Reassessing the Duration of Induction Therapy for Newly Diagnosed, Transplant‐Eligible Myeloma Patients in the Context of Quadruple CD38 Monoclonal Antibody‐Based Regimens: Is 24 Weeks Optimal?

A quadruple induction regimen based on an anti-CD38 monoclonal antibody (CD38 quads) is the current standard of care for all newly diagnosed multiple myeloma (MM) patients, except possibly for older, frail adults 1-4. The idea of induction therapy in MM, similar to the approach in St. Jude protocols for pediatric leukemia, is to lower tumor burden and attain deep disease control prior to autologous stem cell transplant (ASCT) 5. Achieving sustained bone marrow minimal residual disease (MRD) negativity is a key predictor of long-term clinical outcomes for all MM patients, regardless of patient, disease, or treatment factors 6, 7. We believe that attaining MRD negativity should be the primary goal of MM therapy, whether it is newly diagnosed or relapsed, refractory disease 8, 9. A recent analysis that modeled long-term outcomes estimated that patients treated with the PERSEUS regimen, comprising DVRD, upfront ASCT, and response-adapted DR maintenance, have a best-fit median PFS of 17 years, underscoring that long-term remission and survival are achievable for most patients 10. What is the optimal duration of induction for patients with newly diagnosed MM before proceeding to ASCT? Historically, patients were treated with four cycles because that was the practice when standard induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) was given for 16 weeks before ASCT. The length of this induction period was limited by the toxicity of dexamethasone when we used 12 days per cycle of 40 mg oral dexamethasone (cumulative dose of over 1900 mg). Also, there are limits on cumulative vincristine and doxorubicin 11. Is a 16-week induction still the best option in the context of CD38 quads? We believe that extending induction to at least 24 weeks would be more appropriate in today's treatment landscape for several reasons. First, in the context of CD38 quads use (either with bortezomib or carfilzomib; see Table 1 and Figure 1), MRD negativity rates tend to increase with longer induction durations. To develop our recommendations, we assume equal efficacy between daratumumab and isatuximab 12. In the phase 2 GRIFFIN study, MRD negativity after 12 weeks of DVRD induction was 21% 1. MRD negativity deepened to 35% after 16 weeks of DVTD induction in the CASSIOPEIA study and reached 50% with the GMMG HD7 IsaVRD regimen when given over 18 weeks 13, 14. The recent PERSEUS study, which employed a 16-week induction course, reported 75% MRD negativity in those with a complete response or better 2. A similar theme emerges across the carfilzomib-based CD38 quads. At the end of 16 weeks of induction, the MRD negativity was 38% with DKRD and 45% with IsaKRD in the MASTER and IsKia studies, respectively 15, 16. MRD negativity across the GMMG CONCEPT and IFM 2018-04, which enrolled only high-risk myeloma patients, was 41% and 68%, respectively, after 24 weeks of induction 17, 18. Across these trials, there was variation in the MRD assessment method, with flow cytometry used in the GMMG CONCEPT study, and differences in the definitions of high-risk disease. In contrast, the MIDAS study (IsaKRD), which included all participants, reported MRD negativity of 65% at a sensitivity of 10−5 as assessed by NGS at the end of 24 weeks 19. However, the MRD negativity rate stayed roughly the same at 59% from 32 weeks of DKRD induction in the phase III ADVANCE study, indicating no significant benefit from extending induction therapy 20. Cross-trial comparisons of CD38 quadruplet bortezomib versus carfilzomib induction regimens are limited by differences in induction duration across studies, with more prolonged induction treatment in recent carfilzomib trials (Table 1). Taken together, a 24-week CD38 quads induction regimen with either bortezomib or carfilzomib may offer the best opportunity to achieve deep MRD-negative remission before proceeding to ASCT. Second, CD38 quads appear to be well tolerated. While accurately comparing the cumulative toxicities of 16 versus 24 weeks of induction can be challenging, an important factor to consider is the cumulative risk of infections, especially respiratory ones. This is often multifactorial, driven by treatment-related neutropenia, lymphopenia, and hypogammaglobulinemia, among other patient, treatment, and disease-related factors 21, 22. While Grade 3 and 4 infections have been reported in 1%–35% of patients across these clinical trials (Table S1), infection-related mortality remains low. Nevertheless, infection mitigation strategies such as proactive management of cytopenias, prophylactic antibodies, and intravenous immunoglobulin supplementation may be employed as appropriate. Other toxicities include peripheral neuropathy, which can occur particularly with bortezomib; implementing a weekly dosing schedule for bortezomib may help reduce this risk without compromising clinical effectiveness 23. What are some of the potential drawbacks of extended CD38 quads induction? Prolonged inductions may affect stem cell mobilization, likely due to dysregulation of CD34+ cell adhesion caused by CD38 blockade on the stem cells 24. Most stem cell mobilization in these trials used cyclophosphamide and growth factors (Table S1). However, in the IFM 2018-04 study, 6 of 27 patients who were collected after 24 weeks of DKRD induction had insufficient stem cells for tandem ASCT, prompting a protocol amendment to collect at the end of 12 weeks. Yet, 2 of the 21 patients still did not collect enough stem cells for a tandem ASCT 18. In the US, cyclophosphamide-based stem cell mobilization is not routine, and in the MASTER and GRIFFIN studies, plerixafor was added to granulocyte colony-stimulating factor in 97% of patients (after 16 weeks of DKRD) and 72% (after 12 weeks of DVRD), whether upfront or as rescue therapy 25. Furthermore, patients treated with anti-CD38 monoclonal antibodies require more apheresis sessions and higher doses of plerixafor, thereby increasing costs by 23 285 per patient 24. When using a 24-week CD38 quadruple induction regimen, it may be advised to collect stem cells at the end of either 12 or 16 weeks to ensure adequate stem cell yield, then complete the remaining induction treatment leading to ASCT. In conclusion, a 24-week induction CD38 quad regimen may benefit all newly diagnosed patients with MM to maximize clinical response prior to ASCT, as shown in Figure 1. We recognize the limitations of this proposal due to the absence of prospective data comparing 16 weeks versus 24 weeks of induction, as well as the complexities involved in cross-trial comparisons of regimens using either bortezomib or carfilzomib, differences in the relative dose densities, and study populations. Additionally, the role of ASCT may be evolving, especially as combination induction therapy leads to exceptional MRD negativity rates; however, the sustainability of such responses without further treatment needs prospective validation 26. Several clinical trials include extra consolidation cycles following ASCT; can this compensate for shorter induction phases? This could be considered semantic, since patients receive more of the original therapy before proceeding to maintenance. In this context, it would seem that using 24 weeks of the same induction regimen is likely to yield similarly high rates of MRD negativity (Figure 1). In the future, advanced and sensitive peripheral blood MRD testing could enable personalized treatment strategies based on MRD response, allowing adjustments to induction duration, such as is being pursued in the MIDAS and ADVANCE clinical trials 19, 20. However, at present, performing multiple bone marrow MRD assessments during induction may be challenging in the community setting. Based on the presented data, a 24-week induction regimen is justifiable to deepen response beyond the 16-week mark. However, this concept may be challenging in certain scenarios, particularly when patients have not achieved at least a very good partial remission (VGPR) by 16 weeks, and the response has plateaued. These cases indicate the persistence of refractory tumor cells, and continuing the same induction regimen may not be beneficial. The only exception may be the subset of t (11;14) MM, in which time to clinical response and MRD negativity may be prolonged, with a higher risk of MRD resurgence, without compromising clinical outcomes 27. More data are needed on how best to tailor treatment in this subset of patients to avoid the risk of overtreatment, especially if attainment of MRD negativity is the goal. Similarly, the benefits of extending induction to 24 weeks in patients who achieve early MRD-negative remission remain unclear. A study of longitudinal MRD assessment suggests that achieving MRD negativity before ASCT was linked to favorable outcomes in the pre-CD38 quad induction era 28. However, robust data on the long-term outcomes of MRD negativity prior to ASCT remain limited. Future studies will be necessary to identify further which patients will most benefit from extended induction. M. M. and R. F. wrote the first draft of the manuscript. All authors provided critical feedback and approved the final manuscript. M. M. is funded by the Advancing a Healthier Wisconsin Endowment-Medical College of Wisconsin CTSI KL2 award. R. F. is supported by the Mayo Clinic (Getz Family Professor of Cancer), Mayo Clinic Myeloma SPORE CORE A Biospecimens and Clinical Database, National Cancer Institute (P50 CA186781), Paula and Rodger Riney Foundation, U01 Grant Mayo Clinic Center for Clinical Proteomics, and National Institutes of Health (CA271410). The authors have nothing to report. M. M. has received institutional research funding from Sanofi S. A. , Bristol-Myers Squibb Company, Celgene Corporation, and has served on the advisory boards for Sanofi S. A. , Bristol-Myers Squibb Company/Celgene Corporation, Pfizer, Janssen Scientific Affairs LLC, Legend Biotech, and Adaptive Biotech. R. F. Consulting: AbbVie, Adaptive, Amgen, Apple, BMS/Celgene, GSK, Janssen, Karyopharm, Pfizer, RA Capital, Regeneron, Sanofi. Scientific Advisory Board: Caris Life Sciences, Board of Directors: Antengene, Patent for FISH in MM– ~ 2000/year, Believe in stem cell transplant. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. Table S1: Select adverse effects of interest and stem cell yield in clinical trials of CD38 monoclonal antibody-based induction in transplant-eligible newly diagnosed multiple myeloma. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.