New diagnostic criteria and modern imaging techniques, a wealth of new therapeutics, and an update on current thinking as to when to treat patients with smoldering myeloma were highlighted during the National Comprehensive Cancer Network (NCCN) 2020 Virtual Congress: Hematologic Malignancies™.
Diagnostic Criteria and Imaging in Myeloma
Jens Hillengass, MD, Chief of Myeloma, Roswell Park Comprehensive Cancer Center, Buffalo, New York, explained that better understanding of multiple myeloma has led to advances in diagnostic and staging criteria as well as in imaging modalities for multiple myeloma.1
Jens Hillengass, MD
Some patients are diagnosed with monoclonal gammopathy of unknown significance (MGUS) or smoldering myeloma, and both conditions can progress to multiple myeloma. It is important to find markers of early myeloma that would benefit from treatment before patients progress to end-organ damage. Patients with MGUS have a low risk of progression to multiple myeloma, whereas the risk of progression is higher in smoldering myeloma—but not all cases of smoldering myeloma will progress.
“One of the major intentions of the new NCCN Guidelines is to identify high-risk patients with smoldering myeloma who would benefit from earlier treatment,” Dr. Hillengass told the audience. Another reason to treat early, “but not too early,” he added, is that multiple myeloma becomes more genetically heterogeneous as it evolves, and it is better to treat early before that evolution occurs.
“The concept of evolving smoldering myeloma is not easy to put in a guideline. We know that stable markers over time indicate lower risk, and markers that change over time indicate higher risk,” he explained.
Imaging Techniques in Myeloma
Dr. Hillengass emphasized the importance of imaging in multiple myeloma. He distinguished between bone imaging (showing what takes place as a result of the disease) and bone marrow imaging (showing what is going on where active disease is occurring).
“Bone imaging is important for diagnosis. It can localize pain and prevent fractures, but it is not that easy to assess response with bone imaging. Bone marrow imaging, on the other hand, can be used for diagnosis, localization of pain, prevention of complications, and response assessment,” he said.
According to Dr. Hillengass, CT scans should replace conventional x-rays. “X-rays can be negative, whereas CT is positive,” he noted. “Nowadays, we use whole-body low-dose CT to spare patients from radiation. We do this with usual scanners and no contrast agent.”
MRI shows different filtration patterns, and it is also helpful for differentiating between osteoporosis and multiple myeloma as well as between benign vs malignant fractures. PET/CT can be used to monitor treatment response. “Studies have shown focal lesions that persist in patients with a complete response are a prognostic factor,” Dr. Hillengass explained.
Minimal residual disease (MRD) negativity and PET negativity signal a good prognosis compared with positivity of either one of these markers, Dr. Hillengass noted. MRD negativity improves prognosis in all risk categories. “With better prognostic markers, risk stratification becomes more important,” he added.
Currently, patients are categorized by the International Staging System based on the number of risk factors as stage I, II, or III; patients with stage I disease have the best prognosis, those with stage II disease have an intermediate prognosis, and patients with stage III disease have a poor prognosis. “Some high-risk cytogenetics can be overcome by bortezomib-containing regimens, and fluorescence in situ hybridization cytogenetics can guide treatment,” explained Dr. Hillengass. “In real life, this has led to risk-adapted treatment. Risk-adapted treatment can improve survival.”
Bonanza of Treatments for Myeloma
Although there are many new drugs to treat multiple myeloma, and therapeutic advances have led to prolonged survival, “myeloma remains a chronic disease,” stated Shaji K. Kumar, MD, of the Mayo Clinic, Rochester, Montana. “Treatment of myeloma requires a long-term strategy. The key is to deliver the best ‘package’ of treatment at a given stage. Optimal combinations and sequencing are critical. A risk-stratified approach should be used.”2
Shaji K. Kumar, MD
Dr. Kumar continued: “The intent of initial therapy for multiple myeloma is to attain as deep a remission as possible. Unfortunately, most patients relapse. Now, we have newer therapies that change the way we treat.”
Therapies for Newly Diagnosed Multiple Myeloma
Despite efforts to build on bortezomib/lenalidomide/dexamethasone (VRd), this triplet remains standard therapy for newly diagnosed patients. Attempts to improve on this regimen include replacing bortezomib with carfilzomib or ixazomib, which were not a significant improvement over VRd, noted Dr. Kumar.
A regimen of daratumumab/lenalidomide/dexamethasone improved outcomes in newly diagnosed, transplant-ineligible patients vs lenalidomide/dexamethasone alone in the MAIA trial.3 This strategy replaced the proteasome inhibitor (bortezomib) with a monoclonal antibody directed to CD38 (daratumumab). Results showed significantly better objective response rates, complete response rates, and MRD negativity response, with improved progression-free survival for the daratumumab-containing regimen (not yet reached vs 32 months for lenalidomide/dexamethasone).
Studies such as CASSIOPEIA4 and GRIFFIN5 evaluated adding a fourth drug to standard VRd—daratumumab. “We don’t know from these studies if adding a fourth drug to standard VRd will improve survival,” Dr. Kumar said.
The MASTER trial evaluated daratumumab added to carfilzomib, lenalidomide, and dexamethasone using a response-adaptive therapeutic approach.6 Patients who achieved MRD negativity status on two consecutive measurements were discontinued from treatment. Nearly 90% achieved a stringent complete response, and almost 60% were MRD-negative. “This quadruplet approach needs to be replicated in a phase III trial,” noted Dr. Kumar.
Another quadruplet approach adds the oral proteasome inhibitor ixazomid to lenalidomide/dexamethasone/daratumumab in newly diagnosed myeloma as induction therapy given for 12 cycles.7 The overall response rate was more than 90%, he said.
Yet another quadruplet regimen is being tested in the ALCYONE trial: daratumumab added to VMP (bortezomib, melphalan, prednisone) vs VMP alone. With this approach, a significant improvement was observed in objective response rate and duration of response.8
“For older patients, lenalidomide/dexamethasone is still a good combination for those who cannot tolerate quadruplet therapy. We adapt the dose in older patients,” he said.
Dr. Kumar presented the following algorithm for newly diagnosed multiple myeloma:
- For transplant-eligible patients, standard-risk patients should receive four cycles of VRd followed by autologous stem cell transplant (ASCT; preferred) or VRd for four cycles and lenalidomide maintenance or delayed ASCT. For high-risk transplant-eligible patients, the regimen is four cycles of daratumumab/VRd followed by ASCT (consider tandem ASCT) and bortezomib/lenalidomide maintenance until disease progression.
- For newly diagnosed transplant-ineligible standard-risk patients, the regimen is VRd for 12 months followed by lenalidomide maintenance or VRd for 12 months followed by daratumumab/lenalidomide maintenance. For newly diagnosed transplant-ineligible high-risk patients, the regimen is VRd followed by bortezomib/lenalidomide maintenance until disease progression.
Relapsed or Refractory Multiple Myeloma
“There have been significant changes over the past 1 to 2 years in relapsed multiple myeloma,” Dr. Kumar stated.
Several phase III trials of bortezomib-based combinations have shown improvements in progression-free and overall survival. Trials of lenalidomide-based combinations have demonstrated a benefit in progression-free survival, and some demonstrated an overall survival benefit. The majority of patients on these regimens have disease that is refractory to one of these two drugs, leading to attempts to overcome resistance.
Dr. Kumar was most enthusiastic about two newer drugs: selinexor and belantamab mafodotin-blmf.
Selinexor/dexamethasone showed promise in the STORM trial (improved response and progression-free survival, with overall survival of 8.6 months in patients with relapsed or refractory disease treated with three different classes of drugs).9 The BOSTON trial demonstrated an improved response rate, depth of response, and progression-free survival.10 Selinexor is now approved for the treatment of relapsed multiple myeloma.
“Clearly, we have a new drug for this population—selinexor. Keep in mind that it is emetogenic, and you need prophylaxis for nausea. It is used once weekly,” Dr. Kumar said.
“Another exciting drug targeting the B-cell maturation antigen, expressed exclusively in myeloma, has been recently approved for multiple myeloma—belantamab mafodotin,” he continued.
The DREAMM2 trial investigated single-agent belantamab mafodotin in relapsed multiple myeloma.11 Arm B of the DREAMM-6 trial looked at belantamab mafodotin/bortezomib/dexamethasone in pretreated patients; the investigators reported an overall response rate of 78% with this triplet, compared with between 50% and 63% with bortezomib plus dexamethasone alone.12
“Ongoing trials are looking at which combinations are better with belantamab mafodotin in relapsed patients. A host of therapies are on the horizon, including immunotherapies, chimeric antigen receptor T-cell therapy, and bispecific T-cell engager therapies. Stay tuned for progress reports,” Dr. Kumar added.
Smoldering Myeloma: To Treat or Not to Treat
Natalie S. Callander, MD, of the University of Wisconsin Carbone Center, Madison, discussed the threshold for initiating treatment of smoldering myeloma.13 “Until 2003, there was controversy about whether smoldering myeloma was a true entity. We still have ongoing debate about whether to treat, when to treat, and how to treat,” she told the audience.
“The definitions vary in different countries, and the epidemiology is uncertain, because in the United States, there is no diagnostic code for this entity,” Dr. Callander stated. The number of patients with smoldering myeloma is based on patients in the database with a code for multiple myeloma who have not been treated for the past 6 months. Based on that, about 10% to 15% of patients with the code for myeloma have it, and they tend to be women, older, and more often Black than comparable patients with active myeloma.”
“Advanced imaging will upstage 15% to 25% of patients previously classified as smoldering myeloma.”— Natalie S. Callander, MD
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Dr. Callander continued: “If you are going to classify a patient as having smoldering myeloma, you need to show that a patient does not have multiple myeloma by some sort of advanced imaging, including PET, whole-body MRI, low-dose whole-body CT, and FDG-PET. Advanced imaging will upstage 15% to 25% of patients previously classified as smoldering myeloma.”
Dr. Callander shared her recommendations for treatment of patients with smoldering myeloma. “The high-risk group should be treated, and a clinical trial is preferred. They have a 20% to 40% risk of disease progression over the next 2 years.” Patients with low-risk smoldering myeloma should be followed by observation, with repeat imaging every 1 to 2 years.
New Model for Risk Stratification in Smoldering Myeloma
More recently, the 20/2/20 model is being used to stratify patients with smoldering myeloma for risk of disease progression. This model is based on the presence of bone marrow plasma cells more than 20%, M protein spike higher than 2 g/dL, and free light chain ratio of more than 20 of the involved light chain.14
“This is a simpler model than some of the previous risk stratification algorithms, and easy to use in clinical practice to stratify patients with smoldering myeloma for disease progression,” Dr. Callander said. “It has been validated in a larger study and likely will be used for clinical trials.” (For a comparison of the 20/2/20 and SLiM CRAB criteria, see the sidebar below.)
Clinical Trials Updates in Smoldering Myeloma
The randomized QuiRedex study showed that lenalidomide improved progression-free and overall survival in patients with high-risk smoldering myeloma, but this approach has not been widely adopted, and there were several criticisms of the study.15 The study was conducted in Spain, where a different definition of smoldering myeloma is used, and no patients underwent advanced imaging. Further, the value of dexamethasone was not clear.
Risk Stratification in Smoldering Myeloma: SLiM CRAB vs 20/2/20
SLiM CRAB
- High M protein level
- Presence of bone marrow plasma cells > 60%
- Free light chain ratio > 100
20/2/20 Model14
- Presence of bone marrow plasma cells > 20%
- Serum M protein level > 2 g/dL
- Free light chain ratio > 20
More recently, the E3A06 study found that the use of lenalidomide for 2 years vs observation slowed disease progression in high-risk smoldering myeloma by 66%.16 All patients had advanced imaging. Quality of life was similar in the two arms, and there was no increase in secondary malignancies. The intervention seemed to have no effect on low-risk patients with smoldering myeloma, however. “Results were quite striking, but there was some toxicity,” commented Dr. Callander.
The phase II GEM-CESAR trial evaluated carfilzomib plus lenalidomide and dexamethasone (KRd) for six cycles of induction chemotherapy, followed by ASCT, KRd as consolidation, and then lenalidomide/dexamethasone for 2 years.17 One-third of patients met the SLiM CRAB criteria for smoldering myeloma (see sidebar). At 28 months, overall survival was 98%, and progression-free survival was 93%.
The ASCENT trial is planning to study KRd plus daratumumab for four cycles followed by transplant or four more cycles of KRd plus daratumumab; then all patients with receive consolidation with four more cycles of the same chemotherapy followed by KR/daratumumab for 1 more year (ClinicalTrials.gov identifier NCT03289299). Thus far, 50 patients are enrolled. MRD and best response will be evaluated at each phase.
“There are lots of previous trials in the smoldering myeloma space, and many have been negative,” Dr. Callander said. “Newer trials will likely help us refine who benefits the most from early intervention. At ECOG, we are focusing on that high-risk population.”
The phase III EA173 trial, for which Dr. Callander is principal investigator, will enroll patients with high-risk smoldering myeloma and compare daratumumab/lenalidomide/dexamethasone vs lenalidomide/dexamethasone (NCT03937635). Patients will be imaged with MRI and PET to exclude active myeloma. Patients with an abnormal but not myeloma-defining PET will have that study repeated after 12 and 24 months; MRD status will be evaluated for those patients achieving a a very good partial response or better status. The study will include patients’ and physicians’ ratings of side effects as well as quality-of-life measures. Entry criteria will incorporate the 20/2/20 model. Thus far, 54 patients of a planned 288 have accrued.
DISCLOSURE: Dr. Hillengass has received honoraria from Adaptive Biotech, Bristol Myers Squibb, Curio Science, GlaxoSmithKline, Janssen, Oncopeptides, ONCOtracker, Rapid Payer Response, Research to Practice, and Xian Janssen. Dr. Kumar has received grant/research support from AbbVie, Amgen, Bristol Myers Squibb, CARsgen Therapeutics, Celgene, Janssen, Kite Pharma, MedImmune, Merck, Novartis, Roche, sanofi-aventis, Takeda, and TeneBio; has served as a consultant or advisor to AbbVie, Amgen, Celgene, Cellectar Biosciences, GeneCentrix, Genentech, Janssen, MedImmune, Oncopeptides, and sanofi-aventis; and has received honoraria from BeiGene. Dr. Callander reported no conflicts of interest.
REFERENCES
1. Hillengass J: Evolving concepts in the diagnosis and staging of multiple myeloma. NCCN 2020 Virtual Congress: Hematologic Malignancies. Presented October 10, 2020.
2. Kumar SK: Bonanza of new treatment regimens for multiple myeloma: What is right for my patient? NCCN 2020 Virtual Congress: Hematologic Malignancies. Presented October 10, 2020.
3. Facon T, Kumar S, Plesner T, et al: Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med 380:2104-2115, 2019.
4. Moreau P, Attal M, Hulin C, et al: Bortezomib, thalidomide, and dexamethasone with and without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): A randomised, open-label, phase 3 study. Lancet 394:29-38. 2019.
5. Voorhees PM, Kaufman JL, Laubach J, et al: Daratumumab, lenalidomide, bortezomib, dexamethasone for transplant-eligible newly diagnosed multiple myeloma: The GRIFFIN trial. Blood 136:936-945, 2020.
6. Costa L, Chhabra S, Godby K, et al: Daratumumab, carfilzomib, lenalidomide, dexamethasone (Dara-KRd) induction, autologous transplantation and post-transplant response-adapted, measurable minimal residual disease–based Dara-KRd consolidation in patients with newly diagnosed multiple myeloma. 2019 ASH Annual Meeting & Exposition. Abstract 653. Presented December 7, 2019.
7. Kapoor P, Gertz MA, Laplant B, et al: Phase 2 trial of daratumumab, ixazomib, lenalidomide, and modified dose dexamethasone in patients with newly diagnosed multiple myeloma. 2019 ASH Annual Meeting & Exposition. Abstract 864. Presented December 9, 2019.
8. Mateos MV, Cavo M, Blade J, et al: Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): A randomised, open-label, phase 3 trial. Lancet 395:132-141, 2020.
9. Chari A, Vogl DT, Gavratopoulou M, et al: Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med 381:727-738, 2019.
10. Dimopoulos MA, Delimpasi S, Simonova M, et al: Weekly selinexor, bortezomib, and dexamethasone versus twice weekly bortezomib and dexamethasone in patients with multiple myeloma after one to three prior therapies: Initial results of the phase III BOSTON study. ASCO20 Virtual Scientific Program. Abstract 8501.
11. Lonial S, Lee HC, Badros A, et al: Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): A two-arm, randomised, open-label, phase 2 study. Lancet Oncol 21:207-221, 2020.
12. Nooka AK, Stockerl-Goldstein K, Quach H, et al: DREAMM-6: Safety and tolerability of belantamab mafodotin in combination with bortezomib/dexamethasone in relapsed/refractory multiple myeloma. ASCO20 Virtual Scientific Program. Abstract 8502.
13. Callander NS: Smoldering multiple myeloma: What is the threshold to start treatment? NCCN 2020 Virtual Congress: Hematologic Malignancies. Presented October 10, 2020.
14. Lakshman A, Rajkumar SV, Buadi FK, et al: Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J 8:59, 2018.
15. Mateos MV, Hernández MT, Giraldo P, et al: Lenalidomide plus dexamethasone versus observation in patients with high-risk multiple myeloma (QuiRedex): Long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol 17:1127-1136, 2016.
16. Lonial S, Jacobus SJ, Weiss M, et al: EA306: Randomized phase III trial of lenalidomide versus observation alone in patients with symptomatic high-risk smoldering multiple myeloma. 2019 ASCO Annual Meeting. Abstract 8001. Presented June 2, 2019.
17. Mateos MV, Martinez-López J, Rodriguez-Otero P, et al: Curative strategy (GEM-CESAR) for high-risk smoldering myeloma: Carfilzomib, lenalidomide, and dexamethasone (KRd) as induction followed by HDT-ASCT, consolidation with KRd and maintenance with Rd. EHA Congress 2019. Abstract S871. Presented June 15, 2019.
