Recent research of pooled bispecific antibody clinical trial data shows that infections can be common and that more study needs to be performed to know how to best reduce infection rates for patients. 

The authors start a recent article in the journal Blood Advances with a bang:

“The use of bispecific antibodies (BsAbs) in the treatment of relapsed/refractory multiple myeloma (MM) is showing early promising overall response rates in heavily pre-treated patients. Infectious complications related to the use of BsAbs are not well described.”

This research article summarizes a pooled analysis of 11 published clinical studies with 11 different bispecific antibodies, covering 1,185 myeloma patients, where bispecific antibodies were administered as a single agent to patients with no prior exposure to another bispecific antibody.

Let’s pause for a minute and re-hash some education about bi-specifics. Bispecific antibodies bind to a target on the cancerous myeloma (plasma) cells as well as on immune effector cells resulting in cell death of the malignant cell. Bispecific antibodies used in myeloma can target BCMA (and those are the ones we are most familiar with from the more popular myeloma press] or the protein GPRC5D or FcRH5.)

The products included in this study can be categorized as follows:

BCMA Targeted Bispecfic Antibodies

• Teclistamab (JNJ/Jansen - FDA approved)
• Elranatamab (Pfizer – under FDA review)
• Linvoseltemab (Regeneron, clinical trial stage)
• AMG420 (Amgen, clinical development has been halted)
• Pavurutamab (Amgen, clinical trials recently paused)
• Alnuctamab (Bristol Myers – clinical trial stage)

GPRC5D Targeted Bispecfic Antibodies

• Talquetamab (JNJ/Jansen – under FDA review). The above referenced study includes patients dosed with three different dosing regimens of this drug (405 mg subcutaneous weekly, 800 mg subcutaneous bi-weekly, IV)

FcRH5 Targeted Bispecific Antibodies

• Cevostamab (Genentech – clinical trial stage)

Infection Details and Reasons

The authors report the following:

•  All grade infections are reported in 50% of the patients, with grade III/IV infections occurring in about 25% of the patients. “We found higher risk of infections in patients treated with BsAbs targeting BCMA (30 %) when compared to non-BMCA targeting BsAbs (talquetamab and Cevostamab) (12 %).”
• “Significant reported infections included both typical and opportunistic infections. Typical infections reported included: pneumonia, upper respiratory tract infection, adenovirus infection, central line associated blood stream infections, urinary tract infection and helicobacter pylori. Opportunistic infections were also reported including cytomegalovirus infection/reactivation, pneumocystis jiroveci pneumonia [fungal infection of the lungs], candida esophagitis, ophthalmic herpes simplex virus and progressive multifocal leukoencephalopathy.”

The question to ask is, “Why ?” The authors list 3 main reasons:

1. “ …, almost all patients who received BsAbs have been treated with other forms of therapy leading to an already immunosuppressed state with depletion of lymphocytes and immunoglobulins.” This is easy for us to understand as most of us myeloma patients live an immune-compromised life.
2. “…, BsAbs targeted therapy are associated with significant neutropenia, lymphopenia, and hypogammaglobulinemia directly increasing the risk of acquiring bacterial, fungal and viral infections …”. The authors report that nearly 39 % become neutropenic while using BsAbs, and more importantly, nearly 35% of patients report grade III/IV neutropenia.
3. “…, , the results of the pooled analysis showed significant development of CRS which is treated with immunosuppressive agents including glucocorticoids, tocilizumab, and tumor necrosis factor α (TNF-α) blockers such as etanercept, indirectly causing further immunosuppression.”  All grade cytokine release syndrome (CRS) was reported in nearly 60% of the patients.

The authors make several points and recommendations:

1. “There is lack of guidelines to use prophylactic anti-microbials and/or IVIG in patients who receive BsAbs.”
2. “Implementation of prophylactic anti-microbials and IVIG infusions may help in decreasing the risk of infectious complications and should be added to future studies.”
3. “Our analysis showed inconsistent reporting of infections across all included studies. Efforts should be made to better capture infectious complications and report them to help guiding treating physicians.”
4. “Additionally, prophylaxis for opportunistic infections was unclear throughout the studies.”
5.  “ … include infections in the research protocol's adverse events of special interest category, which also includes CRS and requires stringent data collection to include timing, management, and reporting of all patient’s data.”
6. “Baseline and periodic testing for specific infections including CMV (Cytomegalovirus) maybe needed in clinical practice along with use of IVIG and implementation of a mitigation system to help in decreasing infections and/or treating them earlier.”
7. “Future BsAbs should consider studying the incorporation of various prophylactic measures to prevent serious infections including IVIG and/or prophylactic antimicrobials.”

Those patients currently being treated with bispecific antibodies may wish to discuss some of these recommendations with their myeloma specialist, especially point 6 above.