 event occurs, selinexor dose should be maintained, other causes should be ruled out, and additional nutritional counseling and or supplements should be considered. Examples of supplements may include Boost or Ensure.

If grade 2 or greater weight loss, or grade 3 or worse anorexia occurs, nutritional counseling and supplements are advised. Dosing should be interrupted until baseline or weight stabilizes to grade 1. When the dose is resumed, it should be at 1 dose level lower.

Examples of ideal supportive care in this setting include mirtazapine or olanzapine 2.5 to 5 mg orally in the evening, and megestrol acetate at 400 mg daily. Cannabinoids at a dose of 2.5 mg twice daily may be effective as well, along with dose medications and appetite stimulants.

Diarrhea

Diarrhea prevention should include oral hydration with at least 8 oz glasses of fluid per day and scheduled weekly saline infusions for the first month to promote healthy sodium and hydration levels.

At first occurrence of a grade 2 event, the dose should be maintained, and anti-diarrheal treatment should be initiated, per institutional guidelines. At second occurrence of a grade 2 event, the dose should be reduced by 1 dose level, and the antidiarrheal treatment should be initiated.

In the event of a grade 3 or worse event, the dose should be interrupted, and diarrhea should be monitored until resolved to a grade 2. Following resolution, selinexor should be continued at 1 dose level lower.

Loperamide and bismuth subsalicylate (Pepto-bismol, Bisbacter) represent examples of effective supportive care. Loperamide should be given at 4 mg for the first dose and 2 mg thereafter, as needed.

Fatigue

Patients should be assessed for underlying causes of preexisting or predisposition to developing fatigue prior to treatment initiation. Predictive factors may depression, dehydration, and anemia. Patients who are anemic may benefit from transfusions of hemoglobin to raise levels from below 8 g/dL.

If a grade 1 event occurs, dose should be maintained and supportive care per institutional guidelines should be initiated. If a grade 2 event lasting more than 7 days occurs, or a grade 3 event occurs, dose should be interrupted until the event has resolved to a grade 1, and selinexor should be reduced by 1 dose level when it is re-initiated.

Additional supportive care can include methylphenidate once daily at 10 mg, as needed.

Hyponatremia

Patients should maintain their fluid intake and incorporate salty foods and snacks into their dietary routine to prophylaxis against hyponatremia. If their sodium levels drop beneath 130 nmol/L, the selinexor dose should be interrupted, sodium levels should be monitored until they are above 130 nmol/L, and selinexor should be re-initiated at 1 dose level lower.

Key supportive care tactics include encouraging saline and salt tablets, salty snacks, and monitoring hydration status and serum status.

CAR T-Cell Therapy AE Management

As of August 2022, idecabtagene vicleucel (Abecma) and cilta-cel have both been approved for patients with multiple myeloma in the United States.^7,8

Cytokine release syndrome (CRS) is an AE of significant concern when caring for patients on CAR T-cell therapy, Verina noted. CRS is a systematic inflammatory response which is triggered by the high-level immune activation associated with this therapy. It is characterized by the activation of CAR T-cells on tumor recognition.

Patients with a high disease burden, or who have elevated C-reactive protein 3 days post infusion are at an increased risk of severe CRS, as are patients who develop early onset CRS within 3 days of cell infusion.

Symptoms include fever, tachycardia, hypotension, dyspnea, hypoxia, cardiovascular compromise, and organ injury. Unfortunately, if CRS is left untreated, it may lead to death. Corresponding laboratory abnormalities include cytopenia, hypofibrinogenemia, and hyperferritinemia.^7,8

The median onset time may range from days to weeks post infusion and tends to coincide with maximal in vivo T-cell expansion. Of note, IL-6 is considered a central mediatory of toxicity with CRS.

When responding to CRS, the severity of the patient’s CRS and institutional management guidelines should be considered, Verina said. However, if therapeutic intervention is necessary, tocilizumab is an effective response. The FDA approved the humanized monoclonal antibody in 2017 for CAR T mediated CRS, and its mechanism of actions is binding to the IL-6 receptor (IL-6R) and inhibiting inflammatory responses.⁹ Steroids and IL-1 inhibitions, such as anakinra, may also be effective interventions.

References

1. Verina DJ. Managing the toxicities associated with newer targeted therapies. Presented at: International Myeloma Society 6th Annual Nursing Symposium; August 25-27, 2022; Los Angeles, CA. NS-001.
2. Darzalex. Prescribing information. Janssen Biotech; 2022. Accessed August 26, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761036s041lbl.pdf
3. Emplicity. Prescribing information. Bristol Myeres Squibb; 2022. Accessed August 26, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761035s015lbl.pdf
4. Sarclisa. Prescribing information. Sanofi Aventis; 2022. Accessed August 26, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761113s006lbl.pdf
5. Blenrep. Prescribing information. Glaxo Smith Kline; 2022. Accessed August 26, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761158s006lbl.pdf
6. Xpovio. Prescribing information. Karyopharm Therapeutics Inc; 2022. Accessed August 26, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212306s011lbl.pdf
7. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. Updated March 29, 2022. Accessed August 26, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-idecabtagene-vicleucel-multiple-myeloma
8. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. Updated March 7, 2022. Accessed August 26, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ciltacabtagene-autoleucel-relapsed-or-refractory-multiple-myeloma
9. Actemra. Prescribing information. Genentech; 2017. Accessed August 26, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125276s114lbl.pdf