Skip to main content
Vijay Rao, Parth Rao Commented on a Post
  • Saved

BCMA targeted immunotherapy for multiple myeloma

While the introduction of proteasome inhibitors, immunomodulators and monoclonal antibodies targeting CD38 have revolutionized the treatment of multiple myeloma, many patients become refractory to these agents. The B-cell maturation agent (BCMA) is expressed on 100% of plasma cells but not on immature hematopoietic cells or other normal tissue and has emerged as a novel target for immunotherapy in multiple myeloma. Agents targeting BCMA have been shown to significantly improve outcomes in triple-refractory patients. These agents include two CAR-T therapies, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), currently under regulatory review with the FDA for triple-refractory multiple myeloma and the antibody-drug conjugate belantamab mafodotin, approved in 2020 for patients who have received at least four prior therapies.

What factors will you consider when selecting a BCMA-directed therapy for triple-refractory patients? Are there certain groups of patients better suited for either an antibody-drug conjugate or a CAR-T therapy? Do you think anti-BCMA agents will eventually be used in earlier lines of therapy?

  • 4 hours 22 min
    BCMA is an ideal target for myeloma. Belantamab data in triple refractory patients is impressive. Ocular toxicity is unique but easily manageable if partnered with optometrist/ophthalmology.. BCMA-CAR-T is also an option but needs to go to a tertiary center.
  • 23 hours 41 min
    1. Agree- using BCMA directed therapy- Blenrep currently in patients who are triple class refractory
    2. Early to say if we can differentiate patient candidacy for BCMA ADC vs BCMA CAR-T, So far, the BCMA CAR-T seems to have more durable response
    3. it is very likely that these agents will get tested in various combinations in earlier lines of therapy, and you may start seeing them being used for high risk patients, where it might be beneficial to add agents with different MOA, and improving synergy of treatment
  • 23 hours 42 min
    1. Agree- using BCMA directed therapy- Blenrep currently in patients who are triple class refractory
    2. Early to say if we can differentiate patient candidacy for BCMA ADC vs BCMA CAR-T, So far, the BCMA CAR-T seems to have more durable response
    3. it is very likely that these agents will get tested in various combinations in earlier lines of therapy, and you may start seeing them being used for high risk patients, where it might be beneficial to add agents with different MOA, and improving synergy of treatment
  • 1 day 13 hours
    An important question is which of the anti-BCMA approaches would be best suited for a particular patient, particularly in transplant-ineligible patients. BCMA agents will likely move up in line of therapy, including first line use as with daratumumab. With other targets such as FCRH5 in clinical trials, BCMA will likely not be the only target for bispecifics, CART, mAbs, etc. However, I don't anticipate sequential use of anti-BCMA approaches in the same patient, therefore blenrep may be reserved for patients unable to go for CART of bispecific therapy.
  • 1 day 14 hours
    I would reserve use of Blenrep for 5th line therapy. I feel that the most robust patients (performance status of 0-1) are best suited for CAR-T, whereas PS 2 patients may be suited for ADCs and anti-BCMAs. If prospective studies done in earlier lines of therapy show good safety and efficacy, I can foresee BCMA-directed therapies being used in earlier lines.
  • 1 day 14 hours
    I agree with what have been said so far. I think anti-BCMA agents have potential in improving patients outcomes given the very promising safety and efficacy.
  • 1 day 16 hours
    As a community practitioner, when a patient has reached this point in their treatment journey I recommend referral to a tertiary care center to help guide furthur therapy. This will include the menu of BCMA directed therapies along with other investigational therapies. I expect that ultimately these therapies will be moved up in line of treatment once efficacy and toxicity is sorted out.
  • 1 week 2 days
    Currently, the only approved BCMA directed therapy is belantamab mafodotin (Blenrep) approved for patients with 4 prior therapies (does not exactly specify 4 lines of therapy but 4 prior therapies). The response rate to the FDA approved single agent antibody-drug conjugate is approximately 30%. There are numerous DREAMM studies ongoing combining belantamab with proteasome inhibitors or immunomodulatory drugs for 1-3 lines of prior therapy AND even studies in front line therapy. The main toxicities of belantamab is ocular and thrombocytopenia. Belantamab has an FDA mandated REMS program prior to administering EACH dose of belantamab (by FDA indication, every 3 weeks). The REMS program is cumbersome and not user friendly.Currently, the only approved BCMA directed therapy is belantamab mafodotin (Blenrep) approved for patients with 4 prior therapies (does not exactly specify 4 lines of therapy but 4 prior therapies). The response rate to the FDA approved single agent antibody-drug conjugate is approximately 30%. There are numerous DREAMM studies ongoing combining belantamab with proteasome inhibitors or immunomodulatory drugs for 1-3 lines of prior therapy AND even studies in front line therapy. The main toxicities of belantamab is ocular and thrombocytopenia. Belantamab has an FDA mandated REMS program prior to administering EACH dose of belantamab (by FDA indication, every 3 weeks). The REMS program is cumbersome and not user friendly. There are a number of promising antibody-drug conjugates in development.

    Myeloma is lagging behind its sister B cell malignancies of non-Hodgkin's lymphoma and B cell ALL. However, hopefully, we will have an FDA approved product in bb2121 by the March 27, 2021 PDUFA date. Outside of Janssen's CARTITUDE program, most of the other companies are far behind in the clinical trial queue. There are over 20 other companies developing CAR T cells for myeloma-the VAST majority are directed against BCMA although other targets are also being pursued (e.g. Slam-F7). Also, there are a smaller number of companies utilizing allogeneic CAR T cell products. Response rates to CAR T cells have been reported in a range from 60-100% with complete remissions of 50-85%. Progression-free survival has varied substantially between trials from 10+ months to over 24 months. Most of the data is still relatively immature and median follow up is short. CRS and neurotoxicity are significantly lower incidence and severity as compared to those reported for NHL and ALL. Highly manageable. This allows consideration of the elderly and frail, even more so than a stem cell transplant. Car T cells ARE being moved up to 1-3 lines of therapy and even in the upfront setting in high risk disease.

    The other avenue for BCMA directed therapies are bi-specific antibodies (CD3/BCMA) of which there are over 5 reported companies at the recent ASH December 2020. Bispecifics do not have the ocular toxicity as shown with belantamab but may cause cytokine release syndrome although relatively rare neurotoxicity. Response rates for single agent bispecific antibodies have ranged from 50-80%.

    My preference would be for CAR T cells-rather a 'one and done' approach until disease progression. High response rates, manageable CRS and neurotoxicity. In contrast the antibody-drug conjugates and bispecifics are repeated cycles of therapy until disease progression.
  • 1 week 3 days
    Currently the space is rather simple as there is only one FDA approved therapy. The space is likely to become increasingly complex in the near future. One of the primary factors is this selection process of BCMA treatment is CAR T cell candidacy, which spans a number of domains but includes patient age, comorbidities, caregiver support, transportation, and patient/physician preference for more intensive vs less intensive treatment. Generally, some patients will be more inclined for less complex treatment and these patients would likely favor ADC BCMA therapy, whereas those more inclined for complex treatment will favor CAR T. Then there are BITES which will likely have an efficacy/tolerability/complexity "package" that appears in phase I/II studies to be "middle of the road" between ADC and CAR. It is very likely that BCMA inhibition treatments will increasingly move to earlier lines of treatment, particularly for those patients refractory to the 3 primary classes of agents.