May 2019 Edition Vol.11, Issue 5

A Multiple Myeloma Roundtable: Treatment Trends and Recent Clinical Advances

Outcomes for patients with multiple myeloma (MM) have continued to improve over the last several decades with the development of new treatments and therapeutic approaches. Still, questions remain.

A panel of experts recently discussed treatment trends and clinical advances in myeloma. Moderator James R. Berenson, MD, Medical and Scientific Director of the Institute for Myeloma and Bone Cancer Research in West Hollywood, California, was joined by Ruben Niesvizky, MD, Director of the Myeloma Center, New York Presbyterian—Weill Cornell Medical Center, New York City, and Shaji Kumar, MD, Division of Hematology, Mayo Clinic, Rochester, Minnesota.

The panel discussed quadruplet versus triplet drug combinations, the role of stem cell transplant and maintenance therapy, and how best to monitor myeloma and the role of precision medicine.


Quadruplet vs Triplet Combination Therapies

Two recent trials provide limited data on the use of quadruplet versus triplet combinations in subgroups of patients with newly diagnosed myeloma. The ALCYONE trial of bortezomib, melphalan, and prednisone with and without daratumumab in patients not eligible for transplant1 shows adding the monoclonal antibody improves progression-free survival (PFS). Overall survival data are not available.

The Cassiopeia trial of bortezomib, thalidomide, and dexamethasone with and without daratumumab in transplant eligible patients,2,3 shows an increased rate of stringent complete response with the quadruplet combination. The study is ongoing and PFS data are not yet available.

Dr. Berenson: Why should four drugs be used instead of three?

Dr. Kumar: This is the next wave of investigation in myeloma. Proteasome inhibitors (PIs) plus immunomodulatory drugs (IMiDs) currently form the backbone of initial treatment. It seems logical to add a third class of active drugs like the monoclonal antibodies (mAbs), although more data are still needed to see if quadruplet therapy with PIs, IMiDs, mAbs, and steroids changes PFS and overall survival (OS). The cost of  quadruplet versus triplet therapy is also a concern.

Data from the ALCYONE trial (NCT02195479) suggest that combining daratumumab with bortezomib plus melphalan and prednisone for newly diagnosed patients who are not eligible for transplant is a reasonable approach (Figure 1).1

FIGURE 1: PFS was the primary endpoint in patients with newly diagnosed MM who were ineligible for stem cell transplant. Patients received 9 cycles of bortezomib, melphalan, and prednisone either alone (n=356) or with daratumumab (n=350).

Figure 1. Progression-free Survival. Shown are the results of the Kaplan–Meier estimates of progression-free survival among patients in the intention-to-treat population, which included all the patients who underwent randomization. The daratumumab group received treatment with daratumumab, bortezomib, melphalan, and prednisone; the control group received treatment with bortezomib, melphalan, and prednisone alone. The interim analysis of median progression-free survival was performed after 231 events of disease progression or death had occurred (64% of the planned 360 events for the final analysis); the results of the analysis crossed the prespecified stopping boundary. NE denotes could not be estimated.

From N Engl J Med. Mateos M-V, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. 2018;378:518-528. https://www.nejm.org/doi/full/10.1056/NEJMoa1714678. Massachusetts Medical Society. Reprinted with permission.

 

Dr. Niesvizky: The hazard ratio for PFS in the ALCYONE trial is very robust, but follow-up OS data are needed to support this induction protocol. In general, surrogate markers are needed to determine which quadruplet induction combinations are superior in the non-transplant setting in the absence of larger studies and longer follow-up.

In transplant-eligible patients, only early data are available from the Cassiopeia phase 3 trial (NCT02541383), in which VTD (bortezomib, thalidomide, and dexamethasone) is compared with VTD-daratumumab.2,3

Data suggest the quadruplet is associated with a better complete response (CR) rate, but more information is needed about minimal residual disease (MRD). Therefore, I think it is premature to bring quadruplet therapy into general practice.

Dr. Berenson: Do either of you use four drugs in the front-line setting, and if so, under what conditions?

Dr. Kumar: I do not use quadruplet induction therapy outside of the clinical trial setting. It’s known that patients with high-risk myeloma do not do well with current therapies; in the absence of data one might consider quadruplets for this patient population.

Dr. Niesvizky: Approaches similar to that of the phase 3 MAIA trial (NCT02252172)4 for front-line therapy for patients not eligible for transplant include the triplet of daratumumab plus bortezomib and prednisone or daratumumab and lenalidomide, but not in a quadruplet. In MAIA, newly diagnosed, transplant-ineligible patients received lenalidomide and dexamethasone with daratumumab (n=368) or without daratumumab (n=369). In a pre-specified, interim analysis with a median follow-up of 28 months, median PFS was 31.9 months in the lenalidomide and dexamethasone group and not reached in the daratumumab group (HR 0.56; 95% CI, 0.43-0.72; P<.0001).4,5

Dr. Berenson: In the absence of data, the use of the four drug combination Doxil, daratumumab, lenalidomide, and steroids for front-line treatment of higher risk disease could improve response.

Dr. Niesvizky: Another approach might be response-adapted therapy, starting with a triplet, and adding a fourth drug later in induction depending on response.

Dr. Kumar: Questions to be answered include who benefits the most from four versus three drugs and whether four drugs be administered for a limited duration in patients with standard risk myeloma.


Stem Cell Transplant

The next topic is more controversial: the role of stem cell transplant in 2019.

Dr. Niesvizky: The Determination trial (NCT01191060; IFM/DFCI2009),6 comparing RVD (lenalidomide, bortezomib, and dexamethasone) followed by transplant to consolidation and RVD without transplant, has shown that achieving MRD-negativity is what is important.It is possible to achieve MRD-negativity without the use of high-dose alkylating agents and transplant, but the best way to reach MRD-negativity needs to be determined.

Dr. Kumar: Autologous stem cell transplant (ASCT) as front-line therapy for eligible patients seems to be the most effective way to achieve MRD-negativity and improve PFS, in the absence of OS data (Figure 2). The lack of OS data means that ASCT could be considered as second-line therapy at relapse for patients who do not want front-line transplant. It’s important to collect and store stem cells even if ASCT is not part of the initial therapy.

FIGURE 2. Kaplan-Meier curves for PFS and OS for patients who received RVD (n=350) alone versus RVD and transplant (n=350). Median PFS was 50 months in the transplant group and 36 months in the no transplant group (HR, 0.65; 95% CI, 0.53-0.80; P<.0001) at a median follow-up of 44 months and 43 months, respectively. There was no difference between groups in median OS at four years.

Panel A shows progression-free survival among patients who received RVD therapy (lenalidomide, bortezomib, and dexamethasone) alone and among those who received RVD therapy plus transplantation. Median progression free survival was 50 months in the transplantation group and 36 months in the RVD-alone group (adjusted hazard ratio for disease progression or death, 0.65; 95% confidence interval [CI], 0.53 to 0.80; P<0.001).

Panel B shows overall survival in the two treatment groups. Overall survival at 4 years did not differ significantly between the transplantation group and the RVD-alone group (adjusted hazard ratio for death, 1.16; 95% CI, 0.80 to 1.68; P=0.87).

From N Engl J Med. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. 2017;376:1311-1320. DOI: 10.1056/NEJMoa1611750. Massachusetts Medical Society. Reprinted with permission.

 

Dr. Berenson: I do not recommend ASCT for my patients, because it confers no OS advantage. PFS is not an accurate surrogate marker for OS, as patients may be in relapse before the monoclonal protein is detectable. The use of transplant in an era of new drugs may limit the ability of patients to get those drugs because of side effects beyond damaging the bone marrow. In addition, depth of response may be irrelevant for some patients, who may need less therapy, although this population has not been well-defined.

Dr. Kumar: Many combination therapies have been approved and are used based on PFS. The fact that the PFS is higher for transplant essentially meets the same requirement placed on new drugs. Until there are data showing that OS is inferior, there is no reason not to use ASCT.

Dr. Berenson: PFS and OS may not be related after front-line therapy fails.

Dr. Niesvizky: PFS doesn’t tell the whole story. A major issue with the use of alkylating agents in front-line therapy is the emergence of secondary malignancies that may appear more often as survival improves. Our clinic harvests stem cells in best response and uses high-dose melphalan and transplant as salvage therapy, while trying to achieve MRD-negativity by other means.


Maintenance Therapy

In newly diagnosed patients who have received an ASCT, post-transplant maintenance therapy with lenalidomide compared with placebo or observation improves both PFS and OS, although not OS in patients with high-risk disease.7 Protease Inhibitors (PIs) provide an alternative for maintenance with a different mechanism of action than lenalidomide. Bortezomib maintenance improves PFS in both transplant eligible and ineligible patients, although the route of administration and risk of peripheral neuropathy may limit use.7

The ongoing phase 3 TOURMALINE-MM3 trial (NCT02181413) is investigating the oral PI ixazomib as maintenance therapy post-ASCT. Ixazomib prolongs PFS in the post-transplant population, providing an alternative to lenalidomide or bortezomib.8

Dr. Kumar: Maintenance post-ASCT is the current standard of care. A meta-analysis of phase 3 trials shows that maintenance with lenalidomide improves OS after a single ASCT by two to three years.The ideal duration of lenalidomide maintenance is unknown. Data for the use of bortezomib maintenance is not as strong as that for lenalidomide, especially for patients with high-risk myeloma.

The phase 3, double-blind, placebo-controlled, TOURMALINE-MM3 trial looked at ixazomib as maintenance therapy post-ASCT.Patients with myeloma who had at least a partial response to standard-of-care induction therapy followed by high-dose melphalan and a single ASCT within 12 months of diagnosis were enrolled. Patients were randomly assigned 3:2 to maintenance therapy with ixazomib (n=395) or to placebo (no maintenance; n=261).

At a median follow-up of 31 months, the risk of progression or death was reduced by 28% in the ixazomib group (median PFS 26.5 months) versus placebo (median PFS 21.3 months; HR 0.72; 95% CI 0.58-0.89; P=.0023) (Figure 3). There was no increase in the incidence of second malignancies in the ixazomib group compared with the placebo group (3% in each group).

The rate of serious adverse events was 27% in the ixazomib group, with one death, and 20% in the placebo group, with no deaths. Follow-up is ongoing. Although cross-trial comparisons are not appropriate, the magnitude of improvement with ixazomib appeared to be less than what might be expected, based on the prior trials of lenalidomide. Ixazomib certainly remains an option for maintenance for patients who cannot tolerate lenalidomide, he concluded.

FIGURE 3: Kaplan-Meier analysis of progression-free survival in the intent-to-treat population.

From 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;393:253-264. http://dx.doi.org/10.1016/S0140-6736(18)33003-4.

Dr. Niesvizky: Continuous therapy with lenalidomide at a tolerated dose is preferable to maintenance therapy with a lower dose after induction therapy whether the patient has a transplant or not. Continuous therapy increases PFS and OS, whereas stopping therapy can allow the emergence of clones that can rapidly evolve into disease progression. Even with the lack of randomized data comparing bortezomib maintenance versus lenalidomide or placebo, Dr. Niesvizky said that he and others may combine a PI and IMiD for continuous maintenance therapy after induction or transplant for patients with high-risk disease. Ixazomib does not have the results expected from a maintenance drug, but it is an alternative for maintenance.

Dr. Berenson: Our practice is to continue therapy indefinitely, but there are tolerability issues and questions about dosing. Long-term side effects are a major drawback of steroids, although we continue steroids. Patients also grow weary of the side effects of long-term lenalidomide, e.g., gastrointestinal and nervous system toxicity, fatigue, somnolence, and the inability to multitask. Ixazomib as an oral agent is more convenient than bortezomib and requires fewer clinic visits for patients. We use maintenance therapy not only in front-line therapy but also for patients who are on salvage therapy.

Dr. Kumar: Continued therapy until disease progression has become the norm for myeloma, both in the relapsed and upfront setting. Toxicities, like secondary malignancies with lenalidomide, are a concern. Prospective trials are needed to determine which patients need continuous therapy, and if, for example, MRD-negativity sustained for a period could signal the ability to discontinue therapy in a selected group of patients.

Dr. Berenson: Better targeted therapies, perhaps as part of an antibody-drug conjugate, may allow continuous therapy without off-target side effects or the ability to give a therapy that is effective only at every relapse with therapy-free intervals, because the drug only targets the myeloma. That’s a dream and not reality.


Monitoring Multiple Myeloma

Dr. Kumar: Using the monoclonal protein remains one of the best ways to monitor myeloma, especially in the beginning, when most patients have some measurable monoclonal protein. As therapies have improved, patients with CR may have no protein to measure, and novel and emerging technologies to measure MRD become important. Currently, next generation sequencing or flow cytometry are being used to measure MRD at a level of one tumor cell per 100,000 to 106 bone marrow cells. Newer mass spectrometry-based approaches may have increased sensitivity. As it becomes easier to assess depth of response, response assessment over time may provide more value in allowing selection of or changes in treatment.

Dr. Niesvizky: Circulating DNA may also be a technology incorporated in the future and may avoid bone marrow testing, but that’s still hypothetical rather than factual. Better detection of residual lesions via imaging, including PET/CT, PET/MRI, or the incorporation of radioactive isotopes also need to be incorporated going forward.

Dr. Berenson: We have been developing the use of serum BCMA (B-cell maturation antigen) as a new biomarker for more quickly assessing changes in clinical status and monitoring patients with non-secretory myeloma.This may allow detection of rapid disease progression as well as allow patients without disease progression to avoid unneeded therapy. Data from a collaboration with the Mayo Clinic suggest that serum BCMA may also allow predicting the risk of progression from MGUS (monoclonal gammopathy of undetermined significance) or smoldering multiple myeloma to active myeloma.


Precision Medicine

Dr. Niesvizky: Unlike other cancers that may be driven by a single or small number of mutations that can be specifically targeted, multiple myeloma belongs to a highly heterogeneous group of malignancies that carry over a thousand mutations at diagnosis. As myeloma progresses, the mutational landscape changes. Therefore, myeloma therapy to date has focused on myeloma biology. The MyDRUG trial10 is an attempt to incorporate a biological approach and a mutational approach in myeloma therapy.

Dr. Kumar: The MyDRUG (Myeloma—Developing Regimens Using Genomics)10trial (NCT03732703) is led by the MMRF (Multiple Myeloma Research Foundation) CSO Dr. Daniel Auclair and Dr. Kumar. MyDRUG incorporates mutation profiling of myeloma cells from patients with high-risk disease to identify targetable mutations. Therapy with targeted drugs is assigned based on these findings and combined with standard-of-care agents.

Dr. Berenson: Precision medicine means more than just precision medicine addressing the myeloma. Patient comorbidities and side effect profiles, which may be better defined over time, need to be taken into account, as these affect patient quality and length of life. Precision medicine can help the subgroups of patients who may suffer severe toxicity with certain drugs. For example, carfilzomib is associated with cardiotoxicity. If it were possible to predict which patients were at risk with carfilzomib, they could avoid this toxicity. Similarly, the ability to predict patients who are susceptible to severe neurotoxicity associated with some agents would allow dose modification or the use of ancillary drugs to help reduce that risk.

In addition to identifying the patients who may benefit from specific drugs based on mutational biology, precision medicine may also allow the use of drugs in novel ways that may be completely outside of the usual therapies for myeloma. In addition, it also may allow avoidance of treatments altogether until there are either truly curative therapies or therapies with no side effects. There is some ability now to identify patients whose myeloma won’t progress for a long time who don’t need immediate treatment. “With better precision we could do that better,” concluded Dr. Berenson.


References

1. Mateos M-V, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378:518-528. DOI: 10.1056/NEJMoa1714678.

2. ClinicalTrials.gov. A Study to Evaluate Daratumumab in Transplant Eligible Participants With Previously Untreated Multiple Myeloma (Cassiopeia). https://clinicaltrials.gov/ct2/show/NCT02541383.

3. Janssen. Press release. March 26,2019. Janssen Submits Application for DARZALEX® (daratumumab) Combination Therapy to U.S. FDA for Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma. https://www.janssen.com/janssen-submits-application-darzalex-daratumumab-combination-therapy-us-fda-newly-diagnosed.

4. Facon T, Kumar SK, Plesner T, et al. Phase 3 Randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Blood 2018 132:LBA-2. http://www.bloodjournal.org/content/132/Suppl_1/LBA-2?sso-checked=true.

5. Nooka AK, Kaufman JL, Hofmeister CC, et al. Daratumumab in multiple myeloma. Cancer. April 2019, epub ahead of print https://doi.org/10.1002/cncr.32065.

6. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376:1311-1320. DOI: 10.1056/NEJMoa1611750.

7. McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017;35:3279-3289. DOI: https://doi.org/10.1200/JCO.2017.

8. 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;393:253-264. http://dx.doi.org/10.1016/S0140-6736(18)33003-4.

9. Ghermezi M, Li M, Vardanyan S, et al. Serum B-cell maturation antigen: a novel biomarker to predict outcomes for multiple myeloma patients. Haematologica. 2017;102:785-795. doi:10.3324/haematol.2016.150896.

10. Multiple Myeloma Research Foundation (MMRF), MyDRUG. https://themmrf.org/2019/02/mydrug/.

 

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