Introduction

Multiple myeloma (MM) is a hematologic malignancy characterized by the abnormal proliferation of plasma cells within the bone marrow.^1,2 As the second most prevalent hematologic cancer, its incidence is on the rise, particularly in high-income countries.³ This increase is attributed to an aging population and advancements in diagnostic techniques that have refined the diagnostic criteria. In the United States alone, approximately 36,000 new cases are reported annually, with a median age of diagnosis around 69 years.⁴ Clinical manifestations often include bone pain, fatigue, renal dysfunction, hypercalcemia, anemia, and bone lesions.¹

Despite significant advancements in MM treatment over recent decades, the disease remains largely incurable. The 5-year survival rate hovers around 60%, although this can vary widely among newly diagnosed patients based on their individual cytogenetic and molecular risk profiles.⁴ Moreover, the innate resistance of MM to therapies implies that nearly all patients will eventually develop resistance to existing anti-myeloma drugs over the course of their disease.

The therapeutic management of MM has undergone a substantial evolution, now featuring complex combination regimens that incorporate various classes of drugs.⁵ These regimens aim not only to extend a patient’s life but also to improve their overall quality of life by deepening therapeutic responses and minimizing adverse effects. Standard front-line therapy typically comprises a 3- to 4-drug combination that includes a proteasome inhibitor (PI; either bortezomib or carfilzomib), an immunomodulatory agent (IMiD; lenalidomide), an anti-CD38 monoclonal antibody (mAb; daratumumab), and a steroid (dexamethasone). Patients with a suitable performance status often proceed to autologous stem cell transplantation, followed by maintenance therapy, usually with lenalidomide. Some may also receive consolidation therapy or additional maintenance agents. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for multiple myeloma recommend bortezomib/lenalidomide/dexamethasone (VRd) and carfilzomib/lenalidomide/dexamethasone (KRd) as preferred front-line regimens for transplant-eligible patients, with the addition of daratumumab as another recommended option.⁵ For patients who are not candidates for transplantation, the NCCN recommends VRd and daratumumab/lenalidomide/dexamethasone as preferred treatment regimens.⁵

The clinical and genetic heterogeneity of MM presents a formidable challenge, necessitating a tailored, multifaceted treatment approach based on individual patient characteristics and comorbidities. Despite these advancements, the elusive goal of achieving long-term disease control remains a significant hurdle for clinicians. Almost all patients will experience multiple relapses or become refractory to treatment.⁵ In this context, the critical role of clinical pharmacists cannot be overstated. Their deep understanding of the evolving landscape of MM directly informs medication management and patient counseling, making their involvement pivotal in optimizing therapy and critically evaluating emerging literature, especially given the disease's complex nature and the tendency for remission intervals to shorten with each subsequent relapse.

Relapsed/Refractory Multiple Myeloma

Progression in relapsed/refractory MM (RRMM) can be categorized through multiple lenses, offering a structured framework for comprehending and managing this intricate disease. Biochemical progression, also known as biochemical relapse, manifests as a gradual escalation in specific markers, including serum/urine M-protein, free light chain levels, and bone marrow plasma cell percentages.⁶ This form of progression is generally indolent, unfolding over an extended timeframe, in contrast to the more acute clinical relapses.⁷

Clinical relapse typically manifests more acutely and aggressively.⁷ Patients may display new or exacerbated symptoms that align with the CRAB (hypercalcemia, renal dysfunction, anemia, or bone disease) criteria, soft tissue plasmacytomas, or hyperviscosity syndrome linked to elevated serum M-protein levels. The International Myeloma Working Group provides further granularity by delineating specific criteria for defining both relapsed and refractory disease states.⁶

The therapeutic management of RRMM necessitates a meticulous evaluation of a plethora of factors, encompassing both disease-specific characteristics and individual patient variables such as age, frailty, treatment history, drug-class refractory status, and availability of clinical trials. Triplet regimens are generally favored over doublet combinations; however, the optimal sequencing or selection of treatment regimens must also account for additional variables, including performance status, comorbidities, rate of disease progression, renal function, bone disease status, cytogenetic profiles, prior therapies, patient preferences, caregiver accessibility, logistical considerations, and healthcare costs.⁵

This multifaceted landscape underscores the need for a nuanced, patient-centric approach in the management of RRMM. The complexity of treatment decisions and the heterogeneity in disease presentation accentuate the imperative for individualized care, tailored to the unique needs and characteristics of each patient. Within this intricate framework, pharmacists assume a pivotal role in therapy optimization. Their proficiency in staying abreast of the latest literature, formulating rational drug combinations, managing drug interactions and side effects, and providing patient counseling is indispensable for crafting a treatment plan that aligns with each patient's unique medical profile. By collaborating closely with other healthcare professionals, pharmacists enrich a multidisciplinary approach that augments therapeutic outcomes, bolsters treatment adherence, and fosters a comprehensive understanding of the patient's needs in the management of RRMM.

Agents Used in RRMM for Early Relapses (1-3 Prior Therapies)

Immunomodulatory Agents

Lenalidomide and pomalidomide are the primary IMiDs used in clinical practice. Thalidomide, the pioneering IMiD, has seen diminished use due to its associated neuropathy risks and comparatively lesser efficacy than its newer counterparts.⁵

Patients with RRMM who have not been previously treated with lenalidomide may benefit from novel combinations containing lenalidomide, such as those containing carfilzomib, daratumumab, ixazomib, or elotuzumab, in combination with dexamethasone.⁵ Patients who previously received lenalidomide in front-line induction may still be "lenalidomide sensitive"; however, the increased use of lenalidomide as maintenance obscures the picture of who may continue to benefit from lenalidomide in the relapsed/refractory setting. Resistance is acknowledged when there is no therapeutic response or when the disease rapidly progresses after administration of an optimal dose of lenalidomide. In such cases, alternative treatments, such as pomalidomide, are considered a viable option (Figures 1 and 2).⁵

Pomalidomide was incorporated into clinical practice on the basis of the MM-002 phase 2 trial, which assessed patients previously treated with lenalidomide and bortezomib.^8,9 The trial evaluated the efficacy of pomalidomide as a monotherapy and in combination with low-dose dexamethasone. Subsequently, the MM-003 (NIMBUS) phase 3 trial demonstrated superior outcomes for the pomalidomide/dexamethasone combination compared with high-dose dexamethasone monotherapy.¹⁰ Specifically, the trial reported an overall response rate (ORR) of 30% for the pomalidomide/dexamethasone combination, as opposed to 9% for high-dose dexamethasone. Moreover, progression-free survival (PFS) was 4 months for the combination therapy, compared with 1.9 months for the monotherapy, and overall survival (OS) was 12 months versus 8 months. It is crucial to note that an overwhelming majority—approximately 93%—of patients in this study exhibited resistance to lenalidomide. Subsequent investigations employing triplet combinations such as bortezomib/dexamethasone, carfilzomib/dexamethasone, cyclophosphamide/dexamethasone, and ixazomib/dexamethasone, have corroborated the efficacy of pomalidomide.^11-14 Currently, the US Food and Drug Administration (FDA) has approved the use of pomalidomide in combination with dexamethasone, daratumumab/dexamethasone, isatuximab/dexamethasone, or elotuzumab/dexamethasone for patients who have received at least 2 prior lines of therapy, including lenalidomide and a PI.^9,15 In clinical practice, pomalidomide serves as a cornerstone agent in the treatment of RRMM and is frequently combined with various classes of anti-myeloma agents.⁵

Proteasome Inhibitors

Carfilzomib, a second-generation PI, initially gained approval for the treatment of RRMM.¹⁶ Its adoption in clinical practice has been significantly influenced by key clinical trials such as ENDEAVOR (carfilzomib in combination with dexamethasone) and ASPIRE (carfilzomib combined with lenalidomide and dexamethasone).^17-19 Subsequent research has focused on identifying the most effective dosing schedule for carfilzomib. The CHAMPION-1 trial was a seminal study that evaluated the efficacy of a once-weekly dosing regimen of carfilzomib in conjunction with dexamethasone.²⁰ This trial not only validated the feasibility of a weekly dosing schedule but also established a maximum tolerated dose of 70 mg/m² per week. Further substantiating the merits of this approach, the phase 3 ARROW trial demonstrated that patients on a once-weekly dosing schedule experienced a significantly longer PFS of 11.2 months, compared with 7.6 months in the twice-weekly group (hazard ratio [HR] 0.69; 95% CI: 0.51-0.83; P = .0029).²¹ Moreover, the ORR was markedly higher in the once-weekly group, at 62.9%, versus 40.8% in the twice-weekly group (odds ratio 2.49; 95% CI: 1.72-3.6; P = .0001). While the optimal carfilzomib dosage may vary depending on the specific combination therapy, patient compliance, and individual tolerance, accumulating evidence increasingly supports the adoption of a once-weekly dosing regimen.

Ixazomib, an orally administered PI, received approval for use with lenalidomide/dexamethasone for patients diagnosed with RRMM.²² This endorsement was validated by the TOURMALINE MM1 trial, a phase 3, double-blind, randomized, placebo-controlled study.²³ The trial aimed to assess the efficacy of ixazomib when combined with lenalidomide/dexamethasone, as compared with lenalidomide/dexamethasone alone, in treating RRMM. Notably, the median PFS exhibited a marked improvement in the ixazomib cohort, registering at 20.6 months, as opposed to 14.7 months in the control group. In light of these findings, the NCCN Guidelines have designated the ixazomib/lenalidomide/dexamethasone regimen as a Category 1 preferred treatment option for RRMM.⁵

Monoclonal Antibodies

mAbs targeting specific antigens on the surface of plasma cells have been shown to induce cell death through a range of mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and direct cell apoptosis. Importantly, mAbs such as daratumumab and isatuximab, which target the CD38 glycoprotein, as well as elotuzumab, which targets the signaling lymphocyte activation molecule family-7 (SLAMF7), have been successfully integrated into clinical practice.^15,24,25

Daratumumab is a mAb that specifically targets the CD38 transmembrane glycoprotein, a molecule predominantly overexpressed on plasma cells. The drug's extensive clinical adoption can be largely attributed to its robust efficacy coupled with a favorable toxicity profile. In the relapsed/refractory setting, pivotal phase 3 trials—namely, CASTOR, POLLUX, APOLLO, and CANDOR—have evaluated the impact of adding daratumumab to various standard regimens: bortezomib/dexamethasone, lenalidomide/dexamethasone, pomalidomide/dexamethasone, and carfilzomib/dexamethasone, respectively.^24,26-32 Across these studies, the incorporation of daratumumab consistently led to improvements in ORR, PFS, and OS, although the APOLLO trial did not reach statistical significance. These compelling results, bolstered by earlier phase 2 data, paved the way for the FDA's approval of daratumumab, either as a monotherapy or in combination with the aforementioned regimens.³³ Consequently, in clinical practice, daratumumab is frequently integrated into a diverse array of therapeutic combinations. Despite the success of daratumumab as an intravenous (IV) infusion, it necessitates lengthy infusions and commonly results in infusion-related reactions. The COLUMBA study aimed to determine whether subcutaneous (SC) daratumumab could offer a quicker, safer, and equally effective route of administration. This study enrolled 522 patients and revealed that the overall response rates were comparable between IV and SC, and the predefined non-inferiority criteria were met. SC daratumumab is now FDA approved and is used for the same indications as the IV formulation.³⁴

Isatuximab is a chimeric mAb that targets CD38. Isatuximab is distinguished from daratumumab by its ability to bind to a unique epitope on the CD38 molecule.¹⁵ It is approved for use in combination with pomalidomide/dexamethasone in patients who have had at least 2 prior treatments, including lenalidomide and a PI, and carfilzomib/dexamethasone in patients who have had at least 1 prior treatment; its efficacy has been demonstrated in multiple clinical trials.¹⁵ In particular, the phase 3 ICARIA trial examined the potential of combining pomalidomide/dexamethasone with isatuximab, demonstrating a significant improvement in PFS—11.5 months for isatuximab versus 6.5 months for placebo (P = .001). In addition, OS was improved at 24.6 months with isatuximab versus 17.7 months without (P = .028).^35,36 Additionally, the IKEMA trial was a phase 3, randomized trial that compared carfilzomib/dexamethasone with or without isatuximab. PFS was improved with the addition of isatuximab to 35.7 months versus 19.2 months (HR 0.58; 95% CI: 0.42-0.79).^37,38 For some centers, isatuximab has been therapeutically equated to daratumumab and placed as a preferred formulary agent in indications where daratumumab has been approved. Given this off-label use, ensuring insurance prior authorizations are completed before administration is important. Currently, isatuximab is only approved for IV administration, but studies are underway to evaluate its SC formulation.³⁹ Isatuximab also is being evaluated in the front-line setting in combinations where daratumumab is already being used. Additional data should be available soon to support more substitutions between daratumumab and isatuximab in the front-line setting. For example, trials focusing on newly diagnosed patients with MM who are not candidates for transplant have studied combinations of isatuximab with VRd or with bortezomib/cyclophosphamide/dexamethasone, yielding striking ORRs of 98.6% and 93.3%, respectively.^40-43 Moreover, data from the GMMG-HD7 clinical trial corroborated that the incorporation of isatuximab into the VRd regimen led to a significant enhancement in rates of minimal residual disease (MRD) negativity at 10^-5 prior to autologous stem cell transplantation.⁴⁴ Lastly, an analysis from the GMMG-CONCEPT trial demonstrated a PFS rate of 75.5% at 24 months among high-risk newly diagnosed patients treated with a regimen combining isatuximab and KRd.⁴⁵ Cumulatively, these findings support the continuation of isatuximab studies in front-line MM, such as the phase 3 IMROZ study (isatuximab-VRd vs VRd).

Elotuzumab is a mAb that binds to the SLAMF7 receptor found on plasma cells. Its mechanism of action relies on the simultaneous binding of the plasma cell SLAMF7 receptor and the CD16 receptor on natural killer (NK) cells through its Fc receptor. The complex binding mechanism facilitates communication between MM cells and NK cells, resulting in the activation of NK cells to eradicate the malignant MM cells through processes such as antibody-dependent cellular cytotoxicity.²⁵ The preliminary clinical assessments of elotuzumab indicated a modest level of efficacy. Nevertheless, when administered in combination with lenalidomide or pomalidomide, it yielded synergistic results. The aforementioned observation was substantiated by the ELOQUENT-2 phase 3 clinical trial, which sought to evaluate the effectiveness of the combination therapy involving lenalidomide/dexamethasone with elotuzumab in RRMM.^46,47 Concurrently, the ELOQUENT-3 phase 2 clinical trial investigated the efficacy of co-administering elotuzumab and pomalidomide/dexamethasone in patients who demonstrated resistance to lenalidomide and a PI.⁴⁸ As a result of these trials, elotuzumab gained approvals in combination with both lenalidomide/dexamethasone and pomalidomide/dexamethasone.²⁵

Other Novel Agents for RRMM

Selinexor functions as a nuclear exportin-1 inhibitor, playing a critical role by interrupting the nuclear-to-cytoplasmic trafficking that is vital for the viability of MM cells.⁴⁹ In the pivotal phase 2b STORM trial, the combination of selinexor/dexamethasone was administered to patients who had received extensive prior treatments. A substantial number of these patients were resistant to 3 different classes of drugs, and more than half exhibited high-risk genetic factors. The study revealed an ORR of 26% and an average OS of 8.6 months.⁵⁰ These results led to the FDA approval of the selinexor/dexamethasone combination.⁴⁹ The phase 3 BOSTON trial, which combined selinexor with bortezomib/dexamethasone and focused on patients who had undergone 1 to 3 previous treatments, reported a median PFS of 14 months as opposed to 9.5 months without selinexor.⁵¹ This study led to the approval of selinexor with bortezomib/dexamethasone for those with a minimum of 1 previous therapy and also demonstrated that a once-weekly dosing schedule of selinexor may be better tolerated than twice-weekly dosing.

Venetoclax

Venetoclax inhibits the B-cell lymphoma-2 (BCL-2) protein, an anti-apoptotic protein.⁵² This protein tends to be overexpressed in patients with MM, more so among those showcasing the t(11;14) chromosome translocation. By inhibiting BCL-2, venetoclax instigates cell death. The phase 3 BELLINI trial evaluated the efficacy and safety of venetoclax in combination with bortezomib/dexamethasone in patients with relapsed or refractory MM.⁵³ The study found that the venetoclax arm had a significantly longer PFS of 23.4 months compared with 11.4 months in the placebo arm. Additionally, the venetoclax group demonstrated higher ORRs and complete response (CR) rates. However, the venetoclax arm also showed a higher mortality rate, with a median OS of 45.6 months versus 51.4 months in the placebo group. The trial underscores the need for a balanced assessment of the benefits and risks of venetoclax in this patient population. In particular, venetoclax is recommended to be considered in patients with t(11;14) translocation, as this subgroup seemed to derive most benefit from venetoclax in the BELLINI trial.

Agents Used in RRMM for Late Relapses (After ≥4 Prior Therapies, Including an Anti-CD38 mAb, a PI, and an IMiD)

Chimeric Antigen Receptor-T Cell Therapy

Chimeric antigen receptor (CAR)-T cells represent a class of immune cells that have been genetically engineered to target specific cancer cells. These cells are composed of multiple components: an extracellular domain that binds to the target antigen, a hinge or spacer region, a transmembrane domain, and 1 or more intracellular signaling domains. Harvested from the patient, these T cells undergo genetic modification and expansion in a controlled laboratory environment. Upon reinfusion into the patient, the CAR-T cells become activated, secreting cytokines and cytotoxic granules that trigger apoptosis in cancer cells. Notably, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are FDA-approved CAR-T cell therapies specifically designed to target the B-cell maturation antigen (BCMA), which is expressed on the surface of MM cells.^54,55

The phase 2 KarMMa study evaluated the efficacy of ide-cel in a cohort of 128 patients diagnosed with RRMM. The population was heavily pretreated and were generally resistant to IMiDs, PIs, and mAbs targeting CD38. The study revealed a noteworthy ORR of 73%, with 33% of participants achieving a very good partial response, 26% of participants achieving MRD negativity, and a median PFS of 8.8 months.⁵⁶

Subsequently, KarMMa-3, a phase 3 open-label randomized controlled trial with 386 participants who had received 2 to 4 prior therapy lines for RRMM, compared ide-cel to investigator's choice standard of care (SOC). The SOC arm encompassed daratumumab/pomalidomide/dexamethasone, daratumumab/bortezomib/dexamethasone, carfilzomib/dexamethasone, elotuzumab/pomalidomide/dexamethasone, and ixazomib/lenalidomide/dexamethasone. Notably, ide-cel demonstrated improved responses in comparison with SOC, with an ORR of 71% versus 42%, and a substantial increase in CR (39% vs 5%). Importantly, ide-cel led to an enhanced median PFS compared with SOC, measuring 13.3 months versus 4.4 months (P < .001).⁵⁷

The efficacy of cilta-cel was investigated in the CARTITUDE-1 trial, a phase 2 multicenter study involving 97 patients who received CAR-T cells with a median of 6 prior therapy lines. The trial achieved an ORR of 97%, with a stringent CR in 67% of patients. The median PFS was not reached during a median follow-up of 12.4 months, and the 12-month PFS rate reached 77%.⁵⁸

In the CARTITUDE-4 trial, a phase 3 open-label randomized controlled study with 419 participants with lenalidomide-refractory MM after 1 to 3 prior therapies, cilta-cel outperformed SOC. The cilta-cel group demonstrated superior responses compared with SOC, with an ORR of 84.6% versus 67.3% and a significantly higher rate of CR (73.1% vs 21.8%). The median PFS was notably improved with cilta-cel compared with SOC at a median follow-up of 15.9 months (not reached vs 11.8 months; P < .001). Additionally, the 12-month PFS rates showed a marked improvement with cilta-cel at 75.9% compared with SOC at 48.6%.⁵⁹

Both ide-cel and cilta-cel are FDA approved for RRMM in patients who have received 4 or more prior lines of therapy, including an IMiD, a PI, and a CD-38 mAb. Due to the risk for cytopenias, cytokine release syndrome (CRS), and neurotoxicity (ICANS), these therapies can only be administered at specialized centers and under a Risk Evaluation and Mitigation Strategy program.^54,55

Bispecific Antibodies

Bispecific antibodies (BsAbs) are a unique class of mAbs that can simultaneously recognize a designated target on the membrane of MM cells and a second target on effector cells. This dual recognition creates an immunologic bridge that facilitates the destruction of cancerous cells.^60-62 Currently, the majority of BsAbs undergoing clinical evaluation are designed to specifically bind to the T-cell–specific CD3 antigen. Three BsAbs have been approved: teclistamab, talquetamab, and elranatamab.

Initial findings from the phase 1/2 evaluation of the MajesTEC-1 study paved the way for the clinical approval of teclistamab (BCMAxCD3) as a standalone treatment.⁶³ This study included 165 participants, each of whom had previously received at least 3 prior therapies, with an average of 5 prior therapies. Treatment with teclistamab resulted in an ORR of 63%, with a notable 39.4% achieving a CR and 26.7% demonstrating MRD negativity. The population was heavily pretreated, with 77% of patients demonstrating resistance across all 3 drug classes—a phenomenon known as triple-class refractory. Despite this, the median duration of response (DOR) was 18.4 months and median PFS was 11.3 months.⁶² Due to its toxicity profile, which includes CRS, teclistamab requires hospitalization for the first 3 doses.

Elranatamab is a BsAb BCMA–directed CD3 T-cell engager approved for the treatment of adult patients with RRMM who have received at least 4 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 mAb.⁶⁴ The approval was based on the results of the single-arm phase 2 MagnetisMM-3 trial. The ORR in the 97 patients receiving the recommended dose was 57.7%. The DOR was not reached but at 6 months the DOR was 90.4% and 82.3% at 9 months.⁶¹ Due to its toxicity profile, which includes CRS, elranatamab requires hospitalization for the first 2 doses.

In contrast, talquetamab is a BsAb directed against the G protein–coupled receptor, family C, group 5, member D (GPRC5D) on MM cells and CD3 on T cells.⁶⁵ The phase 1 MonumenTAL-1 study assessed the efficacy and safety of talquetamab as a monotherapy in 232 heavily pre-treated participants. These participants had a median of 6 prior treatment lines; 79% of the patients had triple-class refractory disease, 30% had penta-drug refractory disease, and 87% had disease that was refractory to the last line of therapy. After a median of 11.7 months of observation for the 405-μg/kg weekly dose and 4.2 months of observation for the 800-μg/kg biweekly dose, the ORR was 70% and 64%, respectively. The median DORs for the respective dosages were 10.2 months and 7.8 months.⁶⁰ Due to its toxicity profile, which includes CRS, talquetamab requires hospitalization for the first 3 doses for its weekly schedule and the first 4 doses for its biweekly schedule.

These findings highlight the therapeutic potential of BsAbs, specifically for extensively treated patients with RRMM, marking a new direction in the management of MM (Figure 3).⁵

Social Determinants of Health in Multiple Myeloma Treatment

Social determinants of health play a pivotal role in shaping the conditions in which individuals are born, grow, and age. For patients with MM, these factors, rooted in economic and resource dynamics, profoundly affect health disparities and outcomes.^66,67 Recognizing the role of social determinants of health is paramount, especially for pharmacists working in diverse settings including community-based facilities, clinical oncology, and managed care, as it offers them a clearer lens through which they can provide more targeted care.

Historical and systemic barriers, coupled with enduring mistrust stemming from past injustices, have rendered optimal healthcare inaccessible to many Black patients. Despite receiving diagnoses at a younger age or an earlier stage (i.e., high prevalence of monoclonal gammopathy of unknown significance) and having a lower incidence of some high-risk cytogenetics, Black patients encounter limited access to cutting-edge treatments, ultimately leading to diminished survival rates.^66-71 This situation starkly highlights the disparities in care they experience. Financial challenges further compound these issues.^72,73 As frontline healthcare professionals, pharmacists regularly observe the detrimental effects of financial challenges on therapeutic choices, which manifest in missed medication doses, deferred appointments, and curtailed access to both primary treatments and crucial supportive care. Another significant concern is the underrepresentation of Black patients in MM clinical trials. While they constitute almost 20% of the MM population based on the 2016-2020 Surveillance, Epidemiology, and End Results data, their representation in MM clinical trials is a mere 4.5%.⁷⁴ This disparity impacts access to novel therapies for Black communities, fails to provide a holistic understanding of MM biology in Black patients, and limits the scope of research.

A multipronged approach is vital to address these disparities in MM care. Pharmacists, being one of the most trusted healthcare providers, can play a crucial role by championing increased participation of Black patients in clinical trials, partnering with inclusive research institutions, and employing tools such as medication therapy management to enhance patient support. Cost transparency in MM treatments, culturally competent patient interactions, and ensuring broader accessibility to cutting-edge therapies such as triplet or quad novel combinations, BsAbs, and CAR-T cell therapy are imperative. With the increasing popularity of these advanced treatments, the pressing need to address their restricted availability, particularly in underserved regions, becomes evident. Presently, a substantial disparity exists in comprehending and addressing the toxicities linked with CAR-T and BsAbs—specifically CRS and neurotoxicity—in underserved areas. In this context, pharmacists are well-positioned to take the lead in initiating educational initiatives and forging partnerships to rectify these gaps. Through these endeavors, pharmacists can play a pivotal role in advocating for fair and impartial access to healthcare for every individual.

Considerations for Oncology and Managed Care Pharmacists

Patient Education

Pharmacists play an essential role in educating patients about their disease and treatment. This includes explaining the nature of RRMM, the rationale behind each prescribed medication, the expected therapeutic outcomes, the potential side effects, and the importance of medication adherence. Clear instructions on how and when to take the medications, as well as addressing any patient concerns or misconceptions, can greatly influence treatment success.

Recognition and Monitoring of Adverse Events

Oncology pharmacists should routinely assess and monitor patients for potential side effects associated with MM treatments. Early recognition can lead to timely intervention, whether that be dose modification, discontinuation, or supportive care measures. Patients should also be educated on recognizing signs of adverse events and promptly reporting them. A key toxicity pharmacists should know about is the risk of thromboembolic events, or venous thromboembolism (VTE), particularly with IMiDs. The IMPEDE VTE and SAVED scores guide prophylactic therapy: patients with low risk (≤3 points by IMPEDE VTE or <2 points by SAVED) are administered aspirin, while those with higher risk are prescribed treatments such as low–molecular-weight heparin, rivaroxaban, or warfarin.

Another concern is the potential for herpes simplex and varicella zoster infections with agents such as PIs, daratumumab, isatuximab, BsAbs, and CAR-T cells. To mitigate this risk, patients are prescribed antimicrobial prophylaxis with acyclovir or valacyclovir. For protection against Pneumocystis jirovecii infections, especially when receiving BsAbs and CAR-T therapies, patients may be given trimethoprim/sulfamethoxazole or alternatives such as pentamidine.

Addressing CRS and ICANS is also paramount. CRS management varies based on its severity and may include treatments such as tocilizumab, dexamethasone, and intensive care unit admission (Table 1).⁷⁵ ICANS requires a tiered approach with supportive care for mild cases and interventions such as intensive care unit admission and high-dose steroids for more severe manifestations (Table 2).⁷⁵

Collaborative efforts between healthcare providers, with the expertise of pharmacists, ensure that toxicities are managed effectively to provide optimal patient care. Tables 3 and 4 outline the most common adverse events of agents used in RRMM and provide more specific details of how to prevent or manage them.^{5,9,15,16,22,24,25,49,52,54,55,63-65,76,77}

Identifying and Managing Drug-Drug and Drug-Food Interactions

Given the intricate medication regimens of patients with MM, there is a high potential for drug-drug interactions. Pharmacists must thoroughly review the patient’s medication list, including over-the-counter and herbal supplements, to identify any potential interactions. Similarly, they should guide patients on any drug-food interactions, such as certain medications needing to be taken on an empty stomach or with food.

Assisting in Medication Access for Patients

Many treatments for RRMM are expensive. Pharmacists should lead teams consisting of technicians or financial access coordinators who can help patients access these medications by liaising with patient assistance programs, exploring generic or alternative drug options, or advocating for drug coverage through insurance plans.

Prior Authorizations

Pharmacists play a pivotal role in navigating the intricate labyrinth of obtaining prior authorizations for medications, a process that is often fraught with complexity. This entails meticulously ensuring that all requisite documentation is submitted to insurance providers to guarantee coverage for prescribed therapeutic interventions. Within this labor-intensive framework, pharmacy technicians and financial access coordinators serve as indispensable allies. Their specialized skills in managing administrative tasks enable pharmacists to concentrate on areas requiring their unique expertise. By streamlining the paperwork burden, this collaborative approach not only enhances operational efficiency but also mitigates the risk of pharmacist burnout.

Formulary and Clinical Pathway Development

Managed care pharmacists frequently assume a critical role in the formulation of formularies and the development of clinical pathways, aimed at optimizing patient care. This responsibility entails a rigorous review of the most current clinical evidence to identify therapies that are both efficacious and cost-effective for inclusion in treatment protocols. The timeliness of these reviews is paramount to prevent any delays in patients receiving life-extending medications. In scenarios where Pharmacy and Therapeutics committee approval might introduce delays in medication access, pre-formulary review mechanisms and processes serve as vital safeguards. These procedures ensure that patients can safely receive non-formulary approved medications while awaiting determinations from the experts engaged in formulary evaluations.

Provider Consultations

Pharmacists should actively collaborate with the broader healthcare team, offering their expertise in drug therapy optimization. Regular consultations can ensure that the entire care team is aligned in its approach, and that the best therapeutic decisions are made based on the patient’s unique needs and circumstances.

Summary

The field of hematology-oncology continues to undergo a transformative phase, particularly in the management of RRMM. A surge of innovative therapeutic agents, including mAbs, BsAbs, CAR-T cells, and other novel agents, has not only enriched our treatment options but also markedly improved patient outcomes. While these therapies extend patient survival, they also present unique challenges that require specialized management. Pharmacists serve as integral members of the healthcare team, working to maintain or improve patients' quality of life during treatment. This harmonious melding of innovation and patient care underscores the multifaceted role that oncology and managed care pharmacists play in RRMM management. Acting as essential intermediaries between complex pharmacologic regimens and patient experiences, their expertise ensures that care is both clinically rigorous and patient-centric, thereby enhancing accessibility.

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