Recently at ASH, Drs. Saad Usmani and Jonathan Kaufman debated if the addition of proteasome inhibitors to anti-CD 38 treatment was optimal for standard risk, first relapse multiple myeloma patients. The discussion hinged around the use of an immunomodulatory drug such as lenalidomide or pomalidomide, as opposed to the use of a proteasome inhibitor such as bortezomib, carfilzomib, or ixazomib, and which of these approaches better supported optimal outcomes when combined with daratumumab or isatuximab and dexamethasone.

To follow this debate you first need to understand how each of these drugs work.

What is CD38?

CD38 is a protein on the surface of most multiple myeloma cells. Anti-CD38 drugs (such daratumumab and isatuximab) are synthetic antibodies that target the CD38 protein and the cells to which they are attached.

Immunomodulatory Drugs (IMiDs)

Immunomodulatory Drugs (such as lenalidomide and pomalidomide) use the patient’s immune system to limit the growth or directly attack myeloma cells.

Proteasome Inhibitors (PI)

Proteasome inhibitors are a group of drugs that help cancer cells die (apoptosis) by preventing myeloma protein complexes from renewing and continuing to grow. Preventing further growth of the myeloma cells allows the old cells to accumulate and ultimately die.

The Debate

Using IMiDs (Kaufman)

Dr. Kaufman insisted that after a first relapse, the use of an immunomodulatory drug with dexamethasone and anti-CD38 treatment is the standard of care. Dr. Kaufman insisted that further studies need to be conducted in order to determine the efficacy and safety of using proteasome inhibitors (PIs) as an additional line of treatment. 

Much of Dr. Kaufman’s argument against the use of PIs centers largely around assertions that Dr. Usmani himself made in 2019 and 2020, in response to results from multiple trials. In previous Twitter posts, Dr. Usmani declared that the use of daratumumab or isatuximab, combined with dexamethasone and an immunomodulatory treatment after a first relapse resulted in favorable outcomes for patients. The use of daratumumab, dexamethasone, and pomalidomide was determined to be a valuable “salvage” treatment option for first relapse myeloma patients.

Dr. Kaufman concluded that the further study treating myeloma with the addition of proteasome inhibitors is warranted before it is considered a default treatment.

Proteasome Inhibitors Paired with Daratumumab and Dexamethasone (Usmani)

Dr. Usmani immediately recommended taking into consideration the patient’s age, progression, co-morbidities and lenalidomide resistance when determining whether to treat with triplets, proteasome inhibitors paired with daratumumab and dexamethasone after a patient’s first relapse. 

While there have been incidences of increased infections from patients undergoing PI treatments, this hasn’t affected patient overall survival rate. The objective response rate, the rate of minimal residual disease negativity, and progression free survival are all better when compared to previous standards of care. 

Further, patients who experience first relapse, are often resistant to lenalidomide. Switching to PI “triplet” anti-CD38 treatment offers a viable alternative. He insisted that this does not contradict his previous praise for the use of IMiDs. IMiDs in an anti-CD38 line of therapy is a fall-back position when the situation warrants an alternative.

Summary

In summarizing their stances, both Drs. Kaufman and Usmani agree that factoring the patient comorbidities, age, maintenance, and relapse/refractory experiences all must be considered before making a final subjective decision. Each study in the use of anti-CD38 antibodies highlights (often new) variables that must be measured and weighed one against the others when determining the next treatment course for each patient.