Safety Profile of Anti-CD38 Monoclonal Antibodies in MM

Keith Stewart, MB, ChB:Daratumumab is a single agent and a safe drug to use. The issues that one has to be aware of is, No. 1, the drug can interfere with red blood cell cross typing. Therefore, you have to remember to send to your local blood transfusion lab a sample before the patient starts daratumumab so that appropriate cross-matching could be made. Secondly, this drug—like most monoclonal antibodies—is sometimes associated with a first infusion reaction. I emphasize first in that most of the time it is the only time these reactions occur, and they generally are not seen in later rounds.

The infusion reaction is similar to that seen with other monoclonal antibodies, but in this case it’s particularly focused on upper respiratory tract allergy-type symptoms—runny eyes, runny nose, tightening of the throat, and in severe cases wheezing and even some stridor. This can be managed by premedicating the patients appropriately according to the label on the use, slowing down the infusion and reintroducing anti-allergy drugs as part of the management of adverse effects should they occur.

These events occur in up to 40% of patients but are generally mild and fairly easy to manage. However, this reaction can happen in the first dosing. One of the disadvantages of daratumumab is that it does take a long time to do the first-day infusion, up to 8 hours in some cases. Which means that it puts stress, to some degree, on treatment centers that open late or close early. That we hope will be resolved in the near future with the introduction of subcutaneous daratumumab, but that is some time away.

Beyond the first 2 or 3 cycles many academic centers particularly have moved the infusion time down to 19 minutes. The first day can be long. Week 2 and perhaps week 3 can be 5 or 6 hours, but thereafter a 90-minute infusion could be safely employed if the subject has been treated has not seen any evidence of infusion-related reaction.

The final adverse effect that I think people need to be aware of is that this is a very powerful drug at killing myeloma but also at attacking normal plasma cells; therefore, immune suppression is an issue. Infection rates do increase with the use of daratumumab in combination in many of the trials that we’ve looked at the addition of this agent to conventional therapies. The physicians just need to be aware of that—to be thoughtful about how they prophylax and to make sure vaccinations are in place. Perhaps growing evidence that use of a quinolone antibiotic in the first few months of treatment is advisable.

My personal experience using daratumumab has been very positive. I think the concerns that people had about infusion reactions in the very early days of introduction of this drug have generally abated. Unlike many monoclonal antibodies we use in oncology, it is quite easy to use. And once the infusion staff get used to the drug, I don’t foresee problems, or significant problems, for most patients.

I do want to emphasize the need to be vigilant about infection, to make sure your patients are on acyclovir to prevent shingles and their flu vaccine and other vaccines are up-to-date. Remember to tell your nurse to send the blood transfusion compatibility testing before starting the drug.

The use of daratumumab-lenalidomide-dexamethasone is appropriate for a large swath of the patients we see, particularly the transplant-ineligible patients. I think areas in which one might want to consider use of a proteasome inhibitor might be patients with very high-risk disease where there’s evidence that a proteasome inhibitor can be quite useful. Secondly, in patients with renal failure where the use of lenalidomide may not be appropriate. Or in patients who can’t access lenalidomide because of financial toxicity, because of the inability to obtain through insurance, or perhaps because even after 1 or 2 doses they develop rash or intolerance of that drug.

In all those circumstances, I think a proteasome inhibitor should be preferred. When a proteasome inhibitor is going to be used, the regimen that has been approved by the FDA that incorporates daratumumab is Velcade [bortezomib], melphalan, prednisone, and daratumumab. The combination of those 4 drugs would be the recommended treatment for somebody who cannot tolerate or cannot access Revlimid [lenalidomide].

Transcript edited for clarity.

Case: 83-Year-Old Man With NDMM Ineligible for Transplant

History and Presentation:

• 83-year-old man c/o back pain and fatigue
• Cardiac stent placed 3 years ago; high blood pressure; BMI 32

Diagnostic Workup:

• Laboratory findings
  • M-protein 3.8 g/dL
  • Hb 7.9 g/dL
  • LDH 290 IU/L
  • Albumin 3.9 g/dL
  • β2-microglobulin 4.25 mg/L
  • Creatinine 1.5 mg/dL
  • FLC kappa 134 mg/dL

• Bone marrow biopsy
  • Good cellularity with 60% bone marrow plasma cells
• Cytogenetics/FISH: standard-risk, no cytogenetic abnormalities
• Imaging
  • MRI of the spine: multiple focal lesions; moderate diffuse infiltration of spine, pelvis, and proximal femurs.
• ECOG PS: 2
• Durie-Salmon PLUS Stage IIIA IgG multiple myeloma requiring treatment with symptomatic anemia and bone lesions

Treatment:

Patient was started on D-Rd