Amrita Krishnan, MD, FACP of City of Hope S1803, Lenalidomide +/- Daratumumab/rHuPh20 as Post-ASCT Maintenance for MM w/MRD to Direct Therapy Duration (DRAMMATIC)
Patients are registered before or after ASCT for screening (Reg Step 1), but before Reg Step 2. Patients are monitored before they begin maintenance and are then registered (first randomization) for Reg Step 2. Between Lenalidomide for 2 years and Lenalidomide + Daratumumab/rHuPH20, patients are randomized. MRD is measured after 2 years of maintenance to guide further therapy. The assigned care will be continued by MRD-positive patients. In order to either proceed or discontinue the care assigned, MRD-negative patients will be further randomized (Reg Stage 3). Patients are handled for up to 7 years after step 2 and are monitored for up to 15 years after step 2.
Measures of key outcomes:
Overall Survival [Time Frame: measured up to 15 years from the date of initial randomization before death due to some cause]
Using a weighted log-rank test, overall survival will be measured and compared between the primary treatment arms. The review would include all qualifying patients with valid consent. At the date of last touch, patients who are last confirmed to be alive are censored.
Measures of Secondary Outcome:
Progression Free Survival [Time Frame: Measured up to 7 years from the date of initial randomization before progression or death due to some cause, whatever happens first]
Progression-free survival will be measured and compared between primary treatment arms using a weighted log-rank test. The review would include all qualifying patients with valid consent. At the date of last touch, patients who were last considered to be progression-free and alive are censored.
Answer (PR or better) [Time frame: from the date of initial randomization to the date of best response during treatment during the analysis. ]
Per International Uniform Response Requirements for Multiple Myeloma PR- ⁇ 50% decrease in the size of soft tissue plasmacytomas & plasma cells; ⁇ 50% decrease in serum & decrease in urine M protein ⁇ 90% or < 200 mg/24hr or ⁇ 50% decrease in difference in serum free light chain levels uninvolved & involved; VGPR- PR + Serum and urine M proteins detectable by immunofix
[Time frame: 24 months from initial randomization] MRD Negativity
The MRD response rate will be measured as the number of patients who have obtained an MRD response, divided by the number of qualified patients; non-responders will be included in patients without definitive MRD outcomes. A layered Cochran-Mantel-Haenszel test will be used to make comparisons between weapons.
MRD results, including the percentage of cells detected and total cells collected, will be collected from the central testing laboratory. For a typical multiple myeloma MRD sensitivity of 0.0001 percent, 5 x 106 events are collected unless the sample is small.
Negativity of MRDs will be characterized as no templates observed at a sensitivity of 1 per million cells evaluated, with at least 1 million cells evaluated.
MRD positivity will be defined as any of the templates observed irrespective of the number of cells or non-diagnostic specimens examined, even if it is not possible to sequence the reference diagnostic specimen.
Other Indicators of Outcome:
Toxicity evaluation [Time Frame: up to 7 years from the time of initial randomization. ]
For toxicity analyses, all randomized patients that have initiated treatment would be considered evaluable. For each patient, the maximum grade for each toxicity will be registered, and to assess toxicity trends, frequency tables will be checked.