Five-Drug Combination Shows Benefit in Ultra-High Risk Multiple Myeloma

Dawn O'Shea

December 14, 2021

A team of researchers from The Institute of Cancer Research in London and the Clinical Trials Research Unit at the University of Leeds has identified a new five-drug combination that significantly improves progression-free survival (PFS) in patients with ultra-high risk (UHiR) newly diagnosed multiple myeloma (NDMM) or primary plasma cell leukaemia (pPCL).

In a study presented Sunday at the American Society of Hematology annual meeting, the team used a novel methodology to compare PFS from the digital comparator OPTIMUM/MUKnine trial of the five-drug combination against the treatment regimen being used in the NCRI MyXI prior trial. Optimum used daratumumab, cyclophosphamide, bortezomib, lenalidomide, dexamethasone (Dara-CVRd), V-augmented autologous stem cell transplant (V-ASCT) and Dara plus bortezomib, lenalidomide, and dexamethasone (VRD) consolidation.

Study Details

Between September 2017 and July 2019, a total of 472 patients from 39 UK hospitals with suspected NDMM or pPCL were screened, of whom 107 with UHiR NDMM by central trial genetic (≥2 high risk lesions) or gene expression SKY92 (SkylineDx) profiling, or with pPCL (circulating plasmablasts >20%) were recruited to OPTIMUM.

Patients received up to six cycles of Dara-CVRd induction, V-ASCT, followed by Dara-VRd consolidation 1 (Cons1) for six cycles, Dara-VR consolidation 2 for 12 cycles and monthly Dara-R maintenance until progression.

At median follow-up of 27.1 months, median PFS was not reached for OPTIMUM patients. At 18 months, PFS in the OPTIMUM trial was of 81.7% versus 65.9% for MyXI prior.

At 18 months, PFS was 64.5% with cyclophosphamide, lenalidomide and dexamethasone (CRd) and 68.3% with carfilzomib, cyclophosphamide, lenalidomide, and dexamethasone (KCRd).

The difference between the various trial treatment regimens increased over time. Six-month estimates were 95.3% in OPTIMUM, 95.1% in the MyXI KCRd arm, and 93.5% in the MyXI CRd arm. However, 12 month-estimates were similar for OPTIMUM (87.5%) and MyXI KCRd (87.8%), but was lower with CRd (81.7%). This improvement in comparative benefit over time suggests Dara-VRd is likely to have particular efficacy in maintaining responses post ASCT.


In terms of toxicity, grade 4 adverse events (AEs) were rare (<5%). The most common grade 3/4 AEs were thrombocytopenia (27.9%), neutropenia (21%) and infection (19.8%). Despite this, 94% of patients who started OPTIMUM Cons1 completed all six cycles of therapy.

Commenting on the findings, lead author, Dr Martin Kaiser, from The Institute of Cancer Research, London, and consultant haematologist at the Royal Marsden Foundation Trust, said: "We know that patients with multiple myeloma who have ultra-high risk genetic signatures have particularly aggressive cancers that fail to respond to standard treatment. In this study, we have identified a new five-drug combination that can keep myeloma at bay for longer in these patients.

The findings also support the use of genetic testing for MM to facilitate targeted treatment.

"Our study shows the benefit of genetic testing in patients with myeloma to identify those at highest risk, since we now have a new and better treatment option for these people," Dr Kaiser said.

"All these drugs are already individually licensed and available so we know they are safe, and that means the new combination could potentially be made available for patients quickly. I hope the NHS will consider our data as soon as possible," he said.


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