A growing body of evidence suggests that, for all multiple myeloma patients, the goal of treatment should be to achieve the deepest remission possible—including minimal residual disease (MRD) negativity—to prolong as much as possible progression-free survival (PFS) and overall survival (OS) while ensuring a good quality of life (QoL). There are, however, myeloma patients for whom prognosis remains poor—with survival of only 2 or 3 years.
This clinical reality reflects the heterogeneity of multiple myeloma and underscores the inappropriateness of a one-size-fits-all approach. Oncology health care providers (HCPs) must consider which combination regimen to use for induction, how to determine depth of response, whether to include additional cycles of consolidation to improve response rates, and whether to provide long-term maintenance therapy to prolong time to relapse. Data presented at the ASH 2022 Annual Meeting provided guidance and insights into different induction and maintenance strategies for difficult-to-treat patient populations: high-risk and frail. Here, we review some of those important studies.
Unique Patient Populations and Health-Related QoL
Exploring Frailty and QoL
Most patients with newly diagnosed myeloma are over 65, with variable fitness and treatment tolerance. Dexamethasone, a key agent in all myeloma induction regimens, is associated with side effects that disproportionately affect older patients. The IFM2017-03 study investigated a steroid-sparing regimen in frail newly diagnosed myeloma patients over 65. In the study, 295 patients (median age 81 years, with an Eastern Cooperative Oncology Group [ECOG] frailty score ≥2) were randomized to receive either daratumumab-lenalidomide (DR) or lenalidomide-dexamethasone (Rd) and were treated until disease progression or unacceptable toxicity. Overall response rate (ORR) was 77% for Rd and 89% for DR (P=0.025). The treatment benefit with DR was observed for all patient subgroups, such as age, ECOG, Charlson Comorbidity Index, International Staging System (ISS), cytogenetics, and creatinine clearance. Of the 63 patients evaluable for MRD assessment, 18% receiving Rd and 33% receiving DR were MRD negative at 1 year (P=0.36). At least one adverse event (AE) occurred in 64% of patients treated with RD and in 76% with DR. Patients receiving DR experienced more grade ≥3 hematologic AEs such as neutropenia (Rd 15% vs DR 44%) and anemia (Rd 2% vs DR 11%). No differences in the frequency of grade ≥3 infections between the groups were observed (17% Rd vs 13% DR).
These findings support the conclusion that DR provides deep, rapid responses and a favorable safety profile for older, frail patients.
A retrospective study was conducted to assess frailty risk and to identify factors associated with improvements or deterioration in frailty in patients with multiple myeloma in the 3 years following diagnosis. Data on myeloma patients ≥60 years treated with frontline novel agents between 2007 to 2014 were identified from the SEER-Medicare–linked database and analyzed. At baseline, 39% of patients (n=4,617) were considered moderately or severely frail, based on a validated frailty index. Immunomodulatory drugs as frontline treatment was lower among patients with a high frailty status. In a multivariate analysis, the following characteristics were found to be associated with higher frailty status:
- Older age
- Female gender
- Black race
- Medicaid enrollment
Compared to non-frail patients:
- Severely frail patients had inferior OS (median 65 vs 17 months)
- Mildly frail patients had a 60% increase in hazard risk for death, moderately frail patients a 104% increase, and severely frail patients a 165% increase
One year after diagnosis, 15% of patients showed an improvement in frailty status, 33% had a deterioration, 26% remained the same, and 25% died. In a multivariate analysis, the following characteristics were found to be associated with increased odds of worsening frailty status at 1 year:
- Older age
- Male gender
- Medicaid enrollment
Overall, current frailty status is a better predictor of outcomes than baseline frailty status, which suggests that re-measurement is necessary.
An analysis of the health-related QoL (HRQoL) was conducted of patients on the MAIA trial, a phase 3 trial comparing daratumumab-lenalidomide-dex (DRd) with lenalidomide-dex (Rd). Treatment with DRd (compared to Rd treatment) demonstrated PFS benefit, OS benefit, deeper response, and improvements in patient-reported outcomes in both frail and non-frail patients. These findings led to approval of this triplet regimen for use in newly diagnosed myeloma patients who are ineligible for autologous stem cell transplantation (ASCT).
The HRQoL analysis of frail patients in the MAIA trial showed that, in patients receiving DRd (n=172), there were large reductions in pain symptoms over time relative to what was observed in patients receiving Rd (n=169). Other areas that favored DRd treatment included improvements in emotional functioning, social functioning, and nausea and vomiting. No changes from baseline were observed in fatigue symptoms for either group. Data on HRQoL were also reported for patients in GRIFFIN, a phase 2 trial comparing daratumumab-lenalidomide-bortezomib-dex (Dara-RVd) with lenalidomide-bortezomib-dex (RVd). Greater improvements in HRQoL were observed, particularly pain symptoms were notably reduced, in patients treated with Dara-RVd followed by daratumumab maintenance after ASCT vs RVd alone. These results suggest that treatment with a quadruplet regimen does not compromise HRQoL.
Treatment Regimens for High-Risk Disease Features
Investigators at the Memorial Sloan Kettering Cancer Center conducted a retrospective chart review to determine any differences in outcome for patients with high-risk myeloma, defined as the presence of any of the following cytogenetic abnormalities: 1q+, t(4;14), t(14;16), t(14;20), (17p). Patients were treated with standard induction regimens, bortezomib-lenalidomide-dex (VRd) or carfilzomib-lenalidomide-dex (KRd). Of the 67 patients treated with VRd and 87 patients treated with KRd, 76% and 72%, respectively, had one high-risk cytogenetic abnormality (24% and 28%, respectively, had ≥2). Early ASCT (ie, within 6 months of completing induction therapy) had been performed on 32 VRd-treated and 48 KRd-treated patients. ORR following induction was 93% for VRd and 98% for KRd (≥very good partial response [VGPR] 66% and 80%). Median follow-up overall was 42.5 months, and median PFS for VRd was 42.6 months and not reached for KRd. Multivariate analysis showed that KRd induction and revised (R-)ISS stage I were associated with better PFS than was observed in patients with R-ISS stage II or III. Early ASCT was not associated with improved PFS. Additional clinical factors that did not significantly affect PFS were age, cardiac history, and achieving complete response/stringent complete response (CR/sCR) or VGPR/partial response (PR) compared to <PR as best response to induction.
In the OPTIMUM study, an intensive regimen was evaluated in patients considered to have ultra–high-risk disease, defined as having one of the following: two or more of the cytogenetic abnormalities t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p); high-risk gene-expression profiling (SKY92); or plasma cell leukemia (circulating plasma blasts >20%). Treatment involved a five-drug induction regimen of daratumumab-cyclophosphamide-bortezomib-lenalidomide-dexamethasone (DCVRd) followed by ASCT and two consolidation regimens, daratumumab-bortezomib-lenalidomide-dexamethasone (DVRd) and DVR, and maintenance therapy with daratumumab-lenalidomide (DR). Treated patients (n=107) had an ORR of 94% (41% achieving MRD negativity by flow cytometry [10-5]) following induction and 83% (64% achieving MRD negativity) following ASCT. Response rates were lower for patients with plasma cell leukemia. Common side effects were neutropenia, thrombocytopenia, and infection. Even with high ORR and MRD negativity rates, the response in some patients was not long-lived.
The phase 2 CONCEPT study investigated isatuximab as part of a four-drug regimen with carfilzomib-lenalidomide-dex (Isa-KRd) for patients with high-risk multiple myeloma. High-risk patients in this study (n=153) had del17p, t(4;14), or t(14;16), or >3 copies of 1q21, as well as R-ISS stage II or III disease. Patients were treated with six cycles of Isa-KRd induction followed by ASCT for transplant-eligible patients or two more cycles of induction for ineligible patients. All patients received four cycles of Isa-KRd consolidation and maintenance with Isa-KR. After completion of consolidation, 67.7% of transplant patients and 54.2% of transplant-ineligible patients achieved MRD negativity (as assessed by next-generation sequencing [NGS], sensitivity 1 × 10-5). The ORR was 94.9% for transplant patients (≥CR 72.7%) and ≥CR 57.7% for transplant-ineligible patients. Many patients (85.2%) developed grade ≥3 treatment-emergent AEs (TEAEs), with serious TEAEs in 64.8% of patients.
The UK-MRA RADAR study incorporates MRD assessment as a predictive tool to adapt isatuximab-based therapy—by either escalating or de-escalating therapy—according to response in high-risk myeloma patients. Newly diagnosed transplant-eligible patients received four cycles of lenalidomide-cyclophosphamide-bortezomib-dex (with or without isatuximab) induction followed by ASCT. Based on their response post-ASCT, standard-risk patients received specific treatment based on their MRD status. Patients with standard-risk disease who were MRD negative received 12 cycles of isatuximab maintenance and were then randomized to either continue with isatuximab or stop treatment altogether. High-risk patients received four additional cycles of isatuximab-based treatment and continued with lenalidomide-isatuximab maintenance therapy until disease progression.
ASCT in Practice and What Clonal Plasma Cells in Autografts May Be Doing to Patient Outcomes
Canadian investigators examined the real-world results and outcomes of 3,821 multiple myeloma patients at 17 major Canadian institutions who underwent ASCT as part of initial therapy. The majority of patients received a bortezomib-based induction (≥VGPR 63.2%). A second induction (which included lenalidomide) was given to 376 patients who had a suboptimal response or progression after first induction (≥VGPR 35.4%). Tandem ASCT was performed in 314 patients (64% were high risk). After ASCT, only 5% of patients received consolidation, and 53.9% receive lenalidomide maintenance therapy (until disease progression).
The median PFS and OS for all patients from first ASCT was 35.4 months and 125 months, respectively. Outcomes for patients receiving a second induction regimen were inferior to those of patients who did not (median PFS 27.9 vs 36.2 months; median OS 118 vs 126 months). However, lenalidomide maintenance yielded comparable results regardless of induction regimen number (median PFS 55.3 vs 51.1 months; median OS 158.6 months vs not reached). Maintenance therapy overall led to better outcomes than no maintenance therapy (median PFS 48.8 vs 24.5 months; median OS 159 vs 105 months). The study confirms the durability of ASCT, with a median OS of 10 years or more in a real-world setting. Furthermore, the addition of maintenance therapy favorably influences outcomes, especially for subpopulations of patients like those at high risk and those requiring a second induction regimen.
Persistence of clonal plasma cells in myeloma patient autografts was investigated by clinicians at the MD Anderson Cancer Center. They conducted a retrospective analysis of patients with high-risk myeloma—defined as the presence of del17p, t(4;14), t(14;16), and 1q21 gain or amplification by FISH— who underwent ASCT at their institution to see how clonal plasma cells (CPCs) in autografts affect patient outcomes. Apheresis products from 416 high-risk myeloma patients were assessed for the presence of CPCs by 8-color next- generation flow cytometry: 18% of products were CPC positive.
At a median follow-up of 35.7 months, the results showed:
- The 100-day best response rates and CR rates following ASCT for CPC+ and CPC- groups were 8% and 19% (P<0.001) and 33% and 54% (P<0.001), respectively
- Patients in the CPC-positive group
- Were less likely to achieve ≥VGPR after induction
- Were less likely to achieve MRD negativity (11% vs 42%, P<0.001; assessed by next-generation flow cytometry, sensitivity 1 × 10-5)
- Experienced shorter median PFS (12.8 vs 32.1 months; P<0.001)
- Experienced shorter median OS (36.4 vs 81.2 months; P<0.001)
This study showed that the presence of CPCs in autografts was predictive of inferior PFS and OS for patients with high-risk multiple myeloma, even those who achieved ≥VGPR or MRD-negative CR/VGPR prior to ASCT. Strategies to purge CPCs may offer improvements to outcomes.
Investigators at the Memorial Sloan Kettering Cancer Center also looked into the effects of autograft MRD status on patient outcomes after ASCT. This study included 119 newly diagnosed patients who underwent stem cell collection and ASCT. The stem cell collection samples were assessed for MRD by next-generation flow cytometry, and patients were grouped as either autograft-positive or autograft-negative; also, MRD in the bone marrow was assessed post-induction/pre-stem cell collection and at 3-months post-ASCT. All patients in the autograft-positive group (n=35) also were MRD-positive in the bone marrow prior to their ASCT, and 71% of patients in the autograft-negative group were MRD-positive in the bone marrow. More patients in the autograft-negative group than the autograft-negative group had sustained or conversion to bone marrow MRD negativity at 3 months and 1-year post-ASCT (40% vs 9%). At a median follow-up of 40 months after ASCT, results showed that, relative to patients in the autograft-positive group, patients in the autograft-negative group experienced:
- Improved 3-year PFS (78% vs 54%; P=0.21)
- A trend toward improved 3-year OS (96% vs 82%)
Patients with MRD-negative autografts have improved PFS and OS; MRD status of autografts may help clinicians with guiding post-ASCT therapy.
Maintenance Therapy: How Long and at What Risk?
Many clinicians and myeloma patients want to know the optimal duration of lenalidomide maintenance therapy after ASCT. Data from the transplant-eligible arm of the Myeloma XI study was analyzed to determine optimal duration in various subgroups of patients. The Myeloma XI study is a phase 3 trial in which patients were randomized to receive induction therapy (a four-drug regimen [KCRD] or a triplet regimen [cyclophosphamide + thalidomide + dex or cyclophosphamide + lenalidomide + dex]) followed by ASCT and then either no maintenance therapy or maintenance therapy with lenalidomide. At a median follow-up of 44.7 months, median PFS for patients in the lenalidomide arm was 64 months and 32 months for patients in the observation arm (HR 0.52; P<0.001). The PFS benefit was observed across all patient subgroups on the lenalidomide maintenance therapy arm, including standard risk; molecular high risk, which included the presence of del(17p), gain(1q), t(4;14), t(14;16), or t(14;20); MRD positive; and MRD negative. The results of this study provide more evidence for the benefit of longer duration of lenalidomide maintenance in patients who are MRD positive than MRD negative, as well as evidence of ongoing benefit beyond 2–3 years for patients with both standard- and high-risk disease.
A part of the interest in finding the optimal duration of lenalidomide maintenance therapy is the risk of second primary malignancies (SPMs) with its long-term use. The Myeloma XI study data was also used to assess the impact of lenalidomide on the development of SPM, as lenalidomide was used in both transplant-eligible and -ineligible newly diagnosed patients at induction and maintenance. For transplant-eligible patients:
- 5.5% developed an SPM overall
- SPM incidence was 12.2% at 7 years in the lenalidomide maintenance arm compared to 5.8% in the observation arm (P=0.003)
- SPM incidence was greater in double-exposed patients compared to nonexposed or single exposed patients
- For each SPM type, incidence was <1% (except for basal cell carcinoma [BCC], squamous cell carcinoma [SCC] and myelodysplastic syndromes)
- Hematologic malignancies were almost all confined to lenalidomide-treated patients (most of whom were double-exposed)
- In patients who received lenalidomide maintenance, 1.8% of deaths were secondary to SPMs (16.6% of deaths were secondary to myeloma-related and 2.5% to non–myeloma-related causes); for patients in the observation arm, 0.4% deaths were secondary to SPMs, 22.6% to myeloma-related causes, and 3.7% to non–myeloma-related causes
For transplant-ineligible patients:
- 9.9% developed an SPM overall
- SPM incidence was 17.1% at 5 years in the lenalidomide-maintenance arm compared to 10% in the observation arm (P=0.09)
- SPM incidence was greater in double-exposed patients compared to nonexposed or single exposed patients
- Skin cancers were common, particularly in double-exposed patients (SCC 4.6% and BCC 3.1%); prostate cancer (1.2%) and melanoma (1.2%) also developed in double-exposed patients
- No SPM type was diagnosed in >1% of patients who were not exposed to lenalidomide
- Hematologic malignancies were rare
- In patients who received lenalidomide maintenance, 6.1% of deaths were secondary to SPMs (32.7% of deaths were secondary to myeloma-related and 10.8% to non–myeloma-related causes); for patients in observation arm, 2.8% deaths were secondary to SPMs, 41.5% to myeloma-related causes, and 8.9% to non–myeloma-related causes
Investigators concluded that double-exposure to lenalidomide (induction and maintenance) is associated with higher incidence of SPMs and is more marked in transplant-ineligible patients. And although deaths due to SPMs were increased with lenalidomide maintenance, deaths due to myeloma were lower. Clinicians should carefully monitor patients on lenalidomide maintenance, so possible early intervention for SPMs can occur.
The role of MRD assessment in clinical decision-making—such as stopping maintenance treatment—is still an area of active investigation. The MRD2STOP study investigated MRD negativity as a marker to discontinue maintenance therapy. Patients on this study who had at least 1 year of maintenance therapy and were in a CR with MRD negativity (as assessed by PET/CT and either flow cytometry [sensitivity 1 × 10-5] or NGS (sensitivity 1 × 10-6) were permitted to discontinue maintenance and underwent blood testing every 3 months and MRD testing (via NGS) and PET/CT assessments every year for 3 years. An additional subset of patients was assessed via NGS (at a sensitivity level of 1 × 10-7), mass spectrometry, or cell free DNA in peripheral blood. Ultimately, patients off maintenance therapy were assessed for MRD resurgence rate (going from MRD negative to positive): 38 patients met eligibility criteria and discontinued maintenance and 39% of patients had high-risk disease. The majority (95%) had only one line of therapy, with 68% having had an ASCT and 79% consolidation before receiving single-agent maintenance therapy. The median duration of consolidation/maintenance therapy before discontinuation was 42 months (range 12-90 months). At a median follow-up of 14 months:
- 89% remained on study (5% with progressive disease, 6% withdrew)
- MRD resurgence occurred in 13% of patients (2 patients had resurgence of M protein and disease progression)
- Rate of sustained MRD negativity at 12 months was 84%
For further analysis of the clinical data presented at ASH, check our additional blog post here.
Support for this activity has been provided through donations from Amgen and Karyopharm; grants from Bristol Myers Squibb and Genentech, a member of the Roche Group; and sponsorships from AbbVie, GSK, and Sanofi US.
For patient educational resources from our sponsors, be sure to click on the following links:
https://www.karyforward.com/hcp
https://www.gene.com/diversity-inclusion/health-equity
https://www.gskforyou.com/
https://www.sanoficareassist.com/
