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Charise Gleason, MSN, NP-BC, AOCNP:
Next, let’s talk about our 48-year-old patient who was diagnosed with active MM. Approximately 4 months prior to her diagnosis, she started noticing acute onset and gradually worsening neck pain. Then, 2 months ago, she noted that her pain increased in severity and began experiencing a burning sensation in addition to the pain. She denied any fever, chills, night sweats, or weight loss at this time, and an MRI of the neck revealed a C3 pathologic fracture along with a left chest wall mass. Further imaging revealed numerous enhancing lesions in the cervical, thoracic, and lumber vertebral spine as well as a mass on her first left rib. Laboratory testing revealed normal creatinine (0.84 mg/dL) and calcium (8.4 mg/dL) with an albumin level of 4 g/dL and low levels of hemoglobin at 10.1 g/dL with mean corpuscular volume of 99. Her total protein level was 9.9 g/dL, with IgA kappa M-protein of 4.1 g/dL and total IgA of 5665 mg/L, free kappa light chains of 104.7 mg/L for a FLC ratio of 16.
CT-guided biopsy of her rib lesion confirmed a plasma cell neoplasm. A bone marrow biopsy revealed 50% bone marrow plasma cells and her FISH was negative for t(11;14) translocation, del(17p), del(13q), and monosomy 13. With this information, she was diagnosed with standard-risk, symptomatic MM. Given her age and performance status, she is likely eligible for an ASCT after induction therapy.
Sagar Lonial, MD:
This patient has Revised International Staging System (R-ISS) stage 1 active MM with bone disease, is clearly symptomatic, and needs induction therapy. At our institution, we generally divide newly diagnosed patients into 2 groups: those eligible for ASCT and those who are not eligible. For patients, like this woman, who are eligible for ASCT, our choice of induction therapy is typically Dara plus VRd for 4 cycles of induction therapy followed by ASCT and lenalidomide maintenance therapy. For ASCT-eligible patients who have high-risk cytogenetics—del(17p), t(4;14), or t(14;16)—we recommend induction therapy with KRd induction followed by ASCT and the KRd consolidation and maintenance for 3 years.
For patients who are not eligible for ASCT, we typically recommend therapy with Dara-Rd for standard-risk patients or VRd-“Lite” (VRd with dose reductions to improve tolerability) for high-risk patients. In our group, patients must be very frail to be considered ineligible for ASCT.
Let’s go through the data informing these treatment decisions.
Sagar Lonial, MD:
For our ASCT-eligible patients with standard-risk MM, we are currently recommending quadruplet therapy with Dara-VRd based on data from the CASSIOPEIA and the GRIFFIN trials, with the goal of achieving very deep responses by incorporating all 3 effective classes of therapy—an immunomodulatory drug (IMiD), a PI, and a monoclonal antibody.
The phase III CASSIOPEIA trial was conducted at 111 European centers and enrolled 1085 adults with newly diagnosed MM who were eligible for ASCT to assess the clinical utility of adding Dara to VTD both as induction therapy before ASCT and as consolidation after ASCT. In part 1 of this trial, patients were randomized to receive 4 cycles of Dara plus VTD vs VTD alone as induction, ASCT, and 2 cycles of consolidation therapy. The primary endpoint was stringent CR after consolidation, which was assessed either 100 days after ASCT or immediately following consolidation if longer than 100 days. Secondary endpoints included the MRD negativity rate after consolidation, the rate of CR or better after consolidation, PFS, and OS.
At posttransplant Day 100, 29% of patients who received daratumumab plus VTD achieved a stringent CR vs 20% of those who received VTD alone (odds ratio: 1.60; 95% CI: 1.21-2.12; P = .0010). The beneficial effect of Dara plus VTD on stringent CR rates was consistent across most subgroups, with the exception of those patients with high-risk cytogenetics. Also, MRD negativity after consolidation was achieved at a significantly higher rate with Dara plus VTD vs VTD alone (64% vs 44%, respectively; P < .0001).
Furthermore, induction and consolidation therapy with Dara-VTD significantly improved PFS vs VTD, with an 18-month estimated PFS of 93% vs 85%, respectively, although the median PFS has not yet reached in either arm (HR: 0.47; 95% CI: 0.33-0.67; P < .0001). OS data were immature at the time of analysis, but showed a preliminary HR of 0.43.
Based on these data, the FDA approved the use of Dara in combination with VTD for patients with newly diagnosed MM who are eligible for ASCT; however, thalidomide is rarely used in the United States at this time.
Sagar Lonial, MD:
The GRIFFIN study is a multicenter, open-label, randomized phase II study comparing one of the standards of care—VRd—vs the same schedule with the addition of Dara in transplant-eligible adults with newly diagnosed MM. Patients received 4 induction cycles of either VRd or Dara-VRd, followed by ASCT plus 2 consolidation cycles of either VRd or Dara-VRd, and then maintenance with either lenalidomide or Dara plus lenalidomide. The primary endpoint is stringent CR by the end of consolidation.
The median age in both study arms was similar, at 59 years in the Dara arm and 61 years in the control arm. Approximately 13% to 14% of the patients in both study arms have ISS stage III disease and approximately 15% of patients in both arms have high‑risk cytogenetics.
Results presented at ASH 2019 showed that the vast majority of patients responded to this treatment; indeed, 99.0% and 91.8% of patients in the Dara-VRd arm vs VRd arm, respectively, achieved a response and 42.4% and 30% of patients, respectively, achieved the primary endpoint of a stringent CR at the end of consolidation (1-sided P = .068). Encouragingly, MRD negativity was achieved in 51.0% vs 20.4% of patients in the Dara-VRd arm vs VRd arm, respectively. As this study is still quite immature, neither median PFS nor median OS has been reached, but at 24 months, approximately 90% of the patients are progression free in the VRd arm and 96% of patients are progression free in the Dara-VRd arm.
Based on both CASSIOPEIA and GRIFFIN, our group feels confident that adding Dara to the first 4 cycles of induction therapy prior to transplant is a reasonable choice and may be able to improve the depth of response in patients with newly diagnosed MM. In our clinic, we recommend Dara in combination with VRd instead of the approved regimen Dara-VTd. We have not adopted Dara in the consolidation or in the maintenance phases at this time. It will be interesting to see if this decision changes pending additional data on the addition of Dara to lenalidomide maintenance in ongoing trials.
Of note, in our clinic, we typically do not use consolidation therapy in standard-risk patients, given results from the phase III CTN 0702 trial which demonstrated that VRd consolidation did not improve PFS over lenalidomide alone in transplantation-eligible patients with newly diagnosed MM. That said, in newly diagnosed high-risk patients, we may use 1-2 cycles of more-intense consolidation treatment before a 3-drug maintenance regimen.
Before discussing the data informing how we treat high-risk patients with newly diagnosed MM, let’s revisit the second case patient with standard-risk newly diagnosed MM.
Sagar Lonial, MD:
Standard induction therapy for patients with newly diagnosed active MM undergoing ASCT has evolved rapidly during the past few years to now consist of an IMiD combined with a PI and, more recently, with monoclonal antibodies.[11,12] There is an ongoing debate whether addition of an anti-CD38 monoclonal antibody, like Dara, benefits patients with high-risk disease.
Traditionally, treatment with VRd has been one standard of care for patients with newly diagnosed MM, regardless of risk. However, carfilzomib is a second-generation PI that has demonstrated activity in patients with newly diagnosed MM, even for those with high-risk disease. Based on data from various phase II trials, treatment with KRd is our preferred induction regimen for ASCT-eligible patients with high-risk cytogenetic features such as del(17p); t(14;16), t(14;20), or t(4;14) translocations; or 1q gain. After ASCT, we recommend consolidation/maintenance therapy with KRd for 3 years.
Sagar Lonial, MD:
The phase II FORTE trial is an important study addressing 3 different questions in newly diagnosed MM: first, whether KRd and KCd are comparable induction and consolidation therapies in patients undergoing ASCT; second, if a patient is receiving KRd induction and consolidation therapy, whether ASCT can be replaced with 4 additional cycles of KRd; and third, whether maintenance with carfilzomib/lenalidomide is superior to single‑agent lenalidomide.[13,14]
Patients were first randomized to 4 cycles of KCd induction followed by ASCT and 4 cycles of KCd consolidation (arm A: KCd-ASCT); 4 cycles of KRd induction followed by ASCT and 4 cycles of KRd consolidation (arm B: KRd-ASCT); or 4 cycles of KRd induction followed by 4 additional cycles of KRd instead of ASCT and KRd consolidation for a total of 12 cycles of KRd (arm C: KRd12). There was also a second randomization to assess lenalidomide maintenance vs carfilzomib/lenalidomide maintenance after consolidation.
The rate of achieving at least a VGPR prior to maintenance therapy was 76% for KCd-ASCT, 89% for KRd-ASCT, and 87% for KRd12. Rates of premaintenance MRD negativity were 42%, 58%, and 54%, respectively. The likelihood of achieving at least VGPR favored KRd plus transplantation over KCd plus transplantation (OR: 2.53; P = .004), and KRd alone over KCd plus transplantation (OR: 2.11; P = .15).
When stratified by R-ISS criteria, the response rates and depth of response were quite comparable for patients who received KRd induction, ASCT, and consolidation vs those who received KRd12. The patients who were R‑ISS stage I may have had a slightly higher response rate with KRd-ASCT vs KRd12, but this subgroup had the smallest number of patients (48 vs 39 patients, respectively).
These data are still evolving, and we will need more-mature data before we can draw firm conclusions for the clinic, including longer-term follow-up to compare PFS and OS. However, these findings do highlight that KRd is a reasonable treatment option for patients with newly diagnosed MM and shows that there remains a role for ASCT in clinical practice.
Sagar Lonial, MD:
Although ASCT is a standard of care in newly diagnosed MM, not all patients are eligible for this intensive therapy. Older patients who are diagnosed with MM often have multiple comorbidities, are more at risk of toxicities from MM therapy, may not be able to tolerate agents like HDT for ASCT, and may not be candidates for ASCT. In our clinic, for patients who are not eligible for ASCT, we recommend either Dara-Rd, per the MAIA trial, or VRd-lite.
I want to point out that many of these patients may be able to tolerate regimens like KRd without ASCT, and PIs remain a key backbone in MM treatment for these patients. In my clinical practice, I continue to use KRd for my older transplant-ineligible patients who can tolerate this therapy and rely on Dara-Rd or VRd-lite for those who are too frail to tolerate a PI, since adverse events tend to be more tolerable with the antibody.
Sagar Lonial, MD:
Dara-Rd is approved by the FDA for patients with newly diagnosed MM who are ineligible for ASCT based on the phase III MAIA study, which compared Dara-Rd with Rd alone in ASCT-ineligible patients with newly diagnosed MM. Results demonstrated that triplet therapy substantially reduced the risk of progression by 44%. In addition, combining Dara with Rd improved the depth of response: The MRD-negative rate was 24% with Dara-Rd vs 7% with Rd. In patients younger than 75 years of age, the MRD-negative rate with Dara-Rd was 27.9% vs 19.4% in older patients, whereas in both age groups, the MRD-negative rate with Rd was approximately 7.5%.
After a median follow-up of 28 months, median PFS was 31.9 months with Rd and had not been reached with Dara-Rd (HR: 0.56; 95% CI: 0.43-0.73; P < .0001). Median OS was not reached in either treatment arm. The ORR was significantly higher with Dara than without (93% vs 81%, respectively; P < .0001), including an increased rate of stringent CR (30% vs 12%, respectively). Dara treatment was favored in most subgroups, which included age, race, ISS stage, and Eastern Cooperative Oncology Group performance status. However, there was no evidence that Dara improved PFS in the subgroup of patients with high-risk cytogenetics.
Sagar Lonial, MD:
VRd is commonly used in newly diagnosed patients who are not intending on ASCT. However, the dosing schedule of VRd may be more challenging for older or more-frail patients. Another option for this group is VRd-lite, which uses a reduced dosing schedule. Results from a phase II trial of VRD-lite in 50 older or transplant-ineligible patients showed an 86% ORR and a median PFS of 35.1 months. Of note, after 9 cycles of treatment the median OS had not yet been reached. This demonstrates that patients can be treated with VRd-lite with comparable efficacy and better tolerability than standard VRd induction.