GPRC5D-Targeted Bispecifics in Relapsed/Refractory Multiple Myeloma: Practical Expert Consensus on a New Target with Unique Adverse Events  

GPRC5D-Targeted Bispecifics in Relapsed/Refractory Multiple Myeloma: Practical Expert Consensus on a New Target with Unique Adverse Events

Learning Objectives

• Implement best practices for adverse event recognition, grading, prophylaxis, and management of GPRC5D-directed therapy in patients with multiple myeloma.
• Utilize dose and schedule modifications to optimize GPRC5D-directed treatment response and duration as well as patient quality of life.

Targeting GPRC5D in Multiple Myeloma

G protein–coupled receptor, family C, group 5, member D (GPRC5D) is a newer target antigen for the treatment of multiple myeloma. It is an orphan receptor mainly expressed in plasma cells and hard keratinized tissues, but with low expression in normal human tissues.^1-9 Thus it is an attractive target for T cell redirection. Talquetamab is a first-in-class, bispecific antibody (BsAb) that binds to both CD3 and GPRC5D to induce killing of GPRC5D-expressing myeloma cells via T-cell recruitment and activation.^3,9 It is approved by the FDA for the treatment of adult patients with relapsed/refractory multiple myeloma (RRMM) who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.¹⁰ Talquetamab was approved based on results from the phase 1/2 MonumenTAL-1 study, which showed overall response rates of >70%, with a median duration of response of 9.5 months in patients with a median of five prior therapies.¹ Other GPRC5D-directed therapies for treatment of RRMM are under investigation, including the BsAb forimtamig and the CAR T-cell therapies MCARH109, OriCAR-017, and BMS-986393.¹¹

Safety Profile of Talquetamab

The safety profile of the available BsAbs for RRMM is generally similar; however, compared with the BCMA-directed bispecific antibodies, rates of hematologic toxicities reported in clinical trials were lower with talquetamab compared with teclistamab and elrantamab.^1,12,13 Rates of infections, in particular grade 3 and 4 infections, were also lower with talquetamab compared with teclistamab and elrantamab. Investigational combination regimens that include talquetamab are well tolerated, and data indicate there is no evidence of additive hematologic toxicities when combined with pomalidomide¹⁴ or new safety signals when combining talquetamab with daratumumab.¹⁵

On-Target Adverse Events Related to GPRC5D-Directed Therapies

On-target, off-tumor oral and skin adverse events occur with talquetamab.^1,11,16 These toxicities are generally low grade and rarely result in discontinuations. Strategies for keeping patients on therapy include both early and consistent supportive care and dose holds or modifications.^11,16 Interestingly, recent data indicate that patients reporting an on-target AE had a 20% higher chance of responding to talquetamab therapy.¹⁷

Skin and nail toxicities related to talquetamab therapy can normally be managed by the hematologist/oncologist and rarely require consultation with dermatologists. It is important to educate patients and their families regarding talquetamab skin and nail toxicities prior to initiating therapy and to identify strategies to manage them in order to minimize a negative impact on quality of life, or risk discontinuation, due to these adverse events. Management strategies for skin and nail toxicities are summarized in Table 1.

Table 1. Recommended Management Strategies for Skin and Nail Toxicities Related to Talquetamab Therapy.^{1,11,16,18,19}

Although oral adverse events are generally mild, they can negatively impact treatment continuation. Weight loss (due for example to taste disorder, mucositis, or odynophagia) can also occur, sometimes to a significant degree. It is important to be cognizant of the potential impact of oral toxicities on weight, and weight-based medications (eg, hypotensive and hypoglycemic therapies), may require dose modification.¹¹ For grades 2-3 oral toxicity, talquetamab should be withheld until resolution to grade 1; for grade 4, it should be permanently discontinued.¹⁹ Table 2 shows management strategies for oral toxicities.

Table 2. Management of Oral Toxicities^11,18

Managing Skin and Oral TEAEs With Dose and Intensity Modifications

Talquetamab is given either at a dose of 0.4 mg/kg weekly or at a dose of 0.8 mg/kg biweekly (every other week).¹⁹ Recent data indicate that treatment-emergent dermatologic and oral toxicities from talquetamab may be managed with dose and schedule modifications while maintaining reponse.¹⁷ The phase 1-2 MonumenTAL-1 study included 2 prospectively designed cohorts examining dose intensity reductions. Patients who achieved a confirmed partial response or better while receiving talquetamab 0.8 mg/kg every 2 weeks could switch at the next cycle to either (A) 0.4 mg/kg every 2 weeks (reduced dosing intensity); or (B) 0.8 mg/kg every 4 weeks (reduced dosing frequency). Pooled data showed that at 6 months after switching to the reduced dosing intensity regimen, about 90% of responders maintained a response.¹⁷ Furthermore, these modified dosing schedules resulted in improvements in skin, nail, and oral toxicities while maintaining efficacy. As mentioned previously, patients reporting an on-target GPRC5D-related AE had a 20% higher chance of responding to talquetamab therapy.¹⁷

Cytokine Release Syndrome

Cytokine release syndrome (CRS) is perhaps the most challenging treatment-emergent adverse event in the community setting. It most often occurs after the initial exposure to BsAb therapy (most often, with the second dose), but it can occur during subsequent step-up doses. Roughly 3/4 of patients develop CRS during the step up dosing. Risk factors for CRS include high tumor burden, high treatment dose, and concomitant disease.²⁰ In real-world experience, a majority of patients who develop CRS experience mild symptoms (grade 1-2) with low-grade fever and muscle aches, allowing for early intervention to prevent progression of the CRS (Table 3).

Table 3. ASTCT CRS Consensus Grading²¹

Grade 5 CRS is conventionally defined as death due to CRS, in which another cause is not the principle factor leading to mortality. Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading.

*Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.

†CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with a temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS.

‡Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined at >6 L/minute.

All institutions that administer BsAbs and CAR T-cell therapies must be certified through their respective REMS programs; thus, all clinical staff involved in the management of patients receiving these therapies must be trained to manage CRS. Temporary drug discontinuation in the management of CRS is occasionally indicated, and premedication with tocilizumab may reduce the incidence and severity of CRS with BsAbs.²⁰ As with other bispecific antibodies, talquetamab is given in a step-up dosing schedule to reduce the risk of CRS.¹⁹ The FDA label states that patients should be admitted to the hospital for 48 hours after all doses during the step-up dosing phase; however, some institutions are treating patients on an outpatient basis. Pretreatment medications with corticosteroids, antihistamines, and antipyretics also should be given 1-3 hours before each dose during the step-up dosing phase.

Tocilizumab plays an important role in the management of CRS. In the pivotal phase 1 study, roughly 1/3 of patients required tocilizumab to manage the CRS. Many practitioners, however, administer tocilizumab for any grade of CRS, even grade 1 CRS, to prevent progression and complications. Early use of tocilizumab has been shown to reduce the grade of CRS and also recurrence.²² Ongoing studies are evaluating premedication with tocilizumab.

Other management strategies for CRS are shown in Table 4.^19,20

Table 4. Management Strategies for Cytokine Release Syndrome by Grade^19,20

ICANS

Immune effector call-associated neurotoxicity syndrome (ICANS) often arises after the symptoms of CRS resolve, but CRS and ICANS rarely occur simultaneously.¹⁹ However, a few patients may develop ICANS without previous CRS. Other risk factors for developing ICANS include younger age, pre-existing neurological conditions, and high tumor burden. In clinical trials, ICANS was reported in 10% of patients on talquetamab.¹⁷

Talquetamab should be stopped for patients who develop ICANS and permanently discontinued for persistent grade 3 or any grade 4.¹⁹ Patients should be monitored for neurologic symptoms at all grades of ICANS, and consultation with a neurologist considered for further evaluation and management. Dexamethasone should be given where clinically appropriate until resolution to grade 1 or less, and then tapered. Non-sedating, anti-seizure medications can also be considered for seizure prophylaxis.

Infections

As mentioned previously, rates of infections were lower with talquetamab compared with teclistamab and elrantamab in clinical trials.^1,12,13,22 Rates of COVID deaths and neutropenia were substantially lower with talquetamab. Fewer opportunistic infections were also reported with talquetamab versus elrantamab and teclistamab. However, it is important to remember that patients eligible for BsAb and CAR T-cell therapies have heavily pretreated disease which carries an increased risk of developing infection. Table 4 shows risk factors for infection in patients with RRMM receiving bispecific antibodies.

Table 5. Risk Factors for Patients with Relapsed/Refractory Multiple Myeloma Receiving Bispecific Antibody Therapy.²²

Patients who are scheduled to receive BsAb therapy should receive recommended vaccines and to monitor IgG levels and supplement monthly IVIG for the following patients²²:

• Patients whose IgG levels <400 mg/dL
• Patients who have experienced ≥2 severe recurrent infections by encapsulated bacteria, regardless of IgG level
• Patients with a life-threatening infection
• Patients with documented bacterial infection with no or insufficient response to antibiotic therapy

Conclusion

GPRC5D-directed therapies are associated with high response rates of >70% in heavily pretreated myeloma patients, and even with modifications in dose and intensity, response rates are maintained, indicating that these therapies are strongly efficacious in RRMM. It is thus crucial that community clinicians become more experienced with using GPRC5D-directed therapies such as talquetamab, and become more comfortable managing their unique toxicity profile. For patients in particular relapsing after receiving a BCMA T-cell redirecting therapy, utilizing GPRC5D-directed therapies becomes of paramount importance. Moreover, since other GPRC5D-directed therapies are under investigation, clinicians should be confident using therapies in this class by the time these investigational agents become available.

References

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