Daratumumab-Led Quad Therapy Aids MRD Surveillance in MM

Research into quadruplet therapy in multiple myeloma (MM) over the past several years has shown great promise, particularly toward progression-free survival (PFS)¹ compared with triplet therapy, as well as overall survival (OS) and achieving minimal residual disease (MRD) negativity.^2,3

MRD-positive or -negative status indicates detectable or not, respectively, residual (or remaining) cancer cells following treatment.⁴

An abstract presented on Sunday, December 12, at this year’s 63rd Annual American Society of Hematology Annual Meeting and Exposition (ASH 2021) bears out the results of the MASTER trial investigation⁵ into the use of daratumumab, carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Dara-KRd) quadruplet therapy among patients with newly diagnosed MM (NDMM) after autologous hematopoietic stem cell transplantation (AHCT) and stoppage of treatment following an MRD negative result.⁶

MRD negative status (< 10^-5), per International Myeloma Working Group (IMWG) criteria, was the primary end point, with patients on therapy until 2 consecutive measures of MRD < 10^-5 were confirmed. “MRD post initial therapy is prognostic of long-term outcomes in patients with NDMM, but has not been used to modify therapy,” the authors wrote. “We hypothesized that Dara-KRd would be safe and highly active in patients with NDMM.”

This final primary end point analysis also used next-generation sequencing via the clonoSEQ assay⁷ to guide the use of Dara-KRd.

To qualify for this analysis,⁶ the cohort of 123 patients (recruited between March 2018 and September 2020; median age, 60 years) with NDMM had to need treatment and have a creatinine clearance of at least 40 mL/min, adequate liver and heart function, and an Eastern Cooperative Oncology Group (ECOG) score of 0 to 2. Their 30-month treatment consisted of the following:

• 16-mg/kg intravenous (IV) daratumumab on days 1, 8, 15, and 22; subsequent cycles saw a reduction in frequency
• 56 mg/m2 IV carfilzomib on days 1, 8, and 15
• 25-mg oral lenalidomide on days 1 through 21
• 40-mg oral/V dexamethasone on days 1, 8, 15, and 22; repeated every 28 days

This entire cohort also underwent induction with 4 cycles of Dara-KRd, AHCT, and consolidation treatment with 0, 4, or 8 cycles of Dara-KRd. MRD status, employed after induction and AHCT and during each consolidation cycle, determined next treatment steps.

Most patients (43%) were shown to not have high-risk cytogenetic abnormalities (HRCA), and of those reporting 2 or more, those HRCA were [gain 1q, t(4;14[MS1] ), t(14;16), t(14;20) or del(17p)]. In addition, 20% had an ECOG score of 2 and 20% had a Revised International Staging System (R-ISS) score of 3. After a median follow-up of 25.1 months, treatment continued in 4 patients, lenalidomide maintenance started for 20 (these patients finished consolidation absent confirmed MRD negative status), and MRD negativity was seen in 84, who then transitioned to a treatment-free observation period (mean, 14.2 months) and MRD surveillance (MRD-SURE); no patients in this group died.

MRD negativity was achieved by an astounding 80% of the patient cohort, with 66% coming in at MRD < 10^-6. Subsequent therapy phases led to a greater depth of response, and this was seen regardless of patients having 0, 1, or 2 or more HRCA. In addition, patients with these HRCA totals saw similar high MRD-negative rates and MRD < 10^-6 of 78% and 64%, 82% and 73%, and 79% and 58%, respectively.

Most patients also achieved at least a complete response (86%), 2-year PFS (87%), and 2-year OS (94%). At the 1-year mark following treatment stoppage, there were instances of MRD resurgence or IMWG progression, but these results were mixed, with a 0% rate in patients with 1 HRCA but 4% and 27% in those with 0 and 2 or more HRCAs, respectively.

“Monoclonal antibody-based quadruplet therapy, AHCT and MRD response-adapted consolidation therapy leads to the highest rate of MRD negativity reported in NDMM,” the authors concluded. “While most patients with ultra-high risk MM reach deep responses with this approach, novel consolidative strategies are needed, which creates the opportunity of MRD surveillance as an experimental alternative to the burden of indefinite maintenance.”

Daratumumab as part of a quadruplet regimen—along with bortezomib, thalidomide, and dexamethasone—was approved for use among patients with NDMM eligible for AHCT on September 29, 2019,⁸ following its approval earlier that year as part of a triplet regimen—with lenalidomide and dexamethasone—for use in those ineligible for AHCT.⁹

References

1. Inserro A. Quadruple therapy for newly diagnosed patients with MM shows PFS benefit over triple therapy. The American Journal of Managed Care®. October 28, 2019. Accessed December 15, 2021. https://www.ajmc.com/view/quadruple-therapy-for-newly-diagnosed-patients-with-mm-shows-pfs-benefit-over-triple-therapy

2. Branagan A, Lei M, Lou U, Raje N. Current treatment strategies for multiple myeloma. JCO Oncol Pract. 2020;16(1):5-14. doi:10.1200/JOP.19.00244. https://ascopubs.org/doi/full/10.1200/JOP.19.00244

3. Ingram I.Four drugs upfront yield ‘unprecedented’ response in myeloma. Medpage Today. April 16, 2021. Accessed December 15, 2021. https://www.medpagetoday.com/hematologyoncology/myeloma/92146

4. Minimal residual disease.Leukemia & Lymphoma Society. Published April 2019. Accessed December 15, 2021. https://www.lls.org/sites/default/files/National/USA/Pdf/Publications/FS35_MRD_Final_2019.pdf

5. MonoclonalAntibody-Based Sequential Therapy for Deep Remission in Multiple Myeloma (MASTER). ClinicalTrials.gov. Updated September 22, 2021. Accessed December 15, 2021. https://clinicaltrials.gov/ct2/show/NCT03224507

6. Costa LJ, Chhabra S, Callander NS, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd), autologous transplantation and MRD response-adapted consolidation and treatment cessation. Final primary endpoint analysis of the Master trial. Presented at: 63rd Annual American Society of Hematology Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 481. Accessed December 15, 2021. https://ash.confex.com/ash/2021/webprogram/Paper145494.html

7. Adaptive Biotechnologies announces new data demonstrating the benefit of serial MRD testing with the clonoSEQ assay in patients with blood cancers at the 63rd ASH annual meeting.Press release. Adaptive Biotechnologies. December 13, 2021. Accessed December 15, 2021. https://finance.yahoo.com/news/adaptive-biotechnologies-announces-data-demonstrating-210500903.html?guccounter=1

8. FDA approves daratumumab for transplant-eligible multiple myeloma. Press release. FDA. September 26, 2019. Accessed December 15, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-transplant-eligible-multiple-myeloma

9. FDA approves daratumumab for multiple myeloma ineligible for autologous stem cell transplant. Press release. FDA. June 27, 2019. Accessed December 15, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-multiple-myeloma-ineligible-autologous-stem-cell-transplant