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Treatment Landscape in Myeloma
Making Sense of the Evolving Treatment Landscape for Multiple Myeloma

Released: March 02, 2023

Expiration: February 29, 2024

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Key Takeaways
  • Standard-of-care treatment for newly diagnosed multiple myeloma includes triplet combinations of either bortezomib/lenaliomide/dexamethasone (VRd) or daratumumab/lenalidomide/dexamethasone (DRd). A quadruplet regimen containing a CD38-targeted agent (daratumumab or isatuximab) plus VRd can be considered in selected patients.
  • Multiple regimens combining immunomodulatory drugs, proteasome inhibitors, and CD38-targeted agents are available for treatment of relapsed myeloma. For patients with 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 myeloma cells.
  • Additional novel targets in early clinical development may continue to extend treatment options for patients after exposure to multiple classes of therapeutic agents.

In this commentary highlighting key points from a live event at ASH 2022, S. Vincent Rajkumar, MD, addresses recent clinical findings in multiple myeloma (MM), including considerations for smoldering MM, treatment decisions for newly diagnosed patients, and the latest data on therapy for relapsed/refractory (R/R) disease.

When to Start Treatment for Potential Newly Diagnosed Active MM or High-Risk Smoldering MM
The primary factor guiding treatment of new patients with potential MM is whether they have MM-defining events, in which case they should always be treated. However, a patient without MM-defining events who is considered to have smoldering MM should begin therapy only if the patient is considered to be at high risk of progression. Risk has primarily been assessed with the 20/2/20 stratification model (Mayo 2018) or the International Myeloma Working Group scoring system, which incorporates cytogenetics as well. In addition to these scoring tools, it is important to consider whether a patient’s disease is continuing to evolve (defined as an increase in 2 consecutive measurements within 6 months) and remember that we should consider the overall spectrum of each patient’s disease to determine optimal management approaches.

Approximately one third of patients with smoldering MM are high risk and should be considered for treatment with lenalidomide with or without dexamethasone for a duration of 2 years, or enrolled on a clinical trial. Some patients with very high risk of disease progression within 2 years (80%-90%) also can be considered for standard first-line MM therapy with a triplet-based induction followed by transplant. At ASH 2022, promising data were seen in the GEM-CESAR trial with carfilzomib/lenalidomide/dexamethasone (KRd) followed by transplant, KRd consolidation, and lenalidomide maintenance and the ASCENT trial with daratumumab plus KRd given for a fixed duration of 2 years.

Optimal management of patients with smoldering MM is a very important and controversial area, and all patients with smoldering MM should be considered for enrollment on clinical trials.

Newly Diagnosed MM: Transplant Eligible
For transplant-eligible patients with newly diagnosed standard-risk MM, recommended treatment regimens include induction with bortezomib/lenalidomide/dexamethasone (VRd) or daratumumab/lenalidomide/dexamethasone (DRd). Daratumumab/bortezomib/lenalidomide/dexamethasone (dara-VRd) also may be considered based on the results of the phase II GRIFFIN trial, although the evidence for this regimen may be strengthened by upcoming results from the phase III PERSEUS trial. Regardless of induction regimen, the preferred approach for patients with standard-risk MM consists of autologous transplantation after 4-6 cycles of induction therapy followed by lenalidomide maintenance. However, selected patients who respond well to induction treatment have the alternative option to continue with a few more cycles of induction therapy after stem cell mobilization and delay transplantation until the first relapse. Data from the phase III DETERMINATION trial and phase III IFM 2009 trial have shown that overall survival is similar whether transplant is performed early or at the first relapse.

For high-risk patients, however, the standard of care most experts recommend is quadruplet induction therapy with dara-VRd, followed by transplant and maintenance with a proteasome inhibitor (bortezomib or carfilzomib) in addition to lenalidomide. For these patients, delayed transplantation is not recommended.

Newly Diagnosed MM: Transplant Ineligible
For standard-risk patients with newly diagnosed MM who are not transplant eligible, standard treatment options include VRd for 8-9 cycles followed by lenalidomide maintenance or DRd until progression. These regimens were evaluated in separate trials, so their respective outcomes cannot be compared directly, but both are reasonable options. The major differentiating factor is the recommended duration of treatments, with VRd having the advantage of a shorter treatment duration with the combination followed only by lenalidomide maintenance vs DRd continuous treatment with both daratumumab and lenalidomide with DRd.  

Transplant-ineligible patients with high-risk MM should be treated in the same manner as standard-risk patients, except that those who receive VRd should continue both lenalidomide and bortezomib  as maintenance therapy. Deciding which of the standard options is best depends on patient preference, as well as cost of therapy and access to the different agents.

Considerations for Treatment of MM at First Relapse
At first relapse, 2 questions arise: When should you start treatment, and what regimen should you choose? For patients with clinical progression, whether it is symptomatic or asymptomatic (eg, progressive anemia and new bone lesions), new therapy should begin immediately. In circumstances of biochemical progression without any clinical factors, any significant paraprotein relapse should signal the need for treatment. A significant paraprotein relapse is defined as a doubling of the M-spike in 2 consecutive measurements separated by ≤2 months or increase in serum M protein ≥1 g/dL, urinary M protein ≥500 mg/24 hours, or involved free light chain level ≥20 mg/dL. For patients with high-risk MM, any level of relapse may be enough to justify treatment.

For the question of what treatment is optimal, several options are available for patients at first or even second relapse. The key consideration in this choice is selecting at least 2 agents to which the patient is not refractory for combination therapy.

Overall, the treatment goal is to achieve the best possible response after the first relapse. For patients who are not refractory to daratumumab, a combination with a CD38-targeted antibody—either daratumumab or isatuximab—generally is recommended. These CD38-targeted antibodies most often are combined with either lenalidomide/dexamethasone, pomalidomide/dexamethasone or carfilzomib/dexamethasone in the R/R setting based on data from the POLLUX, APOLLO, ICARIA, CANDOR, and IKEMA trials. Because the efficacy and safety are similar for daratumumab or isatuximab combinations, the decision often is based on administration considerations, availability, and cost for each patient. In patients whose disease is refractory to lenalidomide and CD38-targeted antibodies, regimens such as carfilzomib/pomalidomide/dexamethasone (KPd) or carfilzomib/cyclophosphamide/dexamethasone (KCd) are preferred options at first relapse.

Management of Late-Line Relapse in MM
Although we now have various new strategies to help achieve deep and durable responses in early lines of therapy for MM, patients do eventually experience multiple relapses and become triple class—or quadruple class—refractory. Treatment strategies in this setting require consideration of some of the questions already addressed: What treatments have patients received, how long ago did they receive those therapies, and how did they respond to them? In addition, performance status, age, and comorbidities must be taken into account, as at any stage of disease, but residual toxicities from prior therapies also may be present in patients with multiple previous lines of therapy.

An elegant new approach approved for treating MM harnesses the power of anti-MM T‑cells through the use of either CAR T-cell therapy or bispecific antibodies. CAR T-cell therapies are developed by modifying a T-cell receptor to recognize an antigen present on tumor cells. Currently, 2 CAR T-cell therapies targeting B-cell maturation antigen (BCMA) on MM cells are approved for the treatment of MM: idecabtagene vicleucel and ciltacabtagene autoleucel. Bispecific antibodies, or T-cell engagers, are an engineered antibody structure with 2 specificities—1 targeting CD3 on a T-cell and 1 targeting an antigen of interest on the tumor cell—to bring T-cells and tumor cells into close proximity, leading to immunologic synapse formation and tumor cell death. Currently, 1 bispecific antibody targeting BCMA, teclistamab, is approved for MM, and several other bispecific antibodies targeting BCMA or other MM-specific antigens are being evaluated in ongoing clinical trials. The current FDA indication for both the CAR T-cell therapies and the bispecific antibody is for patients with R/R MM who have received ≥4 prior lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

Both CAR T-cell and bispecific antibody therapies have shown very high response rates with >1‑year durability for patients with R/R MM after multiple previous lines of therapy. CAR T-cell therapy is limited to institutions with an approved cell therapy facility, whereas bispecific antibodies potentially have wider availability in clinical practice. Greater toxicity and risk of infection are seen with CAR T-cell therapy in the acute phase following infusion, whereas the ongoing administration of bispecific antibodies means toxicities including cytokine-release syndrome may continue for longer durations. Patients who recently have been treated with alkylators or steroids are not candidates for CAR T-cell therapy, so T-cell health should be kept in mind for patients to preserve the option for CAR T-cell treatment.

Patients who relapse after BCMA-targeted therapy and those who may not be eligible for these BCMA-targeted immunotherapy approaches can be quite challenging to treat and have fewer options. Recommended treatment options for these patients may include alkylator-based therapy, combination approaches with selinexor, and/or cyclophosphamide-based combinations, as well as venetoclax-based therapy for high-risk patients with t(11;14).

Treatment of R/R MM After Previous BCMA-Targeted Therapy: Future Directions
In addition to the new approaches with BCMA-targeted therapy, other novel treatment options are also in development and may be new options for patients who relapse after BCMA-targeted therapy. These new approaches include new CAR T-cell therapy and bispecific antibodies to additional anti-MM targets, such as G protein‒coupled receptor (GPR) C5D or FcRH5, as well as cereblon E3 ligase‒modulating drugs (CELMoDs).

Talquetamab is a bispecific antibody targeting GPRC5D and has shown an impressive clinical response in patients with R/R MM. The MonumenTAL-1 trial enrolled patients with a median of 5 previous lines of therapy and reported an overall response rate (ORR) of 74%, with similar ORR in patients with triple-class refractory or penta-class refractory disease, suggesting an effective response even as later-line treatment. Other GPRC5D-targeting bispecific antibodies and CAR T-cell therapies are in clinical development.

Cevostamab, another bispecific antibody under investigation in R/R MM, targets FcRH5 and has shown a lot of promise, with early clinical data showing a 55% ORR in patients after a median of 6 previous lines of therapy, including 34% who previously were exposed to anti-BCMA therapy.

CELMoDs, such as iberdomide and mezigdomide, are a third exciting new class of targeted agent and have the potential to expand on the efficacy provided by immunomodulatory agents.

Together, these new treatment approaches may provide valuable future options for patients who are refractory to all 5 classes of therapies (immunomodulatory agents, proteasome inhibitors, anti-CD38‒targeted therapies, BCMA-targeted therapies, and alkylating agents).  

Your Thoughts?
How do you consider the impact of prior therapies in your treatment strategies for patients with MM? Join the discussion by posting a comment below.

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