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Expert Point of View: Joseph Mikhael, MD


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The ASCO Post asked Joseph Mikhael, MD, Chief Medical Officer of the International Myeloma Foundation and Professor in the Applied Cancer Research and Drug Discovery Division at the Translational Genomics Research Institute (an affiliate of City of Hope Cancer Center), to comment on the GMMG-HD7 trial.

Four-Drug Combinations

“The results lend further support—this time from a phase III trial1—that adding a fourth drug to the standard RVd [lenalidomide, bortezomib, and dexamethasone] induction regimen serves to deepen responses and potentially improve long-term outcomes,” he said. “This trial is one of many studies (mostly smaller) evaluating the addition of a fourth agent to the classic RVd induction regimen. Some studies are deviating even further from the standard RVd induction protocol. For example, isatuximab is also being evaluated in combination with carfilzomib, lenalidomide, and dexamethasone.”

Joseph Mikhael, MD

Joseph Mikhael, MD

Dr. Mikhael continued: “It’s still too early to see whether a fourth drug affects progression-free and overall survival, but we know the depth of response in myeloma does predict for this. We just know at this point that four-drug combinations are better than RVd alone.”

Of note, the GMMG-HD7 trial found that the addition of isatuximab to RVd significantly improved the chance of achieving measurable residual disease (MRD) negativity—the trial’s primary endpoint. MRD, in fact, has been emerging as an important outcome. The phase II GRIFFIN trial also found that the addition of the similar antibody daratumumab to RVd more than doubled the MRD negativity rate.2

‘The Power of MRD Status’

Regarding the rising recognition of MRD negativity as a component of successful treatment, Dr. Mikhael commented: “We are all recognizing that things are going in this direction. For so long, when we didn’t have regimens that produced that depth of response, the fraction of patients achieving MRD negativity was not that important because not many patients got there. We were more interested in objective response, very good partial response, and complete response. But with these great regimens, we are now getting deep responses, and we know the power of MRD status.”

“So far, it seems that MRD negativity heralds better progression-free and overall survival; therefore, it makes sense to use MRD as a primary endpoint,” Dr. Mikhael stated. He added that its power as a surrogate marker needs to be confirmed in clinical trials; however, he acknowledged, “since it’s not a perfect measure, other measures of response will remain important.” 

DISCLOSURE: Dr. Mikhael has served as a consultant for Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptides, and Sanofi.

REFERENCES

1. Goldschmidt H, Mai EK, Nievergall E, et al: Addition of isatuximab to lenalidomide, bortezomib and dexamethasone as induction therapy for newly diagnosed, transplant-eligible multiple myeloma patients: The phase III GMMG-HD7 trial. 2021 ASH Annual Meeting & Exposition. Abstract 463. Presented December 12, 2021.

2. Voorhees PM, Kaufman JL, Laubach J, et al: Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: The GRIFFIN trial. Blood 136:936-945, 2020.


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