Does it make sense to compare two clinical trials, one for newly diagnosed elderly MM patients and one for average Newly Diagnosed Multiple Myeloma (NDMM) patients? You be the judge.
I’m not talking about comparing elderly MM patients with average MM patients. I’m talking about comparing each induction therapy to each other. My thinking is that once you, the NDMM patient, regardless of age, understands the benefits of the less toxic approach for myeloma induction below, you will want the induction therapy with the longer PFS, OS that also brings less toxicity with fewer average short, long-term and late stage side effects.
The three main criteria that I believe are central for comparisons to NDMM patients are:
- Progression-free survival- PFS-(time in first remission)
- Overall Survival-OS- (time from treatment until death)
- Adverse Events- side effects
In addition to the 3 key issues listed above are the sort of FDA, Health Insurance side of things. Of all the therapies discussed below- Daratumumab, Kyprolis, Velcade, dexamethasone- all are FDA approved both for induction treatment as well as relapsed, refractory treatment. The challenge will be changing the standard-of-care for newly diagnosed MM patients.
- Treatment #1 is daratumumab/lenalidomide (revlimid)/dexamethasone- (Dara-Rd)
- Treatment #2 is Daratumumab/Kyprolis/dexamthasone- (Dara-KRd)
The first treatment above is for elderly, non-transplant eligible NDMM patients. This means that the regimen is for older patients possibly with co-morbidities such as frailty, heart or kidney problems. In essence, this is a gentler, less toxic, induction therapy.
Treatment #2 above is an aggressive, highly toxic approach to therapy designed to achieve the highest percentage of deep remissions (MRD neg.) as possible.
The question then, is to compare results. I don’t mean compare PFS, I mean compare OS or length of life. In the MASTER trial linked below Dara-KRd definitely achieves a higher percentage of MRD responses. In short, a deeper response.
And this makes sense. NDMM patients undergo Dara-KRd induction therapy, ASCT and then more Dara-KRd therapy until they reach the deepest remission possible.
But the question is, does that deeper response mean a longer length of life? A longer overall survival OS? And is there a price to be paid for the deep response? I mean, anyone can see that the patients who undergo aggressive induction followed by aggressive ASCT, followed by aggressive therapy after the ASCT will achieve a much higher average risk of short, long-term and late stage side effects compared to the less toxic approach.
Consider MM Specialist Dr. Rajkumar’s discussion of the Cure vs. Control Debate in MM-
“Although not often openly acknowledged, “cure vs control” is the dominant philosophical difference behind many of the strategies, trials, and debates related to the management of myeloma. Should we treat patients with myeloma with multidrug, multitransplant combinations with the goal of potentially curing a subset of patients, recognizing that the risk of adverse events and effect on quality of life will be substantial? Or should we address myeloma as a chronic incurable condition with the goal of disease control, using the least toxic regimens, emphasizing a balance between efficacy and quality of life, and reserving more aggressive therapy for later?…”
If you have any questions or comments, please scroll down the page, post a question or a comment and I will reply to you ASAP.
Thanks,
David Emerson
- MM Survivor
- MM Cancer Coach
- Director PeopleBeatingCancer
Recommended Reading:
PeopleBeatingCancer- Side Effects Program
“Triple-agent treatment led to skyrocketing overall survival (OS) and progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (MM) who were ineligible for stem-cell transplantation…
In the ongoing phase III trial, median OS was not reached in patients who received a regimen of daratumumab/lenalidomide/dexamethasone and neither was median PFS at 56.2 months (5.8 years)
While median OS was also not reached in the control group, who got lenalidomide/dexamethasone, the median PFS for these patients came in at 34.4 months…
In addition, given the estimated 60-month PFS of 52.5% in the daratumumab group, the median PFS “is anticipated to be more than 5 years, which, to our knowledge, would be unprecedented” in this patient population, they emphasized…
They advised that daratumumab/lenalidomide/dexamethasone should be the go-to treatment for “first relapse in patients whose disease is not refractory to lenalidomide… the magnitude of benefit is impressive, and the regimen is relatively easy to administer, especially after the first 6 months of therapy…”
Daratumumab is a human immunoglobulin-κ monoclonal antibody that targets CD38 with a direct on-tumor and immunomodulatory mechanism of action, Facon’s group explained. The agent is FDA approved, as monotherapy and in combination with standard-of-care regimens, in newly diagnosed MM and relapsed or refractory MM…
Study protocol, including dosing, and results at a median of 28 months follow-up were revealed in a 2019 prespecified interim analysisin NEJM. In an accompanying editorial, Jacob Laubach, MD, of the Dana Farber Cancer Institute of Boston, pointed out that “the median age of the participants in the study was 73 years…”
Patients (n=737) were enrolled in MAIA from March 2015 to January 2017, and among patients who were randomly assigned, 99% in the daratumumab group and 99% in the control group received at least one dose of study treatment, according to Facon and co-authors.
They reported that the median duration of response was not reached in the daratumumab group versus 43.9 months in the control group.
The authors also found that the most common (>15%) grade ≥3 treatment-emergent adverse events (TRAEs) were neutropenia (54% in the daratumumab group versus 37% in the control group), followed by pneumonia (19% versus 11%, respectively). Serious AEs occurred in 77% and 70%, respectively. Treatment-related deaths occurred in 4% and 3%, respectively.
Facon’s group noted that at a median follow-up of 47.9 months and a clinical cutoff date of June 8, 2020, the MRD-negativity rate was “significantly higher in the daratumumab group than in the control group (31% versus 10%)…
“Testing for minimal residual disease (MRD) using next-generation sequencing (NGS) was feasible for informing physicians about the use and duration of daratumumab (Darzalex) in combination with carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Dara-KRd) following autologous transplant (AHCT) in patients with newly diagnosed multiple myeloma, according to data from the phase 2 MASTER Trial (NCT03224507).1
“Patients with standard and high-risk newly diagnosed myeloma have similar depth of response, and low-risk MRD resurgence or progression when treated with this regimen including MRD-adapted treatments…”
In the MASTER trial, Costa and colleagues aimed to determine the rate of MRD-negative responses using NGS in patients treated with Dara-KRd, ACHT, and MRD response-adapted Dara-KRd consolidation therapy.
Secondary end points were toxicity of the combination regimen, conventional International Myeloma Working Group response, and outcomes of observation without maintenance therapy following MRD-negative responses.
Dara-KRd was administered until achievement of 2 consecutive MRD-negative responses, defined as 10-5. Those with confirmed MRD-negativity then underwent treatment-free observation and MRD surveillance, or MRD-SURE…
In the study,
- 53 patients (43%) had no high-risk chromosome abnormality (HRCA [gain/amp 1q, t(4;14), t(14;16), t(14;20) or del(17p)]; standard-risk),
- 46 (37%) had 1 HRCA (high-risk), and
- 24 (20%) had 2 or more HCRA (ultra-high risk).
Among all patients, 80% achieved MRD negativity after MRD-directed consolidation therapy, including 78% of those with standard-risk, 82% of those with high-risk, and 79% of those with ultra–high risk disease. Per the exploratory end point of the trial, 66% of patients achieved MRD negativity 10-6 following MRD-directed consolidation therapy, including 64%, 73%, and 58% of the standard-, high-, and ultra-high–risk groups, respectively.
In addition, MRD negativity was reached in 38% of patients after induction therapy and 65% of patients after AHCT. “The proportion of patients reaching MRD-negativity increases with each phase of therapy with a substantial gain,” Costa said…
The 2-year progression-free survival rates in the standard-, high-, and ultra-high–risk groups were 91%, 97%, and 58%, respectively (P < .001). Similarly, the overall survival rates in those groups were 96%, 100%, and 76%, respectively (P = .003)…
In total, 84 patients achieved MRD-SURE, including 62% in the standard risk group, 78% in the high-risk group, and 63% in the ultra–high risk group.
Median follow-up with MRD-SURE was 14.2 months…
- Twenty-five treatment-emergent serious AEs were reported, including pneumonia (n = 8),
- pulmonary embolism (n = 3),
- fever and neutropenia (n = 2),
- atypical hemolytic uremic syndrome (n = 1),
- infusion-related reaction (n = 1),
- atrial fibrillation (n = 1), and other (n = 9).
Three deaths occurred.
“Quadruple therapy and achievement of confirmed MRD-negative responses enables the exploration of treatment cessation and MRD-SURE as an alternative to continuous therapy,” Costa concluded. “And importantly, effective novel consolidation strategy should be explored to clear MRD and improve outcomes in patients with ultra-high–risk multiple myeloma.”
References
- 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: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, Georgia. Abstract 481. https://bit.ly/3EQZSLo
- Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd), autologous transplantation and MRD response-adapted treatment duration and cessation in newly diagnosed Multiple Myeloma (NDMM). Clinical Lymphoma Myeloma and Leukemia. 2021;21(2):S33. doi:10.1016/S2152-2650(21)02125-X
