Intensified Daratumumab Induction Leads to Promising Response in Ultra High–Risk Multiple Myeloma

Article

Data from the OPTIMUM/MUKNINE trial presented at 2021 EHA Congress show promise for daratumumab plus CVRd as induction in patients with multiple myeloma and certain high-risk disease factors.

For patients with ultra­ high-risk multiple myeloma or primary plasma cell leukemia (pPCL), intensified induction therapy with daratumumab (Darzalex) plus cyclophosphamide, bortezomib, lenalidomide (Revlimid), and dexamethasone (dara-CVRd) followed by bortezomib-augmented autologous stem cell transplant (ASCT) resulted in deep remissions, according to data reported from the prospective OPTIMUM/MUKNINE trial (NCT03188172) at the 2021 European Hematology Association (EHA) Congress.

Currently, most newly diagnosed myeloma patients are treated uniformly, but about 20% experience an early relapse, even if treated with an intensive treatment,” Martin Kaiser, MD, FRCP, of The Institute of Cancer Research and Royal Marsden Hospital, London, United Kingdom, said during a presentation of the data. “The patients need post-hoc treatment modifications which can be a strain on resources, it can be stressful for patients, and increased tumor burden can potentially accelerate tumor evolution.”

Kaiser went on to explain that management requires improved biological risk prediction for early treatment modification and resource adjustment. Biological risk in multiple myeloma can be assessed through genetic markers and gene expression associated with high cell proliferation. In addition, patients with pPCL are characterized by a high degree of proliferation and independence of the bone marrow niche. Together, these subpopulations comprise a patient cohort considered to have ultra­ high-risk disease.

The OPTIMUM trial took patients with primary PCL (n = 10) and suspected newly diagnosed multiple myeloma (n = 462) who were fit for intensive therapy and performed genetic marker and gene expression testing on bone marrow aspirate to determine an ultra­ high–risk population (n = 128) who went on to receive dara-CVRd plus ASCT. The primary end points were MRD and response after induction and ASCT.

Patients received induction treatment with daratumumab at 16 mg/kg for 2 cycles on days 1, 8, and 15 followed by the same dose on day 1 of each subsequent cycle; cyclophosphamide at 500 mg on days 1 and 8; bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11; lenalidomide at 25 mg on days 1 through 14; and dexamethasone 40 mg on days 1, 4, 8, 11 were administered for a maximum of 6 21-day cycles. Patients were then treated for stem cell mobilization and went on to receive ASCT with melphalan and bortezomib. Consolidation with 6 cycles of dara-VRd and 12 cycles of dara-VR was followed by maintenance with dara-R.

Patient characteristics indicated an ultra­ high–risk population, with 53% having double-hit genetics and 77% with SKY92 risk signature present. About 30% of patients had both double hit and SKY92.

Of the 107 patients who received at least 1 dose of study treatment, 2 patients died early from myeloma-related infections. One hundred patients completed induction and 94 were eventually eligible for ASCT. Ninety-two went on to have ASCT.

In the evaluable population (n = 102), the ORR was 99% at the end of induction, which was made up of 23% complete responses (CR), 61% very good partial responses (VGPR), and 16% PRs. On day 100-120 post-ASCT, the ORR was 93% and was comprised of 52% CRs, 35% VGPRs, and 5% PRs. The rate of MRD negativity was 50% at the end of induction and 82% on day 100-120 post-ASCT.

In the safety population, the ORR was 94% at the end of induction with 22% CRs; that rate was 83% on day 100-120 post-ASCT with 47% CRs. The rate of VGPR or better in the 2 groups was 80% and 79%, respectively. The rate of MRD negativity was 41% at the end of induction and 63% day 100-120 post-ASCT.

In just those patients with pPCL (n = 8), 25% each had CRs, VGPRs, PRs, and progressive disease.

Grade 2 events included anemia (18.7%), neutropenia (15.0%), thrombocytopenia (10.3%), infection (17.8%), pain (22.4%), fatigue (15.9%), and neuropathy (12.1%). Grade 3/4 events included anemia (4.7%), neutropenia (20.5%), thrombocytopenia (12.2%), and infection (12.1%).

“Dara-CVRd and bortezomib-augmented transplant-induced deep remission in [ultra­ high–risk] patient population,” Kaiser concluded. “Dara-CVRd is safe and well tolerated in these ultra­ high–risk patients. However, some ultra­ high–risk and pPCL patients relapsed early in this intensified modern therapy, which demonstrates that risk in myeloma is quantitative and subgroups with an unmet need still need further addressing.”

Reference

Depth of response and mrd status in ultra high-risk myeloma and plasma cell leukemia treated with dara-cvrd and augmented autologous transplant: results of the risk-stratified uk optimum/muknine trial. Presented at: 2021 European Society of Hematology Congress; June 9-17, 2021. Virtual. Accessed June 11, 2021. Abstract S181. https://bit.ly/3pWr6db

Newsletter

Stay up to date on recent advances in the multidisciplinary approach to cancer.

Recent Videos
Success with the 177Lu-PSMA-617 radioligand therapy would be transformative for the clear cell renal cell carcinoma treatment landscape.
An ongoing phase 1 trial seeks to prove XmAb819 as an effective treatment and ENPP3 as a plausible target in patients with relapsed or refractory RCC.
“The therapy is designed to prevent both CAR T-cell inactivation and to restore the anti-tumor immunity of the white blood cells that have gotten through the tumor,” said Marasco, MD, PhD.
Ongoing studies aim to combine base immunotherapy regimens with novel agents to potentially improve outcomes among patients with kidney cancer.
Investigators have found a way to reduce liver and biliary toxicity when targeting the molecule CAIX in patients with clear cell renal cell carcinoma.
Neoantigen-targeting vaccines resulted in an absence of recurrence in 9 patients with high-risk kidney cancer, according to David A. Braun, MD, PhD.
The Kidney Cancer Research Consortium may allow collaborators to form more mechanistic and scientifically driven efforts in the field.
Wayne A. Marasco, MD, PhD, stated that by targeting 2 molecules instead of 1, higher levels of tumor cell killing can be achieved in patients with clear cell renal cell carcinoma.
Leading experts in the breast cancer field highlight the use of CDK4/6 inhibitors, antibody-drug conjugates, and other treatment modalities.
Related Content