ASH 2019 Myeloma trials: Expert critique by Dr. Vishwanath S & Dr. Vinayak Maka
M3 India Newsdesk Dec 26, 2019
Dr. Vishwanath Sathyanarayanan and Dr. Vinayak V Maka put forth their respective reviews and anaylses of 4 key trials in myeloma presented at this year's American Society of Hematology (ASH) Annual Meeting.
The premier event for recent updates in malignant and non-malignant haematology was held on December 7-10, 2019 at Orange County Convention Center (OCCC), Orlando in USA.
Here, reviewed, are selected abstracts in myeloma which are relevant to Indian practice. As chimeric antigen receptor (CAR) T-cell therapy for haematological malignancies is not available in India, we have excluded data from discussion.
ALCYONE Trial
Dr. Vinayak: Almost 22% of patients on Daratumumab plus Bortezomib (Velcade), Melphalan, and Prednisone (D-VMP) who achieved persistent minimal residual disease (MRD) for more than 12 months had improved prgression free survival (PFS) at 40 months of follow up. So, achievement of persistent MRD negativity is a reasonable target to be aimed in newly diagnosed multiple myeloma patients who are ineligible for stem-cell transplantation.
Dr. Vishwanath: Melphalan, Bortezomib and Prednisone is a time-tested regimen for myeloma, especially in transplant ineligible patients. Adding Daratumumab to this regimen has led to an excellent overall response rate (ORR), PFS of close to 50% at 42 months and impressive overall survival (OS) as well. This will be a value addition to the existing armamentarium of drugs in the untreated, transplant-ineligible myeloma setting.
D-VMP in patients with transplant-ineligible NDMM
The multicentre global ALCYONE trial involved 706 patients with newly-diagnosed multiple myeloma (NDMM) who were ineligible for stem-cell transplantation. They were randomised to 9 cycles of D-VMP (n = 350) followed by monthly daratumumab until disease progression or to 9 cycles of Bortezomib (Velcade), Melphalan, and Prednisone (VMP) without maintenance therapy. The primary endpoint was PFS.
Key findings:
- Patients treated with Daratumumab plus Bortezomib (Velcade), Melphalan, and Prednisone (D-VMP) had an estimated 42-month progression-free survival (PFS) of 48% compared with 14% for patients treated with VMP.
- The estimated overall survival (OS) was 75% and 62% for the D-VMP and VMP arms, respectively. The initial objective response rate of 91% at 16.5 months did not change after 40 months of follow-up.
MASTER Trial
Dr. Vishwanath: With this quadruplet-based regimen in transplant-eligible NDMM receiving autologous hematopoietic transplantation (AHCT), the depth of response was increased, and it was well tolerated. More than one-third of them achieved stringent complete response (sCR) post induction and 95% at MRD-based consolidation. Response was seen irrespective of standard or high risk patients. This quadruplet-based regimen is the future for patients with transplant eligible NDMM to obtain sustained and deeper remissions. However, at the current time, Daratumumab is very expensive in India and may not be a suitable option in newly diagnosed patients.
Dr. Vinayak: The growing interest in minimal residual disease (MRD) assessment in multiple myeloma (MM) is related to the high quality of responses achieved with novel agents and to the development of reliable techniques to evaluate MRD both within the bone marrow using next-generation sequencing (NGS) or next-generation flow cytometry (NGF), and outside the bone marrow using imaging techniques, such as positron emission tomography-computed tomography. This aggressive regime and MRD evaluation approach can form the basis of clinical efforts to reduce the burden of continuous therapy in those with confirmed MRD-negative remissions.
Response adapted Dara-KRd sequential therapy in transplant eligible patients with newly diagnosed MM
The current study assessed safety, efficacy of sequential Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd) induction, AHCT, response-adapted, MRD-based Dara-KRd maintenance in NDMM and feasibility of using MRD by next generation sequencing to inform the use and duration of post-transplant Dara-KRd consolidation.
Researchers concluded that quadruplet induction therapy of Dara-KRd with AHCT and Dar-KRd consolidation was effective and tolerable in untreated patients with NDMM, where 39% of patients achieved sCR post induction and 95% after MRD-based consolidation with high level of response observed in both high-risk and standard-risk patients. Investigators concluded that delivery of NGS MRD-based, response-adapted therapy is feasible in clinical setting.
GRIFFIN Trial
Dr. Vinayak: So far, the trial results are showing that the combination is well-tolerated with no unexpected side effects. The combination also had high response rate, with responses deepening as time goes on and even as patients move into the maintenance setting. Stem cell mobilisation and autologous stem cell transplant are feasible with the Daratumumab regimen, with no significant effect on hematopoietic reconstitution.
Dr. Vishwanath: In the GRIFFIN trial, the addition of anti-CD38 antibody to a triplet RVd regimen led to deeper responses in patients with transplant-eligible, newly diagnosed multiple myeloma. The odds ratio of developing a stringent complete response (CR) nearly doubled with the addition of Daratumumab to RVd with a higher chance of MRD negativity. This may serve as the new standard of care for newly diagnosed transplant eligible MM patients.
Daratumumab addition to Lenalidomide, Bortezomib and Dexamethasone regimen in NDMM
The addition of daratumumab to Lenalidomide, Bortezomib and Dexamethasone significantly improved rates of stringent clinical response and minimal disease negativity among patients with transplant-eligible newly diagnosed multiple myeloma, according to results of the randomised phase 2 GRIFFIN study. There is dramatic improvement in stringent complete response, an effective doubling of minimal residual disease negativity and excellent safety will see the integration of Daratumumab into induction regimen as a potential new standard of care.
Ixazomib, Lenalidomide and Dexamethasone in SMM
Dr. Vinayak: Patients with smoldering multiple myeloma (SMM) represent a heterogeneous population, with a subgroup of about one-third of patients considered to be at high risk for progression within 2 years.
As first-line treatments for multiple myeloma have advanced to the degree that they are better tolerated with improved responses, the question has become whether the standard of care for patients with SMM should change from observation to initiation of antimyeloma therapy in order to prevent progression. Nevertheless, we now have an accumulating wealth of data to suggest that therapeutic interventions for SMM can provide a clinical benefit that favours treatment over observation, particularly for patients at high risk for progression. The question remains how these data can best be applied in the community off-trial to treatment of patients with SMM.
Dr. Vishwanath: There has always been a growing need for developing an oral regimen for high-risk smoldering myeloma. This phase 2 study shows significant responses and may be well received in this subset of patients.
Phase 2 study of Ixazomib, Lenalidomide and Dexamethasone combination in smoldering multiple myeloma
Bustoros and colleagues presented results of a phase 2 study that used the combination of Ixazomib, Lenalidomide and Dexamethasone for induction and maintenance in high-risk smoldering multiple myeloma (SMM). More than 90% of patients responded to therapy, and 50% achieved complete response or very good partial response.
They had any one of several high-risk features, such as serum M protein of 3.0 g/dL or greater, immunoparesis with reduction of two uninvolved immunoglobulin isotypes, or serum involved/uninvolved free light chain ratio of at least 8 but less than 100. All patients had at least three high-risk criteria, 38% had four high-risk criteria, and 28% had five high-risk criteria. Baseline fluorescence in situ hybridisation showed 56% of patients had translocation t (11;14), deletion 17p or 1q gain.
Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.
Dr. Vinayak Maka is a Senior Medical Oncologist who teaches and practice at the MS Ramaiah Medical College and the HCG MSR Cancer Centre, Bangalore.
Dr. Vishwanath Sathyanarayan is a Medical Oncologist from Apollo Hospitals, Bangalore with a fellowship from MD Anderson Cancer Center.
-
Exclusive Write-ups & Webinars by KOLs
-
Daily Quiz by specialty -
Paid Market Research Surveys -
Case discussions, News & Journals' summaries
