How We Are Integrating New Data Into Relapsed/Refractory Myeloma Treatment

Key Takeaways

• Anti-CD38 monoclonal antibodies are standard-of-care therapies in the management of multiple myeloma and are available for either intravenous or subcutaneous administration
• Appropriate management of adverse events associated with selinexor (XPO1 inhibitor with a high risk of gastrointestinal toxicities) and belantamab mafodotin (B-cell maturation antigen [BCMA] inhibitor carrying a risk of ocular toxicities) is essential
• CAR T-cells targeting BCMA are a new approach for relapsed/refractory myeloma that is being investigated earlier in the disease course

The treatment of relapsed/refractory multiple myeloma is continually evolving with significant advances. In this commentary based on a live webinar, Rebecca Gonzalez, PharmD, BCOP, and Donald C. Moore, PharmD, BCPS, BCOP, DPLA, highlight key updates in the management of relapsed/refractory myeloma.

Current Standards of Care for Myeloma in Early Relapse

Donald C. Moore, PharmD, BCPS, BCOP, DPLA:
An important development in treating relapsed myeloma, particularly early relapse, has been the approval of 3 monoclonal antibodies: daratumumab and isatuximab, which target CD38, and elotuzumab, which targets SLAMF7. Originally, daratumumab required a 7-hour infusion, but it is now reformulated as a subcutaneous injection in combination with hyaluronidase and can be given in less than 5 minutes.

Daratumumab is approved for relapsed/refractory myeloma in combination with either bortezomib/dexamethasone (Vd) or lenalidomide/dexamethasone (Rd) for previously treated patients, based on the POLLUX and CASTOR trials. Significant progression-free survival (PFS) and overall survival (OS) improvements were observed compared with the doublets alone. The CANDOR and APOLLO trials evaluated the addition of daratumumab to carfilzomib/dexamethasone (Kd) and pomalidomide/dexamethasone (Pd) respectively in relapsed/refractory myeloma, and the FDA has approved daratumumab plus both combinations. Results showed significant improvements in median PFS and response rates vs the doublets alone. Daratumumab is also approved as a single agent in patients with at least 3 prior lines or who are double refractory.

Isatuximab in combination with Pd was approved for relapsed/refractory myeloma with at least 2 prior therapies based on results from the phase III ICARIA study showing improved PFS and OS vs Pd alone. Improved PFS and responses were observed in participants, including subgroups with difficult-to-treat disease, of the IKEMA trial, which evaluated the addition of isatuximab to Kd. Elotuzumab is approved for relapsed/refractory myeloma in combination with both Rd (1-3 prior therapies) or Pd (2 or more prior therapies), based on results from the ELOQUENT-2 and ELOQUENT-3 trials showing improved PFS and responses vs Rd and Pd alone.

Administration Considerations for CD38 Antibodies

Subcutaneous daratumumab was approved by the FDA based on noninferior response rates in the phase III COLUMBA study, which compared subcutaneous with intravenous daratumumab as monotherapy in relapsed/refractory myeloma. Patient satisfaction scores were improved with the subcutaneous formulations, likely due to the greatly reduced administration time. Although the rate of infusion-related reactions was lower, it took much longer for reactions to manifest compared with the intravenous formulation, suggesting an observation period may be warranted with the first administration of subcutaneous dosing. At our institution. we monitor patients for 4 hours after the first subcutaneous dose and send them home with rescue medications; so far, no infusion-related reactions have been observed, and the rescue medications have not been needed.

Dr. Gonzalez, what is your clinic’s experience with subcutaneous daratumumab?

Rebecca Gonzalez, PharmD, BCOP:
We have embraced subcutaneous administration for nearly all our patients with myeloma, per the COLUMBA study. We use an monitoring period post-dose of 3 hours for the initial therapy in daratumumab-naive patients, then 30 minutes for the second and third doses, and for subsequent doses, the patient can go home right after administration.

Donald C. Moore, PharmD, BCPS, BCOP, DPLA:
In the CANDOR and APOLLO trials, daratumumab plus either Kd or Pd was well tolerated, but grade 3/4 hypertension was observed with daratumumab plus Kd in a small number of patients in CANDOR, and increased rates of hematological events and respiratory tract infections were observed in both trials. This also was seen with the addition of isatuximab to Pd in ICARIA and Kd in IKEMA. In the ELOQUENT-2 and ELOQUENT-3 studies, the addition of elotuzumab to Rd did not meaningfully affect safety, with similar rates of infections and grade 3/4 adverse events in both arms in each study. It is still unclear whether patients who received daratumumab should subsequently receive isatuximab; in a recent phase I/II study in myeloma, isatuximab produced no responses in a daratumumab-refractory population.

Pharmacists must keep in mind that CD38 antibodies are associated with an increased risk for infectious complications, so baseline hepatitis B serology should be considered, and herpes zoster prophylaxis should be used throughout therapy. Hypogammaglobulinemia also can occur; consider IVIG supplementation for patients with recurrent infections. Other considerations are that subcutaneous daratumumab is given as a flat dose, monthly after cycle 7, whereas isatuximab uses weight-based dosing given by IV every other week and will result in more and longer infusion appointments. Both agents require corticosteroid-based premedication.

Newer Targets in Relapsed/Refractory Myeloma XPO1

Rebecca Gonzalez, PharmD, BCOP:
Selinexor is an XPO1 inhibitor that is approved by the FDA in combination with Vd for patients with relapsed/refractory myeloma after 1 prior therapy and in combination with dexamethasone for those with at least 4 prior regimens, including at least 2 proteosome inhibitors, 2 immunomodulatory agents, and 1 anti-CD38 monoclonal antibody.

Uniquely, it can cause apoptosis independent of TP53 through reactivating tumor-suppressing proteins.

Pharmacists are particularly important with this agent as we optimize implementation of supportive care measures for the common incidence of gastrointestinal toxicities, such as vomiting and diarrhea, and for neutropenia and thrombocytopenia. Good preventive antiemetics—like olanzapine, which is effective for 3-4 days—and as needed antiemetics are important. Antidiarrheal medication is often utilized, following a test to rule out Clostridioides difficile infection. Most patients will need a dose modification at some point in their treatment, whether they are receiving selinexor as part of a doublet or triplet regimen.

In the phase II STORM trial, the addition of selinexor to dexamethasone improved outcomes in patients with 4 or more prior lines of therapy for myeloma; even as a single agent, the response rate was 26%, which is consistent with daratumumab. The addition of selinexor to Vd was shown in the phase III BOSTON trial to significantly improve PFS in patients with at least 1 line of prior therapy.

Donald C. Moore, PharmD, BCPS, BCOP, DPLA:
One question from the audience was: What standard antiemetic regimens are used with selinexor? I typically use a 5-HT3 agonist as well as olanzapine. I usually give this on a weekly basis in combination with a proteasome inhibitor.

Rebecca Gonzalez, PharmD, BCOP:
I also typically use olanzapine. For older patients at higher risk of toxicities and sedation, I start olanzapine at 2.5 mg in the evenings and titrate up from there to as much as 10 mg/day. We also use 5-HT3 agonists. For some patients, I will choose additional prochlorperazine, but this is not my initial choice for scheduled therapy up-front.

BCMA-Targeted Antibody–Drug Conjugate

Rebecca Gonzalez, PharmD, BCOP:
BCMA is a cell-surface protein highly expressed in myeloma, which helps limit off-target effects from BCMA-targeted agents. Belantamab mafodotin is the first FDA-approved antibody–drug conjugate that targets BCMA. Its cytotoxic payload is a microtubule inhibitor that directly causes apoptosis. It shares additional monoclonal antibody activity through immune-dependent mechanisms to induce apoptosis. Ocular toxicities are a risk with belantamab mafodotin, including keratopathy and visual acuity changes. It is currently available under a risk evaluation and mitigation strategies (REMS) program.

Belantamab mafodotin was approved based on results from the phase II DREAMM-2 trial, where it produced a 32% response rate as a single agent in patients with myeloma and a median of 7 lines of prior therapy. In that study, approximately half of the patients had grade 3/4 ocular toxicity, but very few (3%) discontinued due to corneal toxicity. is helpful for pharmacists to establish a collaborative relationship with their local optometrist or ophthalmologist when addressing the safety and tolerability of these agents (eg, examination to determine toxicities and visual acuity changes). Patients need to be counseled that dose delays and modifications are to be expected.

Donald C. Moore, PharmD, BCPS, BCOP, DPLA:
An audience member asked whether we would consider belantamab mafodotin as second-line or third-line therapy after, for example, carfilzomib plus Rd.

Rebecca Gonzalez, PharmD, BCOP:
There is concern that using belantamab mafodotin may decrease responses to future BCMA-targeted CAR T-cell therapy. In my clinical practice, if a patient is planned to start a BCMA-targeted CAR T-cell therapy or a bispecific antibody, we may withhold the earlier administration of a BCMA-targeted agent. For those too frail to go on to CAR T-cell therapy or receive a bispecific antibody, belantamab mafodotin may be a better option.

Triple-class refractory myeloma is challenging to manage. In the retrospective MAMMOTH study, patients with prior CD38 antibody exposure had reduced OS and PFS with subsequent therapies. Those who received carfilzomib-based regimens had the longest PFS and OS, especially with an alkylator or immunomodulatory agent. In the prospective LocoMMotion study of real-world standard of care treatment for patients with at least 3 prior lines or double-refractory disease, the overall response rate to salvage therapy was lower than 30%. In this study, a total of 92 different variations were used as treatment, highlighting the need for individualized treatment instead of a one-size-fits-all approach. Both studies show there is a large unmet need for better treatment in triple class–exposed or triple class–refractory myeloma.

In an adjusted indirect treatment comparison of the DREAMM-2 and STORM trials, belantamab mafodotin provided improved OS in triple class–relapsed/refractory myeloma vs selinexor plus dexamethasone (Xd) (HR: 0.53; P = .005). Patients receiving belantamab mafodotin in DREAMM-2 were twice as likely to achieve a very good partial response or better with Xd in STORM. An important caveat is that the STORM trial had a more highly pretreated and more refractory population.

BCMA-Targeted CAR T-Cell Therapies

Rebecca Gonzalez, PharmD, BCOP:
CAR T-cells have revolutionized immunotherapy for patients with myeloma beyond autologous transplantation. Two BCMA-targeted CAR T-cell therapies have been approved by the FDA, both for patients with at least 4 prior regimens including a proteasome inhibitor, an immunomodulatory agent, and a CD38 antibody: idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). Both are autologous products created for individual patients and can take 4-6 weeks to prepare. In the phase Ib/II CARTITUDE-1 study of cilta-cel, most patients not only responded but achieved a complete response (>95%). In the phase II KarMMa study of ide-cel, approximately three quarters of patients responded and one third achieved a complete response. Additional BCMA-directed CAR T-cells are in clinical development.

The main toxicities of concern with BCMA-targeted CAR T-cells are cytokine-release syndrome and neurotoxicity, similar to the CD19-targeted CAR T-cells. In addition, because ide-cel and cilta-cel, target BCMA, patients are at higher risk of cytopenias and hypogammaglobulinemia. Supportive care with growth factors and IVIG support is warranted. Like the CD19-targeted CAR T-cells, the BCMA-targeted products also are available only through a REMS program. Lastly, cilta-cel specifically has additional warnings for neurocognitive dysfunction (eg, parkinsonism and Guillain-Barré syndrome).

Pharmacists can collaborate in determining optimal bridging therapy for patients who plan to receive CAR T-cell treatment. This can include novel agents like selinexor, but also classic salvage therapies like dexamethasone/cyclophosphamide/etoposide/cisplatin (DCEP) or cyclophosphamide/bortezomib/doxorubicin/dexamethasone (CVVD) if patients cannot tolerate DCEP. There is concern that using a BCMA-targeted therapy like belantamab mafodotin as bridging treatment may impair outcomes with subsequent CAR T-cell therapy, and this is currently being investigated by a real-world myeloma consortium. One of the unique aspects with newer BCMA-directed therapies like cilta-cel is that toxicities can be delayed by a week, with cytokine-release syndrome around Day 7 and neurotoxicity around Day 8.

Donald C. Moore, PharmD, BCPS, BCOP, DPLA:
An audience member asked how therapy might change if mutated TP53 is discovered. In my clinic, I would prefer for them to receive subsequent CAR T-cell therapy vs other options. There are no head-to-head data to answer this question, but some clinical trials are currently looking at risk-adapted strategies for high-risk populations, including moving CAR T-cell therapy earlier in the treatment course.

Overall, optimal sequencing of standard therapy in relapsed/refractory myeloma is currently unknown. Patient-related, disease-related, and regimen-related factors can influence the selection of patients with relapsed disease. Novel agents are emerging as treatment options for relapsed/refractory disease and BCMA-directed immunotherapies have become a very attractive salvage option. As pharmacists, we can collaborate to improve therapy selection, patient education, and supportive care management.

Your Thoughts?

What have been your successes and challenges with newer agents for relapsed/refractory myeloma? Have you seen ocular toxicity in your patients receiving belantamab mafodotin? Answer the polling question and join the conversation by posting a comment in the discussion section below.