Triple-agent induction regimens with proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) plus dexamethasone offer high rates of both overall response and complete response (CR) and are the current standard of care for patients with newly diagnosed multiple myeloma (MM). The subsequent use of autologous stem cell transplantation (ASCT) in eligible patients and continuous or maintenance therapy can further deepen responses—in terms of minimal residual disease (MRD) negativity—following induction therapy. Studies have also looked at the potential value of adding a fourth agent to traditional three-drug combinations. In this blog entry, the MMRF reports on the newest clinical updates on treatment strategies for improving outcomes for patients with newly diagnosed MM, as presented at the 18th International Myeloma Workshop (IMW), held September 8–11 in Vienna, Austria.
At IMW, data were presented on updates to existing and new triplet and quadruplet combinations with and without ASCT followed by single-agent or combination maintenance therapy. Most of these studies evaluated the impact of these regimens on achieving MRD and prolonging progression-free survival (PFS) and overall survival (OS) in standard- and high-risk patients.
Induction Therapy for Transplant-Ineligible Patients: Role of Anti-CD38 Monoclonal Antibodies
For patients who are ineligible for ASCT, data from two phase 3 randomized trials (MAIA and ALCYONE) led to the approval of daratumumab as induction therapy, either in combination with lenalidomide and dexamethasone (DRd) or with bortezomib, melphalan, and dexamethasone (D-VMP). Updated data from both trials were reviewed.
The initial results from the MAIA trial (DRd vs Rd) are published here. At IMW, the MAIA trial investigators provided a 5-year update of patients treated on the trial, which showed that responses to DRd deepened over time compared with Rd (complete response or better [≥CR] 51% vs 30%). PFS was significantly longer in patients receiving DRd compared with Rd (not yet reached vs 34.4 months). Ultimately, DRd treatment was associated with a 32% reduction in the risk of death compared to Rd. No new safety concerns were observed, and the most common grade 3/4 adverse event observed more frequently with DRd than Rd was neutropenia (54.1% vs 37%). The investigators suggest that, given its impressive survival benefit, the DRd regimen is the new standard of care for newly diagnosed patients ineligible for ASCT.
Also presented at IMW was an analysis of recent data from a subgroup of patients with high-risk MM treated on both the MAIA and ALCYONE trials (D-VMP vs VMP, original publication here). In this analysis, led by Dr. Andrzej Jakubowiak at the University of Chicago, high-risk status was measured as the presence of del(17p), t(4;14), or t(14;16). Outcome of high-risk patients receiving an induction regimen with (n=101) or without (n=89) daratumumab was analyzed. Patients receiving a daratumumab regimen had a 41% reduction in the risk of disease progression or death compared with patients who did not receive daratumumab. The estimated 3-year PFS rates were 41.3% and 19.9%, respectively. Higher response rates and deeper responses (MRD negativity) occurred in the patients receiving a daratumumab regimen than in patients who did not receive daratumumab.
These studies show the value of daratumumab-based regimens as induction treatment for patients ineligible to receive an ASCT—even in patients with high-risk disease.
Isatuximab, another anti-CD38 monoclonal antibody, is approved for patients with relapsed or refractory MM, either in combination with pomalidomide-dexamethasone or carfilzomib-dexamethasone. In 46 newly diagnosed patients, isatuximab was administered as part of a four-drug induction regimen in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd). In this trial, isatuximab was administered as a short-duration fixed-volume infusion during treatment cycles. The overall response rate (ORR) was 97.8%, over half of patients achieved ≥CR, and over half of patients in whom MRD could be measured achieved MRD negativity (next-generation flow cytometry or sequencing, 10-5). The most common side effects were constipation, diarrhea, asthenia, peripheral neuropathy, lymphopenia and neutropenia. The Isa-VRd regimen showed promising efficacy and safety and is advancing to phase 3 trials in newly diagnosed patients.
Induction and Maintenance Therapy for Transplant-Eligible Patients With High-Risk Disease: Incremental Progress, But Chromosome 1 Abnormalities Still an Unmet Need
A few trials were presented that looked at different induction and maintenance strategies for patients considered to have high-risk disease. In one study (OPTIMUM), an intensive regimen was evaluated in patients considered to have ultra high-risk disease, defined as having one of the following: two or more cytogenetic abnormalities, high-risk gene-expression profiling, or plasma cell leukemia. Treatment involved a five-drug induction regimen of daratumumab-cyclophosphamide-bortezomib-lenalidomide-dexamethasone (DCVRd) followed by an ASCT, followed by a four-drug consolidation regimen of daratumumab-bortezomib-lenalidomide-dexamethasone (DVRd) and maintenance therapy with daratumumab-lenalidomide (DR). Patients treated (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 FORTE trial studied the use of carfilzomib as a part of an induction and consolidation regimen (carfilzomib-lenalidomide-dexamethasone [KRd] with or without ASCT) and maintenance (with or without lenalidomide) in specific subgroups of 396 patients with newly diagnosed MM—those with high-risk cytogenetics (one or more chromosomal abnormalities), double-hit cytogenetics (two or more chromosomal abnormalities), or standard risk cytogenetics (absence of any chromosomal abnormalities). They evaluated treatment for PFS and 1-year sustained MRD negativity according to patient risk. All risk subgroups benefited from treatment with KRd followed by ASCT with estimated 4-year PFS rates of 80%, 62%, and 55% for patients with standard-risk, high-risk, and double-hit cytogenetics, respectively. Combination maintenance therapy with carfilzomib-lenalidomide (KR) improved PFS relative to what was seen with single-agent lenalidomide maintenance in all risk subgroups. The estimated 3-year PFS rates were 90% vs 73% (standard-risk), 69% vs 56% (high-risk), and 67% vs 42% (double-hit).
The results from this study suggest that KRd followed by ASCT and KR maintenance is effective in most high-risk subgroups—specifically for patients with del(17p); del(1p); t(4;14); or gain 1q—except for patients with amplification (amp)1q.
In a separate presentation, the investigators of the FORTE trial evaluated the impact of chromosome 1 abnormalities on clinical outcome. They showed that, overall, patients with amp1q and gain1q abnormalities achieve shorter PFS than patients with no chromosome 1 abnormalities (21.2 months vs 53 months vs not reached). Also, amp1q predicts a poor OS compared with patients expressing no chromosome 1 abnormalities and patients with gain1q. In a further analysis of the genes located on chromosome 1 from MM patients enrolled on the MMRF CoMMpass℠ study, investigators found that most gene deregulation was present in both amp1q and gain1q patient groups, but was more prominent in amp1q patients. Determining which genes are deregulated in patients with gain1q or amp1q could identify new targets for drug development in this subset of high-risk patients.
An analysis of a subset of patients with chromosome 1 abnormalities from the ENDURANCE trial was also presented by clinicians at the Mayo Clinic. ENDURANCE was a head-to-head trial that compared the efficacy of bortezomib-lenalidomide-dexamethasone (VRd) and carfilzomib-lenalidomide-dexamethasone (KRd) in over 1,000 patients with standard-/intermediate-risk newly diagnosed myeloma who deferred an ASCT (original publication here). Regardless of the treatment regimen used, patients with chromosome 1 abnormalities—specifically amp1q or del(1p)—had inferior PFS compared with patients without these abnormalities. The investigators state that longer follow up and confirmatory studies are needed to draw any definitive conclusions.
Maintenance Therapy and MRD: Agents Beyond Lenalidomide? Is MRD Negativity the Goal of Treatment and Can MRD Results Guide Treatment Duration?
The CARDAMON trial—a phase 3 randomized trial of carfilzomib maintenance following carfilzomib-cyclophosphamide-dexamethasone (KCd) induction + ASCT or consolidation with KCd only—was conducted to determine the effectiveness of carfilzomib as an alternative maintenance therapy to lenalidomide. In this trial, 218 patients received induction therapy with KCd, then received either an ASCT followed by carfilzomib maintenance (Group 1) or carfilzomib-cyclophosphamide-dexamethasone followed by carfilzomib maintenance (Group 2). At 6 months post maintenance therapy, PFS was longer for patients who were MRD negative than for patients who were MRD positive. More patients in Group 1 (ASCT) converted to MRD negativity than was seen in Group 2 (KCd consolidation therapy) (39.1% vs 16.1%). Maintenance therapy resulted in 23.5% of MRD-positive patients converting to MRD negative. More patients who had previously received an ASCT (Group 1) withdrew from maintenance therapy than was seen for patients in the KCd consolidation group (Group 2) (9.1% vs 1%). There was no evidence that the timing of achievement of MRD negativity impacted PFS. The results showed that carfilzomib maintenance therapy improves MRD negativity rates, especially following an ASCT; however, previous ASCT may increase the risk of side effects during maintenance.
The Myeloma XI trial is a phase 3 study in which patients received induction therapy followed by ASCT and then either no maintenance therapy or maintenance therapy with lenalidomide. MRD status was assessed (via flow cytometry) prior to and 6 months after maintenance therapy with or without lenalidomide. Over 60% of patients in both groups achieved MRD negativity at both time points. After 6 months, conversion to MRD negativity occurred more frequently in patients receiving lenalidomide than in patients who did not receive maintenance (30% vs 17%). Regardless of MRD status, patients who received lenalidomide as maintenance experienced longer PFS compared with patients who did not. Sustained MRD negativity at both time points or conversion to MRD negativity after maintenance therapy were associated with the longest PFS and OS. Also, patients on lenalidomide maintenance benefited by improved PFS and OS even without achieving MRD negativity. However, patients with high-risk cytogenetics—characterized as having gain1q, del(17p), t(4;14), t(14;16), or t(14;20)—did not reap the same benefits.
The MASTER trial investigated whether MRD testing (next-generation sequencing) can help guide treatment duration. In this study, 123 newly diagnosed MM patients (most of whom had high-risk cytogenetic abnormalities) were treated with a four-drug induction regimen (daratumumab-carfilzomib-lenalidomide-dexamethasone [DKRd]) followed by an ASCT. Patients then received 0, 4, or 8 cycles of DKRd as consolidation therapy after ASCT, based on their MRD testing results. MRD negativity (<10-5) was achieved in 80% of patients post MRD-directed consolidation therapy (38% of patients post induction therapy and 65% post ASCT). Overall, 71% of patients have reached confirmed MRD negativity (two consecutive MRD-negative tests) and are now being monitored—without treatment—for MRD resurgence 6 months after treatment was stopped and yearly thereafter via the MRD-SURE study. Ultimately, this study showed that patients who achieve a deep response (that is, MRD negativity) might be able to receive fewer cycles of treatment overall.
For further analysis of the information presented at IMW, please check our additional blog post here.
Support for this activity has been provided through a donation from Amgen; educational grants from GlaxoSmithKline, Karyopharm Therapeutics, and Oncopeptides; and a sponsorship from Johnson & Johnson Health Care Systems, Inc.