Daratumumab Becomes Treatment Staple in Newly Diagnosed Multiple Myeloma

Manisha Bhutani, MD, a hematologist at Levine Cancer Institute, Atrium Health

Manisha Bhutani, MD

The foremost choice in the treatment of patients with newly diagnosed multiple myeloma is determining whether a patient is eligible for transplant, as that choice will set the stage for all future decisions.

In the absence of global consensus guidelines, transplant eligibility criteria have become rooted in a patient’s biologic age, frailty, performance status, comorbidities, psychosocial situation, and individual preference, said Manisha Bhutani, MD, in a presentation during the 2020 OncLive^® State of the Science Summit™ on Multiple Myeloma.

At the meeting, Bhutani, a hematologist at Levine Cancer Institute, Atrium Health, discussed the differences in treatment for patients with transplant-eligible and -ineligible newly diagnosed multiple myeloma.

In clinical practice, therapy for transplant-eligible patients consists of 4 to 6 cycles of induction therapy followed by autologous stem cell transplant (ASCT) consolidation and maintenance. If patients are deemed transplant-ineligible, they will undergo a period of extended induction therapy followed by maintenance, according to Bhutani.

“As the therapeutic landscape of multiple myeloma grows every year, a greater proportion of patients are able to achieve stringent complete responses (sCRs) or minimal residual disease (MRD) negativity,” said Bhutani.

Previous research has suggested that the higher the quality of response that is generated, the better patients will fare in the long term, added Bhutani. Additionally, several reports have shown that those who achieve MRD negativity tend to have better outcomes, with prolonged progression-free survival (PFS) and overall survival (OS).^1,2

The improvement in the depth and durability of responses may be attributed to the addition of the CD38-directed monoclonal antibody daratumumab (Darzalex) to initial therapy in patients with newly diagnosed disease. The agent has been evaluated in both the transplant-eligible and -ineligible settings.

Transplant-Ineligible Myeloma

In the phase III MAIA trial, patients were randomized 1:1 to receive daratumumab plus standard lenalidomide (Revlimid) and dexamethasone (DRd; n = 368) versus Rd alone (n = 369). Ninety-nine percent of patients were ≥65 years and 44% were ≥75 years, which made the results easily extricable to an older patient population, noted Bhutani.

At a median follow-up of 28 months, the median PFS was not reached in the DRd arm versus 31.9 months in the Rd arm (HR, 0.56; 95% CI, 0.43-0.73; P <.001).³ According to prespecified subgroup analyses, the PFS favored the use of DRd in all patients, except those with high-risk cytogenetics (HR, 0.85; 95% CI, 0.44-1.65).⁴ Additionally, a higher percentage of patients achieved sCR/CR (47.6% vs 24.9%) and MRD negativity (24.2% vs 7.3%) in the DRd arm versus the Rd arm, respectively.³

After a median follow-up of 36.4 months, the median PFS was still not reached in the DRd arm versus 33.8 months in the Rd arm (HR, 0.56; 95% CI, 0.44-0.71; P <.0001). Additionally, the hazard ratio favored the use of DRd in standard-risk (HR, 0.50) and high-risk patients (HR, 0.57) patients.⁵

Investigators also reported a sustained rate of sCR/CR and MRD negativity that favored DRd with extended follow-up. Based on these data, in June 2019, the FDA approved the triplet for the treatment of patients with newly diagnosed myeloma who are ineligible for ASCT.

The phase III ALCYONE trial was also conducted in the frontline setting and evaluated the addition of daratumumab to bortezomib (Velcade), melphalan, and prednisone (VMP), which is a historical standard of care in Europe, said Bhutani. In the trial, patients were randomized 1:1 to receive either D-VMP followed by daratumumab or VMP alone.

At a median extended follow-up of 40.1 months, the median PFS with D-VMP versus VMP alone was almost double, at 36.4 months versus 19.3 months, respectively (HR, 0.42; 95% CI, 0.34-0.51; P <.0001). Additionally, the 3-year OS rate was 78.0% in the D-VMP arm versus 67.9% in the VMP alone arm (HR, 0.60; 95% CI, 0.46-0.80; P = .0003), which translated into a 40% reduction in the risk of death with D-VMP.⁶ In addition, D-VMP led to a significant improvement in the sCR/CR and MRD-negative rates at initial and extended follow-up, said Bhutani. Specifically, the sum of the rates of sCRs and CRs was almost twice as high with daratumumab versus VMP alone, and the rate of MRD-negative status was more than 3 times as higher.^6,7

Although the quadruplet was approved in May 2018 for the treatment of patients with newly diagnosed myeloma who are ineligible for ASCT, the regimen is not widely used in practices within the United States because VMP was never a frontline standard of care, explained Bhutani.

Transplant-Eligible Myeloma

In the transplant-eligible setting, triplets have served as the historical control, explained Bhutani. For example, in the phase III CASSIOPEIA trial, investigators evaluated the addition of daratumumab to bortezomib, thalidomide (Thalomid), and dexamethasone (VTd) versus VTd alone. Patients were randomized to receive either D-VTd or VTd before transplantation and consolidation treatment after transplant. All responders were then rerandomized to receive maintenance treatment with daratumumab only or observation.

At 100 days post ASCT, the sCR rate was 28.9% in the D-VTd arm versus 20.3% in the VTd alone arm, meeting the primary end point of the study, said Bhutani. Moreover, the rates of MRD negativity among patients who achieved a sCR/CR were higher in the D-VTd arm versus the VTd arm, at 33.7% and 19.9%, respectively. The median PFS rate at 18 months was 92.7% in the D-VTd arm versus 84.6% in the VTd-alone arm (HR, 0.47; 95% CI, 0.33-0.67; P <.0001).⁸

“PFS favored D-VTd across all subgroups, including patients with high-risk cytogenetics and International Staging System (ISS) stage III disease,” said Bhutani.

The results from the trial served as the basis for the September 2019 FDA approval of the quadruplet for the treatment of patients with newly diagnosed disease who are eligible for ASCT.

The phase II GRIFFIN trial is comparing the current standard of lenalidomide, bortezomib, and dexamethasone (RVd) with daratumumab plus RVd (D-RVd). Unlike the CASSIOPEIA trial, which rerandomized patients following consolidation, patients on the GRIFFIN trial who complete D-RVd and RVd induction and consolidation will continue to receive either D-R or R maintenance, respectively.

By the end of consolidation, 42.4% of patients in the D-RVd arm and 32.0% of patients in the RVd arm achieved sCR, meeting the primary end point of the study (odds ratio, 1.57; 95% CI, 0.87-2.82; 1-sided P = .068).⁹

“D-RVd resulted in incremental increases in sCR that deepened over time,” said Bhutani.

Additionally, MRD negativity, which was assessed at a sensitivity of 10^-5, was achieved in 51.0% of patients in the overall population with the addition of daratumumab and 47.1% of those who also achieved a CR or better. The MRD negativity rates in the RVd arm were 20.4% in the overall population and 18.4% in those who achieved a CR or better.

Although the addition of daratumumab to RVd failed to improve the rate of sCR/MRD negativity versus RVd in patients with high-risk cytogenetics and ISS stage III disease,¹⁰ longer follow-up is needed to fully ascertain the impact of these findings, explained Bhutani.

Although the data are still immature at a median follow-up of 22.1 months, the estimated 2-year PFS rate is 95.8% in the D-RVd arm versus 89.8% in the RVd arm; the 2-year estimated OS rates were 95.8% and 93.4% in the in the D-RVd and RVd arms, respectively.⁹

Several trials have demonstrated the importance of achieving deep responses and MRD negativity, but the ongoing MASTER trial (NCT03224507) will implement the first MRD-adapted treatment design into its evaluation of quadruplet therapy. Patients will receive daratumumab plus carfilzomib (Kyprolis), lenalidomide, and dexamethasone (D-KRd) followed by transplant, D-KRd consolidation, and lenalidomide maintenance. If, after transplant or consolidation, patients are MRD negative, they will undergo treatment-free observation and MRD surveillance, said Bhutani.

At a median follow-up of 7.4 months, the rate of sCR with D-RVd was 39% after induction, 81% after transplant, and 95% after MRD-based consolidation with comparable benefit among standard- and high-risk patients, said Bhutani.¹¹

To date, 26 of 81 evaluable patients have achieved MRD negativity and entered into treatment-free observation. At a median follow-up of 4.9 months, investigators have yet to report a case of relapse or detectable MRD.

“It’s a good strategy to offer patients treatment-free observation and MRD surveillance if they are able to achieve a deep level of MRD negativity,” said Bhutani.

In terms of toxicity, the addition of daratumumab to standard therapy does increase the rate of all-grade infections; however, the rate of grade 3/4 infections is considered negligible, according to Bhutani.

An additional trial to note is the phase II FORTE trial , said Bhutani, in which patients were randomized to 1 of 3 arms: carfilzomib, cyclophosphamide, and dexamethasone (KCd) followed by transplant and KCd; KRd followed by transplant and KRd consolidation; or KRd followed by KRd consolidation. Subsequently, patients were randomized to receive either lenalidomide or KR maintenance.

At a median follow-up of 20 months, both KRd arms were found to be superior to KCd in inducing sCR/CR and MRD negativity.¹²

In terms of maintenance, lenalidomide remains the standard of care for standard-risk patients. However, ixazomib (Ninlaro) can be considered as an alternative for those who are intolerant of lenalidomide, said Bhutani.

Additional quadruplet therapies are currently under investigation. Data with these strategies, along with ongoing efforts being made to understand predictors of response and mechanisms of resistance, will have important implications for the treatment of patients with newly diagnosed multiple myeloma, concluded Bhutani.

References

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6. Mateos MV, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020;395(10218):132-141. doi: 10.1016/S0140-6736(19)32956-3.
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8. Moreau P, Attal M, Hulin C, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): CASSIOPEIA part 1 results. J Clin Oncol. 2019;37(suppl 15; abstr 8003). doi: 10.1200/JCO.2019.37.15_suppl.8003.
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