Changing Treatment Paradigms in Smoldering and NDMM

Dr. Jonathan KaufmanJonathan L. Kaufman, MD
Associate Professor
Associate Vice-Chair for Quality and Safety
Department of Hematology and Medical Oncology
Emory University School of Medicine
Atlanta, Georgia

The thinking on smoldering myeloma has shifted considerably over the past year or two. Could you describe some of the most important developments, and how those impact your clinical practice?

There have been a few important changes recently. The first is a simple definition of high-risk smoldering myeloma from the Mayo Clinic that we call the “20-2-20” criteria. These include three factors: bone marrow-plasma cell percentage >20%, M-protein >2 g/dL, serum free light chain ratio of >20. For patients who have two or three of those risk factors, the risk of progression at two years is approximately 15% and 24%, respectively.1 We have now clarified that as our high-risk group of patients who may benefit most from early intervention. It’s actually an easy model to incorporate into daily practice—these are tests that are drawn on every myeloma patient, so you can use this 20-2-20 model to very simply know who’s in your high-risk group.

The potential benefit of early intervention was evaluated in the QuiRedex trial, published in 2013, which showed that early treatment with lenalidomide and dexamethasone delayed progression to active disease and increased overall survival in patients with high-risk smoldering myeloma in Spain and Portugal.2 However, that trial had some limitations, including the use of a flow-based risk assessment, and the imaging to evaluate patients pre-treatment, which was X-ray only.3 I think those concerns were addressed in E3A06, a randomized trial of lenalidomide versus observation alone in patients with asymptomatic, high-risk smoldering multiple myeloma, which was recently presented at the annual meeting of the American Society of Clinical Oncology (ASCO).4

The E3A06 had a phase 2 portion, demonstrating that single-agent lenalidomide could be given safely to patients with smoldering myeloma, while in phase 3, patients were randomized to single-agent lenalidomide 25 mg for 3 of every 4 weeks continued until progression, or to observation. Importantly, about 45% of patients met the 20-2-20 criteria for high-risk smoldering myeloma.

Looking at the primary endpoint of E3A06, which is progression-free survival (PFS) for the entire phase 3 portion, there was a dramatic improvement, with a hazard ratio of 0.28. The three-year PFS in the treated patients was 91%, versus 66% for the observation patients. For those patients who had a diagnosis of high-risk smoldering myeloma based on the 20-2-20 criteria I described earlier, the hazard ratio was 0.15, so just an enormously positive outcome, while the benefit was less clear in the intermediate- and low-risk groups.

Lenalidomide treatment was well-tolerated. There were more non-melanoma skin cancers for lenalidomide versus observation. There did not seem to be a significant increase in other second primary malignancies beyond these non-serious local skin cancers, though of course longer follow-up will help clarify these findings.4

Our current recommendation for those patients who are high risk by the 20-2-20 model is to treat for two years with lenalidomide plus/minus dexamethasone, similar to what was used in the Spanish trial, and similar to what is being used in the next ECOG study, which will evaluate whether early intervention with daratumumab, lenalidomide, and dexamethasone is superior to a less-intensive lenalidomide and dexamethasone approach. Just to emphasize, we are not treating symptomatic myeloma, but preventing the development of symptoms, and so I think it’s very important to understand that difference—we’re really using this as prevention, not as a treatment.

The frontline treatment of multiple myeloma has also undergone considerable change. What would you say are the most important developments in the treatment of newly diagnosed patients?

In terms of standard induction therapy for multiple myeloma patients eligible for autologous stem cell transplant, the two most common treatments we’re using here in the United States are lenalidomide, bortezomib, and dexamethasone (RVd) or carfilzomib, lenalidomide, and dexamethasone (KRd). We’ve been using RVd for over 10 years, and recently put together an analysis of 1,000 patients5 that we treated with RVd followed by transplant and maintenance and that illustrates its impressive response rates and long-term outcomes in both standard- and high-risk patients. A lot of groups have switched over to KRd with the hypothesis that that combination is associated with a higher deep response rate. There is a single head-to-head study of RVd versus KRd6 which is fully accrued; we don’t have the data yet, but that study might inform us on differences in deep responses between these regimens. Our approach has been to recommend RVd for the standard-risk patients and save KRd for the high-risk patients, in part because of a 2% to 5% rate of cardiac toxicity among patients treated in phase 3 trials of carfilzomib.7

However, I think the RVd conversation is going to change shortly based on where we’re going with four-drug therapy. As recently published in The Lancet,8 the combination of daratumumab with bortezomib, thalidomide, and dexamethasone (d-VTd) improved depth of response and PFS as compared to VTd, which is standard for newly diagnosed, transplant-eligible patients in Europe. Something that’s much more relevant to practice in the United States is GRIFFIN, a randomized, phase 2 study looking at daratumumab plus RVd (D-RVd) versus RVd alone, with approximately 100 patients in each arm. Data presented at the annual meeting of the American Society of Hematology (ASH) last year and the safety data was demonstrated that the D-RVd combination can be given safely.9 The study is ongoing, though very recently, we saw some efficacy results presented showing that D-RVd resulted in higher response rates and greater depth of response versus RVd.10 So while RVd has been our standard, we actually have made D-RVd our standard of care for standard-risk patients, and for the high-risk patients, we are continuing to recommend KRd.

What about frontline therapy for newly diagnosed patients who are not candidates for transplant?

We have in large part used RVd for our non-transplant candidates, based on the SWOG S0777 randomized, open-label phase 3 trial. That study, which included both transplant and non-transplant candidates, demonstrated that RVd improved progression-free and overall survival versus lenalidomide plus dexamethasone (Rd) alone.11 However, since patients who are non-transplant candidates often can’t tolerate full-dose RVd, we’ve done some variety of an “RVd lite” regimen. There are different approaches to modified RVd, and we do ours based on lenalidomide 10 mg to 15 mg three out of four weeks, dexamethasone usually 20 mg once per week, and bortezomib at 1.3 mg/m2 on days 1, 8, and 15 of a 28-day cycle. The publication on “RVd lite” by O’Donnell and colleagues in Boston12 was a little bit more complicated, but we thought pairing the 3-out-of-4-weeks bortezomib with the 3-out-of-4-weeks lenalidomide made a lot of sense, just a large part for convenience.

The ALCYONE randomized, phase 3 trial13 gave us confidence that we could use daratumumab with bortezomib, melphalan, and prednisone (VMP) for untreated myeloma patients ineligible for transplant, but quite frankly VMP is just not a regimen that we have used in a very long time, so in that sense, it didn’t change our practice. Then, the randomized MAIA study came out, and the reality is, that did change our practice. In MAIA, daratumumab plus Rd was associated with a very high response rate versus Rd and significantly improved PFS that looked positive in most subgroups, except for the cytogenetic high-risk subgroup, which didn’t seem to have a significant benefit from adding daratumumab. So in a very similar way to the transplant-eligible setting, these data in the transplant-ineligible setting have left us with a different way of managing these patients. For the cytogenetic standard-risk patients, we’re going to give daratumumab with Rd until progression; for the high-risk patients, there may be somewhere where KRd would be appropriate, but for the most part, we’re using RVd or RVd lite.

In light of all these advances, how do factors such as renal failure, neuropathy, or advanced age at baseline impact treatment choice?

Age in and of itself quite frankly does not impact our decision making—it’s really much more about fitness, performance status, and comorbidities. For patients with acute renal failure or acute kidney injury, we’re still using bortezomib, thalidomide, and dexamethasone (VTd), though you often can’t get that thalidomide quickly, and the combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) makes a lot of sense. A lot of times they have rapid benefit, and then we can use lenalidomide once the kidney function is stabilized. Patients who present with baseline neuropathy are much more likely to develop very clinically significant and painful neuropathy from bortezomib, so even if they have standard-risk disease, we will choose to switch to carfilzomib upfront because of the lower risk of peripheral neuropathy. There is also a small group of patients that develops peripheral neuropathy early from bortezomib, and in that situation, we will again switch very quickly to carfilzomib.

Recent studies have shown that maintenance therapy with the immunomodulatory drug lenalidomide following transplant can improve PFS and overall survival. What are the implications of the TOURMALINE-MM3 trial, which evaluated oral ixazomib as post-transplant maintenance therapy?

I think the ixazomib maintenance trial14 is a positive trial, but the benefit seems to be less than what was seen with lenalidomide, and, to date, there are no published trials that have directly compared ixazomib versus lenalidomide. So the group of patients where I would think about using ixazomib as a single agent are those patients who, for whatever reason, didn’t have an immunomodulatory drug (IMiD) upfront, and you can confirm based on their response to their initial therapy that they are proteasome inhibitor-sensitive. The other situation in which I think ixazomib is an option is a patient where you really think they need maintenance therapy, but they can’t tolerate lenalidomide for whatever reason.

Our standard approach for standard-risk patients is to use lenalidomide as a single agent; and there’s a lot of work being done to try to understand length of treatment, and using minimal residual disease (MRD) analysis that help define length of treatment. For high-risk patients, a lot of people are using doublets and triplets, but unfortunately, there are not large randomized studies that help us make that decision, so it’s really a case-by-case decision for an individual patient. We know that proteasome inhibitors are effective in high-risk patients, and that lenalidomide is effective in high-risk maintenance but just not as effective as in the standard-risk patients, and so doing some combination of proteasome inhibitor and lenalidomide makes a lot of sense in the high-risk patients.

What is the take-home message for upfront myeloma therapy when considering current practice and some of the emerging approaches we have discussed?

I think the biggest changes are in the treatment of smoldering myeloma and in the use of monoclonal antibodies as part of primary therapy. We are starting to think about using single-agent lenalidomide or lenalidomide plus dexamethasone as part of a prevention strategy in high-risk smoldering myeloma. And over the next several years, we’re going to be figuring out how to incorporate daratumumab into the upfront setting, and to make that more of the standard of care.


  1. Lakshman A, Rajkumar SV, Buadi FK, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J. 2018;8(6):59. doi:10.1038/s41408-018-0077-4
  2. Mateos M-V, Hernández M-T, Giraldo P, et al. Lenalidomide plus Dexamethasone for High-Risk Smoldering Multiple Myeloma. N Engl J Med. 2013;369(5):438-447. doi:10.1056/NEJMoa1300439
  3. Rajkumar SV, Landgren O, Mateos M-V. Smoldering multiple myeloma. Blood. 2015;125(20):3069-3075. doi:10.1182/blood-2014-09-568899
  4. Lonial S, Jacobus SJ, Weiss M, et al. E3A06: Randomized phase III trial of lenalidomide versus observation alone in patients with asymptomatic high-risk smoldering multiple myeloma. J Clin Oncol. 2019;37(15_suppl):8001. doi:10.1200/JCO.2019.37.15_suppl.8001
  5. Joseph N, Gupta VA, Hofmeister CC, et al. Efficacy of Induction Therapy with Lenalidomide, Bortezomib, and Dexamethasone (RVD) in 1000 Newly Diagnosed Multiple Myeloma (MM) Patients. Blood. 2018;132(Suppl 1):3294-3294. doi:10.1182/blood-2018-99-119895
  6. Bortezomib or Carfilzomib With Lenalidomide and Dexamethasone in Treating Patients With Newly Diagnosed Multiple Myeloma. Accessed September 12, 2019.
  7. Jain T, Narayanasamy H, Mikhael J, et al. Reversible Cardiotoxicity Associated with Carfilzomib Use in Patients with Multiple Myeloma. Blood. 2016;128(22):2126-2126.
  8. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1
  9. Voorhees PM, Rodriguez C, Reeves B, et al. Efficacy and Updated Safety Analysis of a Safety Run-in Cohort from Griffin, a Phase 2 Randomized Study of Daratumumab (Dara), Bortezomib (V), Lenalidomide (R), and Dexamethasone (D; Dara‐Vrd) Vs. Vrd in Patients (Pts) with Newly Diagnosed (ND) Multiple Myeloma (MM) Eligible for High‐Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT). Blood. 2018;132(Suppl 1):151-151. doi:10.1182/blood-2018-151
  10. Voorhees P, Kaufman JL, Laubach J, et al. Daratumumab + Lenalidomide, Bortezomib & Dexamethasone Improves Depth of Response in Transplant-eligible Newly Diagnosed Multiple Myeloma: GRIFFIN. 17th International Myeloma Workshop, Boston, Massachusetts. September 12-15, 2019. Abstract OAB-87.
  11. Durie BGM, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527. doi:10.1016/S0140-6736(16)31594-X
  12. O’Donnell E, Laubach J, Yee AJ, et al. Final Results of a Phase 2 Study of Modified Lenalidomide, Bortezomib, and Dexamethasone (RVD lite) in Transplant-Ineligible Multiple Myeloma. Blood. 2017;130(Suppl 1):3126-3126.
  13. Mateos M-V, Dimopoulos MA, Cavo M, et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018;378(6):518-528. doi:10.1056/NEJMoa1714678
  14. Dimopoulos MA, Gay F, Schjesvold F, et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): A double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2019;393(10168):253-264. doi:10.1016/S0140-6736(18)33003-4