Emerging Strategies to Manage Relapsed and/or Refractory Multiple Myeloma

Multiple myeloma (MM) remains a malignancy that is largely incurable but highly treatable. The prognosis for patients with MM has improved substantially over the past 2 decades with the introduction of therapeutics that have improved patient quality of life and prolonged overall survival (OS). However, nearly all patients with MM ultimately relapse, including those who have experienced a complete response to initial therapy.^1,2 Clinicians are challenged to determine how to treat relapsed and/or refractory MM (RRMM) by integrating previously administered therapies, patient comorbidities, potential treatment-related adverse events, putative benefit of emerging agents, financial toxicity, and patient wishes. In the current issue, Gahvari and Callander provide a comprehensive overview of the current approach to treating patients with RRMM with a focus on practical decision-making and the role of emerging therapeutic options.

At diagnosis, the genetic, epigenetic, metabolic, and cellular architecture of MM is complex and heterogeneous across patients. Somatic mutations, chromosomal translocations, deletions, and epigenetic modifications within each patient are evident and drive clonal evolution. Clonal diversity continuously evolves throughout the treatment continuum, and patients harbor multiple subclones.³ Disease progression leads to the emergence of drug resistance and eventually to relapsed/refractory disease.⁴ Relapsed and progressive MM acquires additional mutations and genetic alterations that render the disease more resistant, leading to progressively shorter durations of remission or response to each salvage therapy. The heterogeneity of myeloma cells within each patient highlights the need to simultaneously target multiple pathways.

Selection of an optimal strategy at relapse is more complicated because at least 10 classes of drugs have been FDA approved for MM, including alkylators, steroids, proteasome inhibitors, histone deacetylase inhibitors, nuclear export inhibitors, immunomodulatory drugs (IMIDs), monoclonal antibodies (mAbs), peptide-drug conjugates, chimeric antigen receptor (CAR) T cells, and bispecific T-cell engagers (BiTEs). With the exception of CAR T cells and BiTEs, these antimyeloma drugs have been combined in doublet, triplet, or quadruplet regimens and have been delivered, when appropriate, antecedent to autologous stem cell transplantation (ASCT).²

As Gahvari and Callander point out, there is currently no consensus treatment for patients with RRMM. While multiple regimens have been approved, none have been evaluated head to head, and individual registry trials have enrolled different patient populations with dissimilar treatment histories. Collectively, these studies demonstrate the benefit of a triplet over doublet regimen at relapse. Based upon results from the phase 3 POLLUX study (NCT02076009), the addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival (PFS) among patients with RRMM.⁵ For patients with newly diagnosed MM who were ineligible for ASCT, the risk of disease progression or death was significantly lower among those who received daratumumab, lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone.⁶ While daratumumab/lenalidomide/dexamethasone demonstrated superior OS, the study utilized an IMID-naive patient population. Regimens that combined mAbs—isatuximab/carfilzomib/dexamethasone, and daratumumab/carfilzomib/ dexamethasone—also demonstrated improved PFS in early-line relapsed disease. These regimens merit consideration in lenalidomide-refractory and mAb-naive patients. There are also limited data on the ideal or recommended sequence of mAbs in the RRMM setting. Isatuximab can directly induce apoptosis in myeloma cells, whereas daratumumab cannot induce cell death without being combined with cross-linking agents. Isatuximab also modulates CD38 enzymatic activity more effectively than daratumumab and may benefit daratumumab-refractory patients, whereas elotuzumab may have reduced efficacy following daratumumab-based therapy.

Patients who are actively relapsing after exposure to multiple lines of therapy (ie, late-line relapse) are likely to be at least triple-class refractory and penta-class exposed. Hence, historically, the likelihood of a response to the next line of therapy is low, regardless of the agent. Bendamustine, as monotherapy or combined with proteasome inhibitors or IMIDs, can elicit responses. Selinexor-based therapy has some benefit. Intensive regimens including PACE (cisplatin, doxorubicin, cyclophosphamide, and etoposide) or hyperfractionated cyclophosphamide-based regimens (with or without bortezomib or daratumumab) can serve as a temporizing bridge to the next line of therapy for aggressive relapses.

The scarcity of trials that have integrated the first salvage regimen into the assessment of frontline therapies to define optimal treatment sequencing in homogeneous or similar patient populations is also problematic. The management of RRMM is made even more complex with the advent of quadruplet therapy for transplant-eligible patients. The phase 2 GRIFFIN trial (NCT02874742) highlighted deeper and more sustained responses with upfront daratumumab plus lenalidomide, bortezomib, and dexamethasone than with lenalidomide, bortezomib, and dexamethasone alone.⁷ Earlier exposure to daratumumab will significantly affect the approach to second-line therapy.

Gahvari and Callander highlight exciting cellular and immunotherapeutics that constitute the next frontier for the management of RRMM. Real-world experience with FDA-approved regimens in specific populations should further guide therapy beyond subgroup analysis of registry trials. For example, the management of patients with primary refractory MM vs those being treated for relapsed MM after a treatment-free interval is of particular importance and may mandate a more cellular immunologic approach compared with current approaches. Also, integrating high-risk cytogenetics (eg, 1q gain) into treatment decisions has not been uniformly applied in trials or real-world practice. Two B-cell maturation antigen (BCMA)-directed CAR T-cell agents, idecabtagene vicleucel and ciltacabtagene autoleucel, have shown efficacy in patients previously challenged with 3 lines or more of therapy.^8,9 Teclistamab is a BiTE that targets CD3-positive T cells and BCMA-positive myeloma cells and is now FDA approved for patients who have received 3 prior lines of therapy.¹⁰ GC012F is an autologous BCMA-CD19 dual-targeting CAR T-cell therapy. In a phase 1 single-arm study, deep and durable responses as well as a favorable safety profile were reported with GC012F in patients with heavily pretreated RRMM. Based on these results, the safety and feasibility of GC012F were tested frontline for patients with newly diagnosed with MM who are high risk and transplant eligible.¹¹ Again, a favorable safety profile and high efficacy, with a 100% objective response rate and 100% minimal residual disease negativity, were reported.

Broader adoption of cellular therapies within the global immuno-oncology market requires careful consideration of costs, and unique toxicities, product quality standardization, and overcoming barriers to minimize production delays. It requires solving health care–related cost-to-value, coverage restrictions, and reimbursement issues. Finally, the broad administration of cellular therapies and the expansion of precision medicine approaches to treat MM will impact patient distribution to community oncologists, academic health centers, and specialized clinical centers that are designed to streamline CAR T-cell production, distribution, and administration. The past 2 decades have seen significant progress in MM, but the future therapeutic landscape may be even more promising, as more effective agents that overcome RRMM are developed and are better tolerated.

AFFILIATIONS:

James J. Driscoll, MD, PhD^1,2; and James Ignatz-Hoover, MD, PhD¹

¹University Hospitals, Cleveland Medical Center, Seidman Cancer Center,
Cleveland, OH, 44106.

²Case Comprehensive Cancer Center, Case Western Reserve School of Medicine, Cleveland, OH, 44106.

REFERENCES

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