Bispecific Antibodies May Change the Face of AL Amyloidosis

AL amyloidosis was often diagnosed late after organ damage was irreversible. Patients were treated with cytotoxic chemotherapies, combined with immunotherapy and steroids . However, these arduous treatment regimens resulted in remission in only about 50-60% of patients. B-cell maturation antigen targeting (BCMA) bispecific antibodies may very well change the course of the disease.

While bispecific antibodies are only approved for relapsed/refractory multiple myeloma, real-world experience has demonstrated that they can be highly effective for AL amyloidosis patients as well. By shutting down production of the amyloid protein, these medications often result in deep, rapid hematologic response.

"These medications work quickly in virtually all patients we've seen with AL amyloidosis," says hematologist/oncologist Sandra Mazzoni, DO. "We need access to these drugs to help rapidly shut down amyloid production.”

FDA approval of these medications for refractory AL amyloidosis may be forthcoming. In the meantime, clinicians can sometimes gain approval of their use based on NCCN guidelines stating that light chain amyloidosis is a myeloma-defining event.

How bispecific antibodies work

These bispecifics antibodies bind to T cells through CD3 and to plasma cells through BCMA. Since amyloid plasma cells are very ubiquitous – and are essentially saturated with BCMA, this approach works very well in treating AL amyloidosis. There's emerging data that patients can also achieve organ recovery in a matter of months. "This is likely to make a real difference in the mortality and morbidity we see with this disease," says Dr. Mazzoni.

Currently, bispecifics are primarily available at academic centers, and there’s a need to ensure access at community oncology settings. Fear of acute toxicity may be one barrier for community providers. However, as Dr. Mazzoni explains, preventative measures have come a long way when it comes to managing adverse events.

Managing toxicities

There are two stages of toxicities with bispecific antibodies:

• The risk of cytokine release syndrome (CRS) during the 7-10 days of step-up dosing. Proactive use of steroids or other medications can mitigate interleukins that lead to CRS. “It’s very rare to see high-grade CRS these days,” says Dr. Mazzoni. We’re gathering more real-world data of outpatient administration during step-up dosing, and I think that will be key to making this treatment available in community settings.”
• Long-term risk of infection while patients are on maintenance therapy. BCMA targeting doesn't just knock out plasma cells. It knocks out a portion of B cells, which makes patients very immune compromised. Shutting down a good portion of their natural immune protein production opens the door to infections. Measures such as IVIG, shingles prevention and PJP pneumonia medications have reduced the risk of infection from roughly 80% of patients to about 10% of patients.

Open questions

There are still some unknowns when it comes to treating AL amyloidosis with bispecifics. Researchers aren't sure the length of exposure needed to achieve curative results. Shutting down the plasma cell clone that produces the amyloid protein may only take a few weeks with these drugs. It is expected that a fixed duration, but of what length of time is unknown, will achieve long-term hematologic complete remission (hCR).

Additionally, there is a need for concurrent management of AL amyloidosis and multiple myeloma. Some patients with multiple myeloma also develop AL amyloidosis. There is a concern that the amyloidosis diagnosis may be missed if patients are treated in centers without a lot of familiarity with the condition.

"If you have a strong suspicion or a proven tissue biopsy showing light chain amyloidosis, I'd recommend referring the patient early on to a center that specializes in amyloid care," says Dr. Mazzoni. "The patient will really benefit from having multi-specialty care in that setting. Often they can receive some of their therapy close to home while gaining access to BCMA-targeting bispecifics, which have rapid, deep hematologic response in pretty close to all patients we’ve seen."

Cleveland Clinic Cancer Institute partners with community providers to ensure patients with suspected amyloidosis receive rapid diagnosis and treatment as well as the medical management needed to address affected organs.

In the meantime, the Institute is participating in a study of BCMA bispecifics in the refractory setting and hopes to open a study of this medication class in newly diagnosed patients this fall. Notably, the study will be open to patients with moderately higher-stage cardiac involvement as well as those on dialysis, both of whom are populations are often excluded from clinical trials.