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Pharmacist Myeloma Summary
My Key Pharmacist Takeaways for Multiple Myeloma Treatment

Released: May 06, 2022

Expiration: May 05, 2023

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Multiple myeloma (MM) remains an incurable B‑cell malignancy in which monoclonal immunoglobulins can be secreted into the urine, blood, and bone marrow. These monoclonal immunoglobulins are denoted as M-proteins and have the ability to disrupt normal organ function and increase cytokine production. They can lead to infections, reduced quality of life, and increased mortality.

The clinical picture of a patient with symptomatic MM can be noted by the CRAB acronym, which represents the defining events of MM. Hypercalcemia can be present due to renal and bone involvement. Renal failure is a unique presentation in that impairment can improve as the patient undergoes therapy. If renal impairment is believed to be MM-driven, consider avoiding renal adjustments of anti-MM therapy. Anemia, which occurs most often, is driven by both renal and bone marrow involvement. Bone disease is a hallmark of MM. The disease process can present before other symptoms, leading to some patients being diagnosed after a fracture. This occurs due to lytic lesions of the bone marrow and abnormal bone remodeling and loss. 

Triplet, Quad Regimens as Standard Therapy for Patients With Newly Diagnosed MM
The key to optimal MM treatment is to offer patients an opportunity to achieve deep, durable, and sustainable responses after initial therapy with a focus on obtaining a stringent complete response with measurable residual disease negativity. Typically, patients receive triplet and quad therapies up-front, based on data showing overall improvement in progression-free survival and overall survival. Of most importance, offer all patients the ability to consolidate responses with autologous stem cell transplantation. Regardless of transplant eligibility, every patient should be offered maintenance therapy.

Treatment of R/R MM Depend on Prior Therapies, Timing of Relapse, Patient Preferences, Other Factors
It is important to remember that the most durable and deepest response is within the first treatment cycle. The more cycles that a patient receives, the shorter the remissions are until the disease becomes refractory to all available therapies. 

There are several considerations for how best to treat a patient. Disease‑related aspects are important as those patients with more active or aggressive disease may warrant initiation of a new therapy combo or a class switch, whereas the patients who may have a biochemical relapse (ie, rising M protein) may be able to increase dose of an immunomodulatory drug or incorporate an anti‑CD38 monoclonal antibody (mAb) into the mix. Patient-related factors should be reviewed, including performance status, existing comorbidities, and adverse events from initial treatments to guide the appropriate selection. Of most importance for a treating pharmacist, regimen‑specific details are necessary for a patient-specific approach—what prior therapy were they exposed to? How long did they get a response?—because these all are influential in treatment decisions.

Novel Drug Targets Provide Opportunities for Deeper, More Durable Responses in R/R MM
When treating patients with relapsed/refractory (R/R) MM, there is no one‑size‑fits‑all approach, but several considerations can help determine what’s the best therapy for the patient. First, patients at relapse should be offered a clinical trial, if available. Second, assess whether a patient is lenalidomide sensitive or refractory, as this initially will guide the selection. Third, it also is important to consider lingering toxicities from first-line and second-line therapies, past exposure to anti‑CD38 mAbs, and the use of second-generation and third-generation immunomodulatory drugs and proteasome inhibitors. 

mAbs have a significant role in the R/R MM setting. The FDA has approved 2 anti-CD38 mAbs, daratumumab and isatuximab, and 1 anti-SLAMF7 mAb, elotuzumab. Daratumumab in particular has been approved in numerous triplet and quad regimens, from newly diagnosed MM to multirefractory MM. Keep in mind, however, that the use of anti-CD38 mAbs up-front as part of a 4‑drug regimen for newly diagnosed MM has significant impact on what subsequent therapies are available for a patient in later lines of therapy.

Two small molecule inhibitors, selinexor and venetoclax, work intracellularly within the MM cell itself. Selinexor is a first-in-class oral exportin‑1 inhibitor, approved in combination with dexamethasone with or without bortezomib. Venetoclax is a BCL2 inhibitor, and like selinexor, is an oral formulation specifically used in patients with MM and t(11;14) translocation. Both selinexor and venetoclax have significant gastrointestinal toxicities and are associated with increased risk of infections and cytopenias, and venetoclax has an added risk of tumor lysis syndrome.

BCMA-Targeted Therapies
Belantamab mafodotin, an antibody–drug conjugate, targets B-cell maturation antigen (BCMA) with a toxic payload called monomethyl auristatin F. It is available under a risk evaluation and mitigation strategy program due to significant ocular toxicities associated with it. Patients are required to be assessed prior to each dose by an ophthalmologist to evaluate for visual acuity changes and any ocular toxicity that would warrant a dosage modification or delay.

And last, we have 2 BCMA-directed CAR T-cell therapy options for R/R MM. As with other CAR T-cell products, patients’ cells are apheresed and genetically modified to reprogram their T-cells to target MM cells. These “living drugs” are patient-specific autologous products that may take 3‑6 weeks to manufacture. Once infused, these cells attack the MM cells that are evading the immune system. The current products on the market are approved after 4 or more lines of therapy: idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). Despite both products being BCMA‑directed therapies, cilta‑cel has 2 epitope bindings proposed to increase the affinity to BCMA. Both contain 4‑1BB costimulatory domain, are lentivirus vector derived, and use similar lymphodepleting chemotherapy to increase overall expansion and persistence.

Similar to CD19 CAR T-cell products, the most common toxicities for BCMA products are cytokine-release syndrome (CRS) and neurotoxicity (NT), which require a risk evaluation and mitigation strategy program to evaluate and support each patient. Depending on overall presentation of CRS or NT, this may warrant supportive care such as acetaminophen or initiation of tocilizumab and/or steroids to manage more severe toxicities.

Highlighting the toxicity profiles for both agents, ide‑cel toxicities are immediate within 24‑48 hours of administration, whereas cilta‑cel presentation of both CRS and NT is delayed up to a week after administration. This toxicity profile will affect how you treat a patient, admitting them up front and keeping them there for cell infusion, or keeping them outpatient and admitting them if the patient has toxicity.

Conclusion
In summary, despite MM being an incurable malignancy, triplet and quad therapies have significantly improved progression‑free survival and overall survival. Therapy options for R/R patients are driven by the patient, provider, and pharmacist. Novel drug targets CD38 and BCMA have significantly changed the MM landscape, and I look forward to potentially seeing patients cured in the future.

Your Thoughts?
Which MM treatment strategies would you like to know more about? I encourage you to answer the polling question and join the discussion in the comments box below.

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