Top 10 burning questions for immunotherapy in MM
| Question . | Assessment and perspective in 2020 . |
|---|---|
| Will high-risk disease become standard risk in the era of novel CAR T-cell therapy? | Potentially yes. BCMA CAR T cells are effective in patients with high-risk cytogenetics, including double-hit TP53 mutation. |
| Is MRD negativity the best end point for immunotherapy trials? | Probably yes. However, there is an issue with obtaining high-quality MRD samples shortly after CAR T-cell therapy because of hypocellular bone marrow. Furthermore, MRD assessment should be combined with functional imaging to exclude residual focal lesions or extramedullary disease. |
| Should we deliver novel immunotherapies preferentially in early treatment lines (and what is the optimal sequence of novel immunotherapies)? | Probably yes. T cells from patients in early disease stages and early in the treatment course exhibit better fitness compared with those in late stages. Determining the optimal sequence of immunotherapy modalities is an open issue (eg, What is the optimal interval between Dara and Elo [because Dara diminishes NK cells that are required for Elo mode of action? If 1 BCMA-targeting agent fails, can another still work? How soon after CAR T-cell therapy can bsAbs be considered [if lymphopenia after lymphodepletion has not resolved]?). |
| Is relapse from immunotherapy more difficult to treat? | Probably no. However, the selective pressure of immunotherapies on tumor and microenvironment has yet to be defined. |
| Will we cure myeloma with CAR T cells and T cell–engaging bsAbs? | Probably yes. A subgroup of patients with low tumor burden and favorable biology will exceptionally benefit. |
| Will we deliver chemotherapy-free immunotherapy combinations? | Probably yes. Strategies include combination of anti-CD38 mAbs with ADCs or bsAbs (anti-BCMA or anti-GPRC5D) or combination of T-cell–redirecting therapies with IMiDs to reprogram and improve fitness of endogenous T cells. |
| Do we need additional diagnostics in the era of immunotherapy? | Probably yes. There is a need and opportunity to implement advanced diagnostics in MM immunotherapy to guide patient and antigen selection and monitor disease response as well as advanced genomic analyses to monitor clonal composition and evolution and potential gene or even chromosome loss. |
| Will targeting >1 antigen on MM cells improve response rates and durability of response? | Probably yes. Multiple-antigen targeting is an appealing strategy to counteract the antigen downregulation and loss that limit the efficacy of BCMA CAR T cells in a subset of patients in current clinical trials. |
| Is there a place for immunotherapy in early asymptomatic stages of MM? | Probably yes, but these therapies need to be well tolerated. |
| Will the COVID-19 pandemic stop the success of novel immunotherapies? | Definitely no, but the timelines for completion of trials, approval of novel trials, and reimbursement may decelerate. |
| Question . | Assessment and perspective in 2020 . |
|---|---|
| Will high-risk disease become standard risk in the era of novel CAR T-cell therapy? | Potentially yes. BCMA CAR T cells are effective in patients with high-risk cytogenetics, including double-hit TP53 mutation. |
| Is MRD negativity the best end point for immunotherapy trials? | Probably yes. However, there is an issue with obtaining high-quality MRD samples shortly after CAR T-cell therapy because of hypocellular bone marrow. Furthermore, MRD assessment should be combined with functional imaging to exclude residual focal lesions or extramedullary disease. |
| Should we deliver novel immunotherapies preferentially in early treatment lines (and what is the optimal sequence of novel immunotherapies)? | Probably yes. T cells from patients in early disease stages and early in the treatment course exhibit better fitness compared with those in late stages. Determining the optimal sequence of immunotherapy modalities is an open issue (eg, What is the optimal interval between Dara and Elo [because Dara diminishes NK cells that are required for Elo mode of action? If 1 BCMA-targeting agent fails, can another still work? How soon after CAR T-cell therapy can bsAbs be considered [if lymphopenia after lymphodepletion has not resolved]?). |
| Is relapse from immunotherapy more difficult to treat? | Probably no. However, the selective pressure of immunotherapies on tumor and microenvironment has yet to be defined. |
| Will we cure myeloma with CAR T cells and T cell–engaging bsAbs? | Probably yes. A subgroup of patients with low tumor burden and favorable biology will exceptionally benefit. |
| Will we deliver chemotherapy-free immunotherapy combinations? | Probably yes. Strategies include combination of anti-CD38 mAbs with ADCs or bsAbs (anti-BCMA or anti-GPRC5D) or combination of T-cell–redirecting therapies with IMiDs to reprogram and improve fitness of endogenous T cells. |
| Do we need additional diagnostics in the era of immunotherapy? | Probably yes. There is a need and opportunity to implement advanced diagnostics in MM immunotherapy to guide patient and antigen selection and monitor disease response as well as advanced genomic analyses to monitor clonal composition and evolution and potential gene or even chromosome loss. |
| Will targeting >1 antigen on MM cells improve response rates and durability of response? | Probably yes. Multiple-antigen targeting is an appealing strategy to counteract the antigen downregulation and loss that limit the efficacy of BCMA CAR T cells in a subset of patients in current clinical trials. |
| Is there a place for immunotherapy in early asymptomatic stages of MM? | Probably yes, but these therapies need to be well tolerated. |
| Will the COVID-19 pandemic stop the success of novel immunotherapies? | Definitely no, but the timelines for completion of trials, approval of novel trials, and reimbursement may decelerate. |