Blurring the Lines: Beyond Using Transplant Eligibility to Guide Induction Therapy in Myeloma

Induction regimens for patients with newly diagnosed multiple myeloma (NDMM) have long been determined based on patients’ fitness for upfront autologous stem cell transplantation (ASCT), but results of recent trials now call this approach into question. Traditionally, patients with NDMM who are either transplant ineligible (TIE) or for whom transplant is deferred — typically those older and frailer than their transplant eligible (TE) counterparts — have received gentler treatment regimens.¹  For years, continuous treatment with lenalidomide and dexamethasone (Rd) was the standard of care for TIE patients, until being supplanted by bortezomib plus Rd (VRd) in the SWOG S0777 trial and daratumumab plus Rd in the MAIA trial.^1-4  Despite these advancements, the most potent quadruplet regimens, such as the GRIFFIN trial’s combination of daratumumab plus VRd (DVRd), were still primarily reserved for TE patients with NDMM.⁵  In this analysis, we highlight key studies investigating quadruplet regimens for TIE patients that closely resemble those used for TE patients, raising the question of whether transplant eligibility should continue to dictate induction regimens for multiple myeloma.

Triplet induction regimens have long been the standard for TIE patients. In patients with NDMM who deferred transplant, SWOG S0777 first demonstrated the superiority of VRd over Rd. However, enrolled patients had a median age of 63 and tolerated twice-weekly bortezomib, casting doubt on whether the results could be generalized to a truly TIE population.³  A subsequent phase II study enrolling only TIE patients used the more tolerable modified regimen of lenalidomide, bortezomib, and dexamethasone, yielding a median progression-free survival (PFS) of 35.1 months and supporting the use of this triplet in TIE patients.⁶ 

The next question was whether adding a fourth agent would enhance outcomes or merely increase toxicity in TIE patients. Years earlier, studies like the randomized phase II EVOLUTION trial proved that not all quadruplets are superior to triplets (e.g., the addition of cyclophosphamide to VRd increased toxicity without improving efficacy compared to VRd and the combination of bortezomib, cyclophosphamide, and dexamethasone).⁷  However, anti-CD38 antibodies, known for their tolerable safety profile, stood out as ideal additions to VRd that could offer a favorable risk-benefit balance.

The CEPHEUS and IMROZ studies each investigated whether the addition of anti-CD38 antibodies —daratumumab and isatuximab (Isa), respectively — could improve upon the standard VRd. IMROZ enrolled TIE patients with NDMM, while CEPHEUS enrolled either TIE or transplant-deferred patients with NDMM, with both studies randomizing patients to VRd alone or VRd plus an anti-CD38. IMROZ met its primary endpoint of PFS, achieving a 60-month PFS of 63.2% with Isa plus VRd (Isa-VRd) compared to 45.2% with VRd (hazard ratio [HR] = 0.60, p<0.001).⁸  In parallel, CEPHEUS met its primary endpoint of minimal residual disease (MRD) negativity at a threshold of 10^-5 (61.9% vs. 39.4% with DVRd and VRd, respectively, p<0.0001).⁹  Additionally, 54-month PFS was 68.1% with DVRd and 49.5% with VRd (HR=0.57, p=0.0005). Together, these two studies definitively demonstrated the superiority of anti-CD38-based quadruplets over VRd.

Notably, by the time the results of IMROZ and CEPHEUS were coming out, the classic VRd triplet used for both comparator arms had largely fallen out of favor.¹  In the MAIA study, published two years prior, daratumumab plus Rd (DRd) had produced a striking median PFS of 61.9 months, compared with 43 months with VRd in the SWOG S0777 study, dethroning the latter as the gold-standard induction regimen for TIE patients.^3,10  The most relevant question then became whether bortezomib was truly needed when the triplet of anti-CD38, lenalidomide, and dexamethasone was already so efficacious.

The BENEFIT trial sought to address this lingering question by comparing Isa plus Rd (Isa-Rd) to Isa-VRd in TIE patients with NDMM.¹¹  The trial employed once-weekly bortezomib and used MRD negativity at 10^-5 assessed 18 months after randomization as its primary endpoint. At 18 months, Isa-VRd produced higher MRD negativity rates than Isa-Rd (53% vs. 26%, p<0.0001), as well as higher complete response or better rates (58% vs. 33%, p<0.0001). At a median follow-up of 23.5 months, PFS and overall survival data were immature. However, estimated 24-month PFS rates for Isa-VRd and Isa-Rd were 85.2% (95% CI 79.2-91.7) and 80.0% (95% CI 73.3-87.4), respectively.¹¹  Importantly, rates of peripheral neuropathy were almost doubled in the bortezomib-treated arm, with Isa-VRd showing 52% at any grade and 27% at grade 2 or higher, compared to Isa-Rd’s 28% at any grade and 10% at grade 2 or higher. These results demonstrate the continued benefit of bortezomib when included in Isa-VRd in TIE patients, although at the cost of increased peripheral neuropathy.

Transplant eligibility remains an integral early decision point in the initial management of NDMM, as well as a frequent distinguishing criterion between clinical trials of NDMM treatment. However, the results of CEPHEUS, IMROZ, and BENEFIT have echoed a common refrain: quadruplet induction regimens typically used for TE patients are also superior to triplets in the TIE setting. Still, it is prudent to recognize that patients enrolled in these three studies represent only a subset of TIE patients — no patients over the age of 80 were enrolled in these trials, and patients considered “frail” with a Myeloma Geriatric Assessment score of 2 or higher were excluded from CEPHEUS.^8,9,11  A post-hoc analysis of IMROZ, however, found consistent PFS benefit in both frail and non-frail patients.¹² 

Ultimately, it remains to be seen how these regimens will fare when applied to a broader real-world population. Historically, applying regimens from clinical trials to real-world myeloma patients results in substantially shorter treatment durations, particularly when parenteral agents are included.¹³  Thus, determining the duration of quadruplet-based treatment needed to provide PFS benefit over MAIA’s DRd will be essential to fully understanding its utility in the TIE setting. Nevertheless, the consistency of findings across recent trials demonstrates definitively that transplant eligibility should no longer dictate the regimens for which patients with NDMM are candidates. Both TE and TIE patients can derive significant benefit from upfront quadruplet regimens.