Blood cancers

Early intervention with daratumumab may head off myeloma

Daratumumab monotherapy may be useful in patients with intermediate-risk or high-risk smouldering multiple myeloma (SMM) to delay their progression to MM.

A phase 2 study of the monoclonal antibody in 123 patients from 47 sites worldwide said a primary end point of progressive disease (PD)/death rate less 0.346/ patient-year suggested activity against SMM.

It found daratumumab treatment with all three dosing schedules – extended intense (intense), extended intermediate (intermediate) and short – met that criteria (0.055, 0.102 and 0.206 respectively).

However the pre-specified co-primary endpoint of complete response (CR) rate >15% was not met at the time of clinical cutoff.

It found CR was 2.4% with the intense dosing schedule of daratumumab (weekly in Cycle 1, every 2 weeks in Cycles 2 and 3, every 4 weeks in Cycles 4–7, every 8 weeks in Cycles 8–20), 4.9% with intermediate dosing (weekly in Cycle 1 and every 8 weeks in Cycles 2–20) and 0% with the short dosing (one cycle of weekly daratumumab). 

The 24-month biochemical or diagnostic (BOD) PFS rates were 77.5%, 70.2% and 26.8% respectively.

“The co-primary endpoint of CR rate of >15% was not met at the time of clinical cutoff, which suggests that single agent daratumumab may not be sufficient to eradicate SMM. However, the PD/death rate and ORR demonstrated that daratumumab does have single-agent activity in SMM.”

“Furthermore, the PFS and BOD PFS data suggest that prolonged dosing of daratumumab monotherapy delays both diagnostic progression and biochemical progression compared with short-term dosing.”

The study, co-authored by Australians Professor Andrew Spencer (Alfred Health and Monash University) and Dr Jane Estell (Concord Hospital and University of Sydney), found adverse events including fatigue, URTI and cough in most patients (100% in intense and intermediate dosing groups, 92.5% with short dosing). 

Grade 3 and 4 treatment-emergent adverse events including hypertension and hyperglycemia were reported in 43.9% of the intensively treated patients, 26.8% of the patients receiving intermediate dosing and 15.0% of those with the short dose duration. 

The authors acknowledged that the idea of treating a disease such as SMM that had not yet manifested clinically was likely to be a challenge, especially for health funding systems. 

“However, the potential risks of early intervention should be balanced with the comorbidities, diminished quality of life, and higher risk for death associated with MM,” the study said.

“Rapid advancements continue to be made in MM therapy, and some of these new therapies may translate into development of earlier treatments for SMM.”

Professor Spencer told the limbic the purpose of this study had been to select a schedule for the phase 3 trial of daratumumab versus observation which was now underway.

“…and what this study showed was that, not surprisingly, the longer you give daratumumab the better the outcome.”

“The people with really short duration of treatment tend to lose any benefit fairly promptly and their outcome was significantly different to the other groups.”

He said how to manage SMM was somewhat contentious given there wasn’t a uniformly agreed upon criteria to define the patients at higher risk of progression.

“With that caveat, the fact they are doing the phase 3 trial of daratumumab versus observation is quite legitimate. It’s probably less dangerous to the patients than some of the other studies that have been done.”

“There are some studies going on in Europe and the US where they are giving four drug combinations and tandem autologous transplants to these “high risk SMM” patients and I think a fair number of clinicians find that quite inappropriate because some of these people are never going to get myeloma.”

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