SOHO & IMW 2019 | Induction therapies for multiple myeloma

During the Society of Hematologic Oncology (SOHO) annual meeting in Houston, US, Ajay Nooka, Winship Cancer Institute of Emory University, Georgia, US, provided a thorough overview of induction therapies for multiple myeloma (MM), with a focus on what to use in the era of monoclonal antibodies (mAbs), such as daratumumab (dara).1 Induction regimens were also discussed at the XVII International Myeloma Workshop (IMW), Boston, US, where Adam Olszewski, Brown University, Providence, US and Salomon Manier, Dana Farber Cancer Institute, Boston, US, presented oral abstracts AB8192 and AB2003, respectively, looking at the efficacy of lenalidomide- (R), bortezomib- (V) and dexamethasone- (d) based induction therapies.  

Options for induction therapy

The treatment paradigm for newly diagnosed MM (NDMM) involves disease and risk stratification, followed by assessment for autologous stem cell transplant (ASCT) eligibility. Transplant eligible (TE) patients receive induction, consolidation and maintenance therapy, whilst transplant ineligible (TI) patients receive induction followed by continuous therapy. Subsequent relapses are then managed according to the characteristics at the time.¹

There are several well-established options for induction therapy, including Rd, VRd, V + thalidomide (T) + d (VTd), carfilzomib (K) + Rd (KRd) and V + melphalan (M) + prednisone (P, VMP). In the era of mAbs, these well-established doublet and triplet combinations are being investigated with the addition of dara with an aim of improving efficacy. Dr Nooka provided an overview of trials under investigation as shown in Table 1.¹ 

Table 1. Induction therapies for NDMM^4-12

In the phase III FORTE trial in TE patients with NDMM who were ≤ 65 years old, patients with Revised International Staging System (R-ISS) stage II/III disease had a higher rate of MRD-negativity indicating a benefit in this population.¹³

Dr Nooka then presented the current Winship Cancer Institute of Emory University algorithm for induction therapy for patients with NDMM:¹

• TE, standard-risk: dara-VRd
• TE, high-risk: KRd
• TI, standard-risk: dara-Rd, dara-VRd or dara-VMP
• TI, high-risk: VRd-lite

Dr Nooka concluded that mAb-containing induction regimens show promising efficacy, including deep rates of MRD-negativity. Additionally, Dr Nooka believes experience with VRd indicates patients will benefit from a quadruplet induction such as dara-VRd. When considering the cost implications of mAbs in the frontline setting, Dr Nooka stated he believes the cost is justifiable and that now is the time to “embrace the change”.¹

Population-based analysis of VRd, Rd and Vd as frontline therapies for older patients with MM²

Given the number of available induction regimens and new combinations under investigation, it is a challenge for treating physicians to determine the correct course of treatment for patients. Adam Olszewski and colleagues used population-based data to compare the efficacy of VRd with doublet therapies (Rd and Vd), and then Rd to Vd, in TI patients with NDMM. They analyzed OS and time to treatment failure (TTF) as shown in Table 2 and Table 3.

Table 2. Efficacy of VRd compared to Rd/Vd²

VRd provided a longer TTF and OS compared to Rd/Vd, though it also led to higher hospitalization rates (relative risk [RR]: 1.17, 95% CI, 1.03–1.32), higher rates of anemia (RR: 1.16, 95% CI, 1.09–1.23), higher rates of neuropathy (RR: 1.49, 95% CI, 1.14–1.96) and increased consolidative transplant (26% vs 6%).

Table 3. Efficacy of Rd compared to Vd²

Rd surprisingly provided a longer TTF and OS compared to Vd. Rd was associated with higher rates of thromboembolism (RR: 1.44, 95% CI, 1.13–1.83), but lower rates of neuropathy (RR: 0.39, 95% CI, 0.29–0.53) and there was no difference in rates of hospitalization or anemia (RR was 0.96 and 0.95, respectively).

Adam Olszewski and colleagues found that VRd offers a TTF and OS benefit for older patients with MM who can tolerate slightly higher, short-term toxicity. This confirms the results of the SWOG S0777 trial in a population-based setting. With regards to doublet therapies, unexpectedly, Rd showed an advantage over Vd indicating it may be the more efficacious option, despite Vd being the most commonly used in this population.²

Meta-analysis of trials utilizing Rd³

During the IMW meeting, Salomon Manier presented the results of a meta-analysis which aimed to obtain a pooled estimate for PFS and OS from phase III trials utilizing Rd for patients with NDMM who are not intended for ASCT. The trials analyzed were the FIRST¹⁴, MAIA¹² and SWOG S0777⁵ trials (Rd arms).

Efficacy

• Median PFS, OS and ORRs were similar across the three trials (Table 4)
• Median PFS with Rd was estimated to be 28.9 months (95% CI, 26.8–31.3 months)

Table 4. Efficacy results from the FIRST, MAIA and SWOG S0777 trials^12,14,15

Safety

• Grade 3–4 AEs with Rd were in line with the known safety profiles for the regimen (Table 5)
• More patients discontinued treatment with R due to AEs in the FIRST trial compared to MAIA and SWOG S0777, though there were no differences in the starting dose of R between the FIRST and MAIA trials (Table 6)
• Patients stayed on treatment for longer in the MAIA trial (Table 6) which may reflect increased physician experience at the time of study

Table 5. Select grade 3–4 AEs affecting ≥ 5% of patients on study^5,12,14

Dr Manier concluded that Rd provided a consistent benefit across the three phase III trials evaluated, with median PFS exceeding two years and OS exceeding five years. No new safety signals were identified in MAIA or SWOG S0777.

The meta-analysis performed by Dr Manier and colleagues support the European Myeloma Network, European Society of Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN®) recommendations that Rd is used as frontline SOC. It also supports the investigation of Rd in novel combinations such as dara-Rd and dara-VRd.

Conclusion

These presentations highlight the vast availability of induction regimens for the treatment of NDMM, in both the TE and TI setting, as well as how many new combinations are under investigation. The addition of mAbs to traditional doublet and triplet backbones will likely become the SOC regimens, though this will vary in each specific patient scenario, with further data required to reach a consensus. In the meantime, traditional induction regimens, such as Rd and VRd, continue to prove efficacious in meta-analyses and population-based studies.