CAR T-cell therapy, bispecific T-cell engagers, other exciting treatments in multiple myeloma
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Maung Myo Htut, MD, associate clinical professor in the division of multiple myeloma within the department of hematology and hematopietic cell transplantation at City of Hope, discussed treatment developments in multiple myeloma, including exciting data from ASH 2020, the role of CAR T-cell therapy, autologous hematopoietic stem cell transplant, consolidation therapy and more.
Healio: What exciting treatment developments in multiple myeloma did you take away from ASH 2020?
Htut: The most exciting news related to anti-myeloma therapy at ASH 2020 are about CAR-T cells and bispecific T-cell engagers (BiTEs). There were presentations of maturing data for idecabetagene vicleucel (Ide-cel, bb2121) as well as ciltacabtagene autoleucel (cilta-cel), both of which are anti-BCMA CAR T-cells. Both CAR T-cells had very high response rates in patients who had progressed after multiple prior lines of chemotherapy. Their toxicities are as expected with high rate of cytokine release syndrome but, very severe/uncontrolled cytokine release syndrome is not common. Most of the cytokine release syndrome cases were easily manageable with supportive care and other specialized treatments such as tocilizumab (Actemra; Roche) and steroids.
These autologous CAR T-cells use patients’ own immune cells but take time to be collected from the patients and manufactured in the labs (which usually takes about 4 weeks) and some patients may not have enough time to wait for them to be produced, which led to off-the-shelf CAR T-cells. Allogene data related to one of those allogenic CAR T cells (using donor's immune cell), was also presented.
Multiple promising BiTE trials targeting BCMA were presented. BiTE trials targeting different antigens on myeloma cells such as GPRC5Dand FCRh5 were also presented. All those BiTE trials showed very promising high response rate with limited and manageable toxicities.
There were updates about antibody drug conjugates, and consolidation therapy (chemotherapy) after autologous stem cell transplant.
Healio: What is the role of CAR T-cell therapy in multiple myeloma?
Htut: Most of the autologous CAR T-cell trials including ide-cel and cilta-cel enrolled patients with relapsed and refractory multiple myeloma after three or more lines of prior chemotherapy. Idecabtagene vicleucel (Abecma; BristolMyer Squibb), or Ide-cel, was approved by the FDA in late March 2021 for patients with relapsed myeloma who progressed after four or more prior lines of chemotherapy.
In short, CAR T-cell therapy currently is only for patients who have relapsed after several lines of therapy. There are several ongoing CAR T trials for participants who have unsatisfactory response to autologous stem cell transplant (KarMMA-2) and participants with high risk (R-ISS Stage III), newly diagnosed multiple myeloma (KarMMA-4). CARTITUTE-4 trial compares CAR T-cells with three drug regimens. It appears that CAR T-cells might play a role in myeloma earlier than currently approved in patients with high-risk disease or unsatisfactory response to initial therapies.
Healio: What patient subgroups will benefit the most from autologous hematopoietic stem cell transplant?
Htut: More than several decades after introduction, autologous stem cell transplant remains the standard of care for young and fit patients after induction chemotherapy. Development of newer drugs including monoclonal antibodies have not replaced autologous stem cell transplant. There are several factors to consider when deciding whether patients should undergo autologous stem cell transplant including patient/physician preference;
Age: There is no absolute cutoff for autologous transplant. Upper age limit varies depending on transplant centers and countries. Several studies showed that fit and healthy patients with advanced age share similar outcomes, including toxicities, compared with patients in younger age groups.
Renal insufficiency: Patients with renal insufficiency who undergo autologous stem cell transplant, especially patients on hemodialysis, tend to have higher complications, such as mucositis and infections. Some observational studies showed that transplant related mortality rate for patients with severe renal insufficiency is higher than patients with normal renal function.
Healio: What are the risks and benefits associated with consolidation treatment?
Htut: Consolidation therapy is generally defined as a short course of therapy (ie, 2-4 cycles) usually with the same regimen used for induction therapy, following autologous stem cell transplant. The goal is to further deepen the response (to potentiate effect of autologous stem cell transplant). It may also worsen some residual toxicities of transplant, such as worsening of cytopenias.
Consolidation therapy in non-transplant patients can be defined as continuation of additional two to four cycles of chemotherapy after four to six cycles of initial induction chemotherapy. It may contribute to worsening of pre-existing toxicities such as peripheral neuropathy if the same regimen is given longer than typical induction therapy.
The role of post-transplant consolidation therapy has been investigated in several trials.
In BMT–CTN 0702 trial, adding consolidation therapy after autologous stem cell transplant for up front treatment of transplant eligible patients with myeloma did not improve progression free survival or overall survival compared with single autologous stem cell transplant followed by lenalidomide maintenance therapy. In the same trial, consolidation therapy after autologous stem cell transplant did not significantly increase toxicities compared with patients who did not receive consolidation therapy and proceeded to lenalidomide maintenance directly.
In the Forte trial presented at ASH 2020, 474 patients with newly diagnosed multiple myeloma were divided into three groups and each given a carfilzomib (Kyprolis; Amgen) based regimen as both induction and consolidation:
Group A received KRd (Kyprolis plus revlimid plus dexamethasone) followed by an autologous stem cell transplant and consolidation with KRd. Group B received KRd alone (no transplant and consolidation). Group C received KCd (Kyprolis plus cytoxan plus dexamethasone followed by an autologous stem cell transplant) and consolidation with KCd.
Researchers randomly assigned patients in all groups to receive Kyprolis-lenalidomide or lenalidomide alone as maintenance therapy.
Group A patients were found to have longer progression free survival.
In general, consolidation therapy can be considered in patients who achieve only suboptimal response after an autologous transplant.
Healio: How should clinicians approach heavily pretreated patients?
Htut: Antimyeloma therapy should be individualized. It depends on three different categories;
Patient-related: It depends on the patient's age, performance status, organ functions, patient's own preference and comorbid conditions. For older adult patients, dose reduction of chemotherapies should be considered, such as RVD-lite. Dexamethasone dose should also be reduced for patients aged older than 70. Some patients may prefer oral chemotherapy, such as Ninlaro plus lenalidomide plus dexamethasone to reduce frequent visits for chemotherapy infusion/injection. Chemotherapy dosages need to be adjusted based on renal function, such as using a lower dose of lenalidomide (Revlimid; Bristol Myers Squibb) or pomalidomide (Pomalyst; Bristol Myers Squibb) in the presence of renal dysfunction. Some agents such as carfilzomib or Doxil (doxorubicin hydrochloride liposome; Baxter) are known to cause cardiac toxicities and avoidance or close monitoring is warranted in a patient with pre-existing cardiac conditions.
Disease-related: Initial induction therapy for patients with high-risk disease should include at least proteosome inhibitor as part of combination chemotherapy such as triplets (combined with one IMiD plus dexamethasone). Any patient who does not achieve satisfactory response to given therapy, including autologous stem cell transplant, should consider changing therapy to a different class of combination therapy. Multiple myeloma tends to be more and more aggressive with each relapse. For patients with certain cytogenetics, such as (11:14) translocation, which enhances BCL-2 expression, they may benefit from venetoclax (Venclexta; Abbvie, Genentech), which is a BCL-2 inhibitor.
Drug-related: Chemotherapies from different classes with different mechanism of action should be combined such as bortezomib (Velcade; Takeda) plus lenalidomide plus dexamethasone or daratumumab (Darzalex; Janssen) plus pomalidomide plus dexamethasone. Toxicities from prior chemotherapies may limit usage of the same chemotherapy or same class of chemotherapy. Severe and persistent peripheral neuropathy from bortezomib therapy may limit usage of bortezomib therapy again. Multiple and recurrent venous thromboembolism may limit usage of immune modulators (IMiDs) such as lenalidomide and pomalidomide.
Healio: What does the future treatment landscape look like in multiple myeloma?
Htut: Anti-BCMA CAR T-cell therapy Abecma was just approved by FDA for patients with myeloma who progressed after four or more lines of prior chemotherapies. CAR T-cell therapy may be useful earlier in the course of natural history of myeloma and multiple clinical trials ongoing. Another anti-BCMA autologous car T-cell therapy (CARTITUTE-1 trial) with high efficiency from Janssen is also awaiting FDA approval.
Other CAR T-cells targeting different antigens such as GPRC5D should also be available soon. Allogenic CAR T-cells (off-the-shelf) targeting different antigens should eliminate manufacturing time and readily available so that patients can be treated without waiting for leukapheresis and manufacturing of autologous stem cells.
BiTE targeting different antigens should also be available within the next few years.
The role of autologous stem cell transplant has been challenged as newer therapeutic options are available, which produce higher complete remission status, including negative minimal residual disease with limited toxicities. Natural killer cells targeting multiple myeloma associated antigens are also on the horizon.
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