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Where We Are in Myeloma
Where Are We Now With the Evolving Treatment Landscape for Multiple Myeloma?

Released: January 31, 2024

S. Vincent Rajkumar
S. Vincent Rajkumar, MD
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Key Takeaways
  • Standard-of-care treatment for newly diagnosed multiple myeloma includes triplet combinations of either bortezomib/lenalidomide/dexamethasone (VRd) or daratumumab/lenalidomide/dexamethasone (DaraRd), and the choice of using a quad-based induction therapy with the addition of daratumumab or isatuximab to standard VRd may depend on factors such as accessibility and financial considerations.
  • Multiple regimens combining immunomodulatory drugs, proteasome inhibitors, and CD38-targeted agents are available for treatment of relapsed multiple myeloma.
  • For patients with multiple myeloma that is refractory to all of these approaches, BCMA-directed CAR T-cell or bispecific antibody therapies may provide further disease control by directing interaction between T-cells and multiple myeloma cells.

In this commentary highlighting key points from a live webinar covering recent advances in multiple myeloma (MM) presented at ASH 2023, S. Vincent Rajkumar, MD, addresses the latest clinical findings in MM, including considerations for smoldering multiple myeloma (SMM); treatment decisions for newly diagnosed patients; and new data on therapy for relapsed/refractory (R/R) disease.

Considerations for Patients With High-Risk SMM
The primary factor guiding treatment of new patients with potential MM is whether they have MM-defining events based on the SLiM CRAB criteria, in which case they should always be treated, and patients who have low-risk SMM should be watched for evolving disease. The question of when to consider therapy for patients with SMM revolves around assessing risk factors and making informed decisions to optimize outcomes.

Approximately one third of patients with SMM have high-risk disease using current scoring systems, including the 2/20/20 classification (2 g or >20% free light chain ratio or >20% plasma cells), complemented by the presence of cytogenetic abnormalities or the Myeloma Working Group evaluation. However, other factors that can be used to assess risk include evolving SMM (M-protein increasing >0.3 g/dL in 6 months, hemoglobin decreasing >0.5 g/dL in 1 year, or free light chain ratio increasing or risk scoring increasing), high circulating plasma tumor cells, the level of Bence-Jones proteinuria, and/or a new focal lesion or increase in the existing focal lesion or progressive diffuse infiltration.

Once patients are deemed at high risk of progression, informed counseling becomes paramount, emphasizing shared decision-making for each patient’s course of action. Some may opt for interventions such as lenalidomide or lenalidomide/dexamethasone (Rd), which has shown a impressive reduction in the risk of progression in studies such as the Spanish and ECOG trials. Trials comparing milder treatments such as Rd with standard treatments for active MM such as daratumumab/Rd (DaraRd) or isatuximab/Rd are underway, with a focus on determining whether using a myeloma-like regimen yields better outcomes. Finally, there are clinical trials testing more intense strategies to test the hypothesis of whether early intervention in such a manner can be curative for a subset of patients.

Recent data presented at the ASH 2023 meeting discussed studies such as CENTAURUS, which explored daratumumab monotherapy in different cycles and demonstrated promising results with sustained overall response and prolonged progression-free survival (PFS). Other studies assessed treatment options such as carfilzomib/lenalidomide/dexamethasone (KRd) or daratumumab/VRd and showed promising efficacy in this population. Finally, one study explored the use of the BCMA-targeting bispecific antibody teclistamab and demonstrated a significant measurable residual disease (MRD) negativity. These studies provide a glimpse on potential new interventions being tested in high-risk patients with SMM. However, these are all early phase, nonrandomized studies with limited sample size. These treatments are investigational and should be used only in the context of clinical trials until we have data from randomized trials to determine safety and clinical benefit in this patient population.

Current Landscape for Patients With Newly Diagnosed MM
The decision-making process for patients with newly diagnosed, active MM involves a nuanced approach based on risk status, comorbidities, and patient preference. For high-risk patients with disease characterized by abnormalities such as t(4;14), t(14;16), t(14;20), del(17), 1q gain, and P53 mutations, more aggressive approaches should be considered. The identification of 2 or more abnormalities as double hit and 3 or more as triple hit significantly amplifies the risk.

For transplant-eligible patients, the PERSEUS and IsKia data from ASH 2023 suggest considering combining CD38 monoclonal antibodies, either daratumumab or isatuximab, with VRd or KRd as induction therapy. The PERSEUS trial incorporated daratumumab into the standard VRd regimen, demonstrating a significant improvement in PFS compared with VRd alone. Similarly, the IsKia trial assessed isatuximab plus KRd in a quadruplet regimen and reported impressive MRD negativity rates.

However, the choice of using a quad-based induction therapy instead of standard VRd may depend on factors such as accessibility and financial considerations, particularly because the cost of these regimens can be prohibitive in some regions. Of note, the overall survival advantage of daratumumab or isatuximab plus VRd vs VRd remains to be seen. With either induction regimen, the next step remains transplant and lenalidomide maintenance. Although some patients may opt to delay transplant, especially for standard-risk cases, high-risk patients necessitate a quadruplet induction, early transplant, and doublet maintenance with a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD).

For patients who are ineligible for transplant based on fitness and/or comorbidities, the choice between treatment with VRd and DaraRd is influenced by factors such as potential adverse events, ease of administration, and cost. Many prefer DaraRd based on current clinical trial results, despite the lack of direct trial comparisons. High-risk patients may benefit from VRd followed by bortezomib and lenalidomide maintenance rather than starting with DaraRd and then switching to a PI-based maintenance, because I think PIs are important in management of high-risk disease. There are limited data on the role of quadruplets in patients who are not candidates for stem cell transplantation.

The Evolving Landscape for Sequencing Therapy in R/R MM
When considering treatment options for patients with R/R MM, tailoring the approach based on the patient's treatment history and sensitivity to specific classes of therapy becomes pivotal. If a patient exhibits sensitivity to lenalidomide, a lenalidomide-based strategy remains a viable option for the first relapse. Similarly, if the patient is responsive to anti-CD38, incorporating an anti-CD38 regimen is recommended. This personalized framing of treatment decisions allows for optimizing outcomes and addressing the unique characteristics of each case.

For patients not refractory to lenalidomide or anti-CD38, the POLLUX trial demonstrates promising outcomes with DaraRd. In cases where a patient is refractory to daratumumab, evidence from the ASPIRE trial supports the use of KRd as a viable option for the first relapse. When patients become refractory to lenalidomide but have not yet received an anti-CD38 monoclonal antibody, options include daratumumab or isatuximab plus carfilzomib/dexamethasone (Kd) or pomalidomide/dexamethasone (Pd). In instances where patients are refractory to both lenalidomide and an anti-CD38 monoclonal antibody, treatment options such as carfilzomib/cyclophosphamide/dexamethasone (KCd) or carfilzomib/pomalidomide/dexamethasone (KPd) may be necessary.

As the complexity of refractoriness increases—such as when patients become refractory to IMiDs, PIs, and anti-CD38 therapies—adopting a BCMA-targeted strategy with either a CAR T-cell therapy or a bispecific antibody is crucial. However, in the United States, for example, these options currently are approved after progression on 4 prior lines of therapy. This creates a challenge, as patients may reach this stage within the first few lines of treatment. Advocacy efforts aim to redefine refractoriness based on patient response rather than a fixed number of treatment lines.

In regard to CAR T‑cell therapy, both idecabtagene vicleucel and ciltacabtagene autoleucel, the response rates are quite impressive, with a large portion of patients achieving a complete response, which is really key when it comes to CAR T‑cell therapy. There is now a third CAR T‑cell therapy with a human scFv that targets BCMA, equecabtagene autoleucel, but it is approved only in China. In addition, there are two BCMA-targeted bispecific antibodies, teclistamab and elranatamab, and one GPRC5D-targeted bispecific antibody, talquetamab, currently approved for R/R MM. With the availability of these agents, the next question we need to explore is the best options for sequencing all available therapies for individual patients and the optimal combinations of these agents. The other consideration with these novel agents is potential complications from these immunotherapeutics, including hematologic toxicity, cytokine-release syndrome, neurologic toxicity, and infection.

Looking ahead, for patients who eventually may become refractory to all available therapies—including alkylators, IMiDs, PIs, anti-CD38 therapies, and BCMA-targeted therapy—the main currently available options in clinical practice are talquetamab (an approved bispecific antibody that targets GPRC5D), venetoclax in patients who have t(11;14) myeloma, and other treatment options that have not been previously used such as bendamustine, selinexor, and elotuzumab. Innovative approaches and potential new advancements with GPRC5D-targeted CAR T-cell therapy, cevostamab (an investigational bispecific antibody targeting FcRH5), as well as next-generation cereblon modulators (CELMoDs) are currently being explored in clinical trials. This breadth of ongoing research reflects the continued commitment to exploring cutting-edge solutions for the most challenging cases in the MM treatment landscape.

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