New Paradigm Is Shaping Up for High-Risk Smoldering Myeloma

Elisabet E. Manasanch, MD

The nature of smoldering multiple myeloma (SMM) is such that it can develop very rapidly into multiple myeloma (MM) or take years. However, since the disease was first identified almost 40 years ago by Robert Kyle, MD, and Philip Greipp, MD, observation has remained the standard of care.¹ During that time, more than a dozen new treatments have boosted survival times for individuals with MM. Now, researchers have begun trials to investigate whether any of those MM treatments might improve on observation for patients with SMM who are at the highest risk of progression.

There have been many discussions whether to treat with established regimens for MM or attempt novel agents that may produce less toxicity. Both options are currently under investigation in numerous trials, said Elisabet E. Manasanch, MD, an assistant professor in the Department of Leukemia and Myeloma at The University of Texas MD Anderson Cancer Center in Houston. The use of established MM therapies has been very successful and results in a large proportion of patients with deep responses. “However, this is at the expense of some toxicity, and long-term follow-up data are lacking,” she said. The alternative approach consists of testing other better-tolerated regimens, such as immunotherapeutics, as single agents, combination elements, or vaccines.

High-dose chemotherapy has the potential to reduce SMM to undetectably low levels, but its use comes with a high risk of toxicity and the potential for secondary cancers. “These drawbacks are particularly serious in patients who have no symptoms and may not develop any symptoms for years to come, which is why there’s also a lot of interest in testing other types of combinations that might prove a less traumatic way to improve outcomes,” Manasanch said.

SMM was originally defined to identify a group of 6 patients with 10% or more plasma cells (PCs) in the bone marrow and no organ damage at diagnosis who did not develop organ dysfunction related to MM for ≥5 years. It is now clinically defined as a clonal PC disorder that is diagnosed when patients have ≥10% to 59% clonal PCs in the bone marrow or elevated levels of monoclonal protein (M-protein; ≥3 g/dL in serum or ≥500 mg/24 h in urine) or both, but an involved/ uninvolved free light chain ratio (FLCr) <100, no end-organ damage, and no more than 1 focal bone lesion.² The asymptomatic nature of the condition means that many cases go undiagnosed, so researchers have struggled to estimate the overall incidence.³

Whereas SMM may progress to MM rapidly or not at all, investigators have developed several systems for differentiating patients with higher and lower progression risks. The Mayo Clinic model, for example, uses M-protein (≥3 g/dL), bone marrow PC% (BMPC; ≥10%), and FLCr ≥8 to sort patients into 3 risk categories. Patients who reach or exceed 1 of those thresholds have the lowest risk of progression, while patients who reach or exceed all 3 of those thresholds have the highest risk of progression: 76% of them develop MM in 5 years.⁴ More recently, the International Myeloma Working Group has developed a proposed stratification model based on a slightly different set of biomarkers: BMPC >20%; M-protein > 2 g/dL; and FLCr > 20. Patients are classified based on 1, 2, or 3 of these biomarkers into low- to high-risk categories (Figure).⁴

At least 1 trial for patients with high-risk SMM has demonstrated an overall survival (OS) benefit for early immunotherapy intervention versus observation alone. The Spanish Myeloma Group randomized 119 patients with high-risk SMM to observation or a combination of lenalidomide (Revlimid) and low-dose dexamethasone. In the treatment arm, a partial response (PR) or better of 90% and a complete response (CR) of 26% were achieved during the trial’s maintenance phase. The median time to progression was 21 months in the observation group versus not reached among treated patients (P <.001). OS was not reached in either group, and the proportion of patients alive at 3 years after study enrollment was 94% versus 80% in the treatment and observation groups, respectively (P = .03).⁵

Hard-Hitting Combinations

Figure. Conventional and Proposed Risk Stratification Models for SMM⁴

The study, which was published in 2013, was not enough to change SMM standards of care. Observers noted that the high number of patients who progressed within the first 6 months suggested that many of them would have had MM diagnosed at baseline had the trial used diagnostic imaging. It’s important to note that the investigators did not use the current definition of SMM, which was established after their study was published. Another objection was that treatment was initiated at time of end-organ damage rather than biological progression, which is not generally the norm.⁶Other trials of aggressive combination treatments in patients with SMM have also produced promising results, although none of them have amounted to large paradigm-changing randomized studies. In one, a carfilzomib (Kyprolis), lenalidomide, and dexamethasone combination demonstrated efficacy in high-risk SMM. A 2016 paper reported outcomes for 12 patients with high-risk SMM who received eight 28-day cycles of carfilzomib 20/36 mg/m² on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on days 1 through 21; and dexamethasone 20/10 mg (cycles 1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, and 23. Multiparametric flow cytometry found minimal residual disease in 11 of 12 patients (95% CI, 62%-100%). Among the 11 patients who completed all 8 cycles, 6 achieved a stringent complete response (sCR; 55%; 95% CI, 23%-83%), 2 achieved a CR (18%; 95% CI, 2%-52%) and 3 achieved a near CR (27%; 95% CI, 6%-61%).⁷

Reporting on a phase II trial, investigators said the combination of elotuzumab (Empliciti), lenalidomide, and dexamethasone produced high response rates and was very well tolerated among patients with high-risk SMM, boding well for a “paradigm shift toward early therapeutic intervention in patients with high-risk SMM.”⁸

The 2016 paper provided data on 39 patients who received elotuzumab (10 mg/kg) on days 1, 8, 15, and 22 for the first two 28-day cycles while receiving lenalidomide on days 1 to 21. Patients on this treatment arm received dexamethasone 40 mg on days 1, 8, and 15. In a second arm, patients were randomized to a low-dose dexamethasone treatment, but this arm was discontinued. Among 34 evaluable patients enrolled to both arms who received all 3 medications, the overall response rate (ORR) was 71%, with 9 very good partial responses (VGPRs) (26%) and 15 PRs (44%). No patients progressed during or after therapy. Grade 3 toxicities included hypophosphatemia (23%), neutropenia (8%), infection (8%), anemia (3%), pulmonary embolism (3%), rash (3%), and diarrhea (3%).⁸

DNA Repair Pathways

Late last year at the annual meeting of the American Society of Hematology (ASH), a multicenter group led by researchers at Dana-Farber Cancer Institute in Boston reported results from a slightly larger trial of the same triple therapy, but with different dosing. Again, investigators found the combination well tolerated with a high response rate. There were 3 CRs (6%), 18 VGPRs (37%), 20 PRs (41%), 5 minimal responses (10%), 3 instances of stable disease (SD; 6%), and 2 unevaluable patients. No patient had progressed to MM by the time of data collection. The most common grade 3 or higher adverse events (AEs) were hypophosphatemia (34%), neutropenia (26%), and decreased lymphocyte count (22%). A trio of patients (6%) had grade 4 hypophosphatemia during treatment, while grade 4 cholecystitis, cataract, lymphocyte count increase, hyperglycemia, neutropenia, and thrombocytopenia occurred in 1 patient each (2%) and diabetic ketoacidosis and sepsis led to death in another patient (2%).⁹Investigators also observed modest response among patients harboring mutations in DNA repair pathways and concluded that use of genomic studies can help to define the patients most likely to benefit from this combination of therapies.

The same meeting saw the Spanish Myeloma Group report the first results from the GEM-CESAR study of a regimen intended to be curative. Investigators found the data encouraging. They recruited 90 patients with SMM who were younger than 70 years and faced at least a 50% risk of progression in 2 years. Asymptomatic patients with MM with any of the 3 biomarkers recently included in the definition of active MM (≥60% clonal PCs; FLCr ≥100 mg/L; >1 focal lesion on MRI ≥5 mm) were eligible for inclusion.²

Induction therapy was six 4-week cycles of carfilzomib (36 mg/m² twice per week), lenalidomide (25 mg on days 1-21) and dexamethasone (40 mg weekly). Melphalan 200 mg/m² followed by autologous stem-cell transplant (ASCT) was given as intensification therapy. Three months later, patients received 2 triple-drug consolidation cycles followed by maintenance with lenalidomide (10 mg on days 1-21) plus dexamethasone (20 mg weekly) for up to 2 years.

Although 2 patients discontinued during induction, 88 patients completed the 6 cycles. The sCR rate was 32%, the CR rate was 9%, and the VGPR rate was 41%. A handful of patients experienced progression (n = 2), mobilization failures (n = 2), or ASCT rejection (n = 1), but 83 were evaluable 100 days after transplant. Among those, the ORR was 100%, including 51% with a sCR, 12% with a CR, and 23% with a VGPR. Grade 3 or 4 AEs included neutropenia (6%), thrombocytopenia (11%), infections (18%), skin rash (9%), and hypertension (1%). After a median follow-up of 17 months (range, 5-36 months), 97% of patients remained alive and 94% had yet to progress. “Although longer follow-up is required, this curative strategy for high-risk SMM continues being encouraging, with an acceptable toxicity profile,” the investigators concluded.¹⁰

Two additional trials are testing potentially curative strategies in SMM, but they have yet to report any results. The ASCENT trial is seeking to enroll 83 patients with high-risk SMM to receive 24 cycles (6 induction, 6 consolidation, and 12 maintenance) of a 4-drug combination: carfilzomib, lenalidomide, dexamethasone, and daratumumab (Darzalex).¹¹ The iStopMM trial will offer early triplet therapy treatment with carfilzomib, lenalidomide, and dexamethasone to patients with SMM as part of a much larger trial that involves offering to screen everyone born in Iceland before 1975 for monoclonal gammopathy of undetermined significance (MGUS) and seeing how early knowledge of that SMM and MM precursors affects outcomes.¹²

The best approach to finding therapies that are effective in the setting of SMM is to explore widely and without assumptions that may interfere with discovery, said S. Vincent Rajkumar, MD, a Mayo Clinic professor and hematologist who is participating in several trials.

“The results of several trials suggest that early therapy may be of benefit in high-risk smoldering myeloma,” he said. “But it is not clear whether combination therapy, let alone a particular combination therapy, should replace observation as the standard of care. There is a range of trials exploring monotherapy, doublet, and triplet combinations as well as multidrug combinations for high-risk smoldering myeloma. We owe it to patients to test all of these options rather than relying on our preconceived notions of what’s likely to work, and the research community is doing just that. That’s why there are so many trials going on in parallel right now.”

Trials of Monotherapies

Among the many ongoing trials is a Dana- Farber—based study of a less toxic triple therapy that consists of oral medications that can be taken at home. Patients with high-risk SMM receive 9 cycles of induction therapy: ixazomib (Ninlaro) 4 mg on days 1, 8, and 15; lenalidomide 25 mg on days 1 to 21; and dexamethasone on days 1, 8, 15, and 22. After induction, patients receive another fifteen 28-day cycles of maintenance with ixazomib 4 mg and lenalidomide 15 mg. Preliminary results reported at the 2018 ASH meeting for the first 26 patients showed 5 CRs (19.2%), 9 VGPRs (34.6%), 9 PRs (34.6%), and 3 minimal responses (11.5%). None of the patients have shown progression to MM to date. The most common grade 3 AEs were hypophosphatemia (13%), leukopenia (13%), and neutropenia (8.7%). There was 1 grade 4 neutropenia during treatment and 1 grade 4 hyperglycemia.¹³Monotherapy trial results have generally shown lower response rates and far fewer CRs in patients with high-risk SMM, but other findings have shown significant effects on proxy endpoints while producing fewer and less-severe AEs than triple therapies.

A 2013 paper showed the phase II results of a phase II/III trial of lenalidomide versus observation alone in patients with high-risk SMM. Investigators gave 44 patients lenalidomide 25 mg per day on days 1 to 21 in each of at least six 28-day cycles. After a median follow-up of 17 months, 15 patients had discontinued treatment for the following reasons: disease progression (n = 2), AE/complication (n = 5), death (n = 2), patient withdrawal/refusal (n = 5), and other (n = 1). Among all 44 patients, 11 (25.0%; 95% CI, 13.2%-40.3%) experienced treatment-related nonhematologic toxicity of grade 3 or higher, with neutropenia and fatigue being the most frequent. This includes 2 fatalities. Overall, 12 patients achieved a PR or better (33.3%; 95% CI, 15.0%- 42.8%) and 25 patients reported SD.¹⁴ The phase III portion of the trial has yet to report results.

Results from a recent phase II study of elotuzumab monotherapy in patients with high-risk SMM were also disappointing. Investigators gave elotuzumab 20 mg/kg (days 1 and 8 of the first cycle and monthly thereafter) to 15 patients and 10 mg/kg (weekly for the first 2 cycles and every other week thereafter) to 16 other patients. With a minimum of 28 months’ follow up, the ORR was 10% (90% CI, 2.7%-23.2%) and 2-year progression-free survival (PFS) was 69% (90% CI, 52%-81%). Upper respiratory tract infections occurred in 18/31 (58%) patients, while 4 (13%) patients experienced infusion reactions, all of them grade 1/2. The study’s authors concluded that although there were some signs of clinical benefit, the elotuzumab monotherapy demonstrated “minimal” activity in patients with high-risk SMM.¹⁵

An ongoing trial expected to reach its primary completion date in August 2019 is testing the anti—IL-6 monoclonal antibody siltuximab (Sylvant) in 87 patients with high-risk SMM randomized between placebo and intravenous injections of the experimental treatment, delivered every 4 weeks until progression to symptomatic MM, unacceptable toxicity, withdrawal of consent, or the end of the study.¹⁶

A 2017 paper reported results for 123 patients with intermediate- or high-risk SMM who were randomized equally among 3 treatment arms with daratumumab 16 mg/kg. The first group (long) received the drug every week during cycle 1, every other week in cycles 2 to 3, every 4 weeks in cycles 4 to 7, and every 8 weeks up to cycle 20. The second group (intermediate) received the drug weekly during the first cycle and every 8 weeks up to cycle 20. The third group (short) received the drug weekly for one 28-day cycle. ORRs were 23%, 21%, and 15%, respectively. With a median follow-up of 9.6 months, the median PFS was not reached in any treatment arm, but the estimated 12-month PFS rates were 98%, 93%, and 89%. Grade 3 or 4 AEs were reported in 34%, 10% and 15% of patients, respectively.¹⁷

Investigators presented updated data from the same study at ASH. At a median follow up of 25.9 months, the median PFS based on SLiMCRAB criteria was still not reached in any arm; 24-month PFS rates were 90% (long), 82% (intermediate), and 75% (short). The median PFS based on biochemical and diagnostic criteria was reached in the short arm only (14.8 months); 24-month PFS rates were 78%, 70%, and 27%, respectively. The greater efficacy of longer daratumumab regimens in this study led investigators to select longer regimens for AQUILA, an ongoing phase III daratumumab trial.¹⁸ Daratumumab, which is already approved for use against previously treated MM,¹⁹ binds to CD38, a protein that is expressed on several types of immune cells and is often overexpressed on MM cells. The drug is thought to work both by killing tumor cells directly and by stimulating an immune response against them. Isatuximab, a newer agent that binds to CD38, is also being tested as monotherapy in patients with highrisk SMM. Investigators from Memorial Sloan Kettering Cancer Center and Mount Sinai, both at New York, New York, are enrolling 61 patients in a single-arm phase II trial, with initial results of the first stage of the study expected in 2019.²⁰

CD38 antibodies are not the only immunotherapies that have drawn interest as potential treatments for SMM. The PD-1 inhibitor pembrolizumab (Keytruda) also underwent early-stage trials against the condition, but aside from 1 extraordinary response (a patient who shows no signs of disease up to 2 years later), results were underwhelming and 2 patients suffered acute kidney injury, resolved with discontinuation of treatment or prednisone administration.²¹ “It doesn’t seem that pembrolizumab will move forward in smoldering myeloma, either as monotherapy or in combination at the present time,” said Manasanch, who led the pembrolizumab study.

Search for New Directions

Table. Efficacy in Trials of Combination Therapy and Monotherapy for High Risk SMM^a

“We are still interested in the potential of immunotherapy for this condition, however, and we’re currently working on an early-stage trial of a neoantigen vaccine,” she said.²² “We are taking smoldering myeloma cells from individual patients, sequencing their DNA and RNA to predict neoantigens that will be expressed in tumor cells but not in the normal cells of the patient, and then vaccines are designed containing those neoantigens to teach the patient’s immune system to attack the abnormal plasma cells that express them. It’s entirely novel in smoldering myeloma, but it has been done in melanoma and colon cancer.”Researchers at Dana-Farber, meanwhile, have identified another potential target for SMM and MM treatments. The study team compared the expression of 4 inhibitors of DNA binding (ID) proteins in normal plasma cells and myeloma cells from 360 patients with MM and found that ID2 was significantly downregulated in the myeloma cells. They then overexpressed ID2 in myeloma cell lines and found that cell proliferation dropped markedly. The mechanism of ID2 downregulation, they discovered, was bone marrow stromal cells.²³ The accumulating body of evidence clearly shows that there is a treatment benefit for highrisk SMM (Table^{5,7-10,13-15,17,18}). As researchers continue to test existing therapies and look for new drug targets, they are also continuing to do basic research designed to better predict which patients with SMM will progress quickly to MM, which will progress slowly, and which will never progress. A handful of papers presented at ASH addressed the topic, as did a paper published last year that showed 2 distinct progression patterns via retrospective analysis of 11 patients with SMM who went on to develop MM.

In some cases, patients moved from SMM to MM without the appearance of any new and genetically distinct myeloma cells, and they tended to experience these “static” progressions very quickly. In other cases, SMM only progressed to MM after patients generated new types of myeloma cells that were genetically different than anything that led to the SMM diagnosis. These “spontaneous” progressions tended to take considerably longer.²⁴

“We can’t predict right now which patients will experience static progression and which will experience spontaneous progression, but we are analyzing more samples to develop and validate prediction tools,” said co-author Nikhil Munshi, MD, director of basic and correlative science at Dana-Farber’s Jerome Lipper Multiple Myeloma Center. “If we can do that, we can explore different treatment options for both groups—perhaps with standard myeloma treatments for static progression and something designed to prevent mutation in patients who will experience spontaneous progression…. Differentiating different types of disease and customizing treatment hasn’t happened in myeloma yet, but it has worked well in other tumor types, and it may be the next step for us as we learn more about the disease.”

References

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