Dr Rajkumar Talks Frontline Therapy of Myeloma for Transplant-Ineligible Patients

At the virtual 2021 Great Debates & Updates in Hematologic Malignancies, S. Vincent Rajkumar, MD, Professor of Medicine, Mayo Clinic, overviewed the frontline therapy of multiple myeloma (MM) for transplant-ineligible patients.

A doctor’s approach to treating patients with newly-diagnosed myeloma may be different, Dr Rajkumar said, especially since there are several subtypes of the disease. Some subtypes are considered standard-risk, including trisomies, the t(11;14) translocation and t(6;14), and some are considered high-risk, such as t(14;16), t(14;20), t(4;14), del (17p) and gain (1q). About 25% of patients with myeloma have high-risk disease and about 75% have standard risk-disease.

“The reason I say this … is because our approach to therapy varies somewhat between these 2 groups and the prognosis and expectations also are different,” Dr Rajkumar said, before delving even further and noting that patients with 2 high-risk abnormalities are double-hit myeloma and patients with 3 high-risk abnormalities are triple-hit myeloma.

“As these high-risk abnormalities accumulate, your prognosis and refractoriness to treatment also increases. And so, for patients with double- and triple-hit myeloma, we may approach them even more aggressively than high-risk disease,” he told attendees.

Currently, most patients with MM who are not eligible for transplant receive a triple regimen of bortezomib, lenalidomide and dexamethasone (VRd) as their initial frontline therapy, Dr Rajkumar said. This is based off the SWOG S0777 study, which compared VRd to lenalidomine plus dexamethasone (Rd). What was found was that VRd had significantly better PFS (95% CI, 39-52) versus Rd (95% CI, 25-39). Overall survival was also prolonged with VRd (6 years) compared to Rd.

The key thing to remember with this trial is that VRd was given for only 6 months and after that, patients received only Rd. So, it’s not a triplet forever, it’s a triplet for 6 months followed by Rd, Dr Rajkumar said.

A number of randomized trials have looked into improving the VRd triplet either by changing the proteasome inhibitor from bortezomib to carfilzomib, or changing the triplet itself by using daratumumab instead (Dare-Rd). Another way would be to add another drug, making it a quadruplet, however, it’s important to note the added extra cost and toxicity, Dr Rajkumar said.

The Dara-Rd versus Rd trial found that similar to VRd, using Dara-Rd is better than Rd alone with significant improvement in progression free survival. Compared to the SWOG S0777 trial, Dara-Rd was used continuously, not just 6 months.

“So, you are going to have Dare-Rd months after month for 3 to 4 years or longer. And you have to take that into account when you decide should I used VRd or Dare-Rd? The difference is not in the PFS or survival, because these 2 regiments have not been compared head-to-head, but really the differences in cost, convenience and toxicity of giving a triplet indefinitely versus giving a triplet only for a short duration of time,” Dr Rajkumar said.

On the topic of changing the proteasome inhibitor, Dr Rajkumar discussed a study that looked into KRd, or carfilzomib, lenalidomide and dexamethasone, versus VRd in patients with MM, and found that there was no difference in PFS or overall survival when using carfilzomib instead of bortezomib. Also, carfilzomib does not seem to add anything to VRd, however, the toxicity with carfilzomib is cardiac and renal, and that was higher than bortezomib, which had more neurotoxicity.

“This shows you why we need to do randomized trials, because otherwise people were saying KRd is better, but it’s clearly not in this trial,” Dr Rajkumar said.

There are reasonable options for elderly and frail patients who cannot travel due to COVID-19 or other concerns, Dr Rajkumar said, referring to the Tourmaline MM-2 study, which looked at the oral produce inhibitor ixazomib-Rd (IRd) versus placebo-Rd. The study found patients had a PFS of 35 months with IRd versus only 21.8 months with Rd. The median follow-up for PFS was 53.3 vs. 55.8 months in ixazomib-Rd and placebo-Rd arms, respectively.

In all, patients with newly-diagnosed MM that cannot receive a transplant and are standard-risk, Dr Rajkumar said, will be treated with VRd with lenalidomide as maintenance therapy or DRd until progression. Patients that are high-risk are treated with VRd and move to bortezomib-based maintenance.—Emily Bader