Patients are often diagnosed with myeloma precursor conditions, either monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM), before they are diagnosed with active myeloma. Sometimes these precursor conditions go undetected for years, as patients usually have no symptoms, and they are detected only through routine bloodwork or other tests. Patients with MGUS or SMM have varying risk of progressing to active myeloma; on average, the risk is 1% per year for MGUS patients and 10% per year for SMM patients.
However, some patients progress more rapidly from SMM to active myeloma. It is still unclear if a patient’s risk of rapid progression can be predicted by clinical or genomic markers, and if progression might be delayed by treatment. Recent clinical trials for patients diagnosed with SMM have shown promise in decreasing the rate of progression of high-risk patients from SMM to active myeloma, but many questions remain. As many SMM patients have no symptoms, it may not make sense to treat them with toxic therapies which may cause uncomfortable side effects and may cause patients to become refractory earlier to standard of care MM drugs, resulting in poorer outcomes. In fact, there is preliminary data to suggest that low risk patients may not derive the same benefits from treatment that many high risk patients do, but more work needs to be done to confirm these findings.
To help answer some of these questions, the inaugural meeting on Advances in Myeloma Precursor Conditions in the 21st Century, a joint effort by the MMRF and the Dana-Farber Cancer Institute (DFCI), was held virtually on August 20th 2020. This meeting was co-chaired by Drs. Irene Ghobrial of DFCI, Marivi Mateos of the University of Salamanca, Spain, Nikhil Munshi of DFCI, and Daniel Auclair of MMRF, and attracted a distinguished international myeloma faculty. The meeting was attended by 425 participants, including researchers, pharma partners, and patients.
The meeting was kicked off by co-chairs Ghobrial and Mateos, who laid out the purpose of the meeting as discussing two important questions:
- Are there clinical/genomic markers to predict which patients will progress from SMM to active myeloma, and how quickly that progression will happen?
- What if any course of treatment should SMM patients receive to potentially delay progression and improve overall survival?
The day started with an overview from Dr Rafael Fonseca of Mayo Clinic in Scottsdale, AZ on the history of research and clinical practice for myeloma precursor conditions. Dr. Jesus San Miguel of University of Navarra, Spain then gave an overview of clinical and other prognostic markers for progression.
The current predictors for risk of progression from SMM to active MM, often referred to as the Mayo 2018 guidelines or the 20-2-20 rule, include the following factors:
- bone marrow plasma cell burden of 20% or greater
- M spike level of 2 g/dL or greater
- Free light chain (kappa/lambda) ratio of 20 or greater
Using these factors, patients are categorized using the following risk stratification:
- Patients with none of these risk factors are characterized as low risk;
- those with 1 risk factor are characterized as intermediate risk;
- those with 2 or more risk factors are characterized as high risk.
Dr. San Miguel went on to describe an International Myeloma Working Group (IMWG) study of 2000 patients initiated to help develop a risk score to predict 2 year progression with additional stratification of patients, using chromosomal abnormalities as determined by FISH (cytogenetic) testing. Abnormalities detected by FISH including translocations t(4;14) or t(14;16), gain (or amplification) of 1q, or deletion (loss) of 13q were each considered risk factors, along with the 20-2-20 criteria. In this study,
- Patients with 0 risk factors had an 8% risk of progression at 2 years (low risk)
- Patients with 1 risk factor had an 21% risk of progression at 2 years (low intermediate risk)
- Patients with 2 risk factors had an 37% risk of progression at 2 years (intermediate risk)
- Patients with 3 or more risk factors had an 59% risk of progression at 2 years (high risk)
Dr, San Miguel ended his presentation by summarizing the utility and availability of various prognostic markers, noting that more work needs to be done to reliably predict progression using these markers.
After another morning session of detailed reports on genomic markers of progression, the working lunch session focused on clinical trials in SMM, with speakers addressing completed trials, immunotherapy trials, and ongoing trials using 3 and 4 drug regimens.
The first speaker, Dr. Sagar Lonial of Emory University, gave an overview of completed trials and their results. SMM trials range from a preventative approach, with less intensive therapies, to the curative approach, with more intensive treatments. There are also intermediate trials which provide therapy similar to what a newly diagnosed MM patient might receive. There are pros and cons to each, and patients should make sure their care teams are aware of what their treatment goals are.
The first trial reviewed was the Spanish QuiRedex study from Dr. Mateos’ group, which was a landmark study first published in 2013, the first phase 3 trial done in a large group of high risk SMM patients. High risk was defined by bone marrow plasma cell burden of at least 10%, M spike of 2 g/dL or greater, and at least 95% abnormal plasma cells in the bone marrow plasma cell compartment. 119 patients received either Revlimid/dexamethasone for 24 months, or observation. Follow-up of these two groups of patients after 10.8 years showed that progression to active myeloma took an average of 9 years for patients receiving treatment compared to 2 years for patients receiving no treatment. Importantly, once patients in either group progressed to active myeloma, there was no difference in their overall survival, indicating that early treatment during SMM did not induce resistance to standard of care MM therapies.
The second trial reviewed was the ECOG E3A06 phase 3 trial, where 180 patients received either Revlimid as a single agent or observation for 24 months. Follow-up of these 2 groups of patients 3 years after the completion of the study revealed that 91% of the treated patients had not progressed to MM compared to 66% of the untreated patients. When these 180 patients were classified according to risk using the Mayo 2018 criteria, only the high risk patients had benefitted from early intervention, and no benefit was seen for intermediate or low risk SMM patients. In conclusion, based on the data from these 2 studies, Dr. Lonial recommended that only SMM patients that meet the 20-2-20 criteria for high risk be treated, with either Revlimid alone or Revlimid in combination with dex, for no more than 2yrs.
The final trial discussed in this section was the phase 3 GEM-CESAR trial, a curative intent approach for high risk SMM patients. Patients received Kyprolis/Revlimid/dex induction therapy, followed by transplant, followed by Kyprolis/ Revlimid/dex consolidation therapy, followed by Revlimid maintenance therapy, over the course of 2 years, at which point all therapy was discontinued. Similar to the ECOG study, 92% of the treated patients had not progressed to MM 3 years after the completion of the study.
Dr. Lonial concluded his talk with several points:
- The new 20-2-20 definition should be used to assess risk in SMM patients
- High risk SMM patients should receive intervention; if a clinical trial is not an option, providers should consider treating them with Revlimid or Revlimid/dex
- The questions of whether to use the preventative approach or the curative approach is not yet answered, but it is clearly time for the field to move toward early intervention for some SMM patients
The session’s second speaker, Dr. Elizabet Manasanch of MD Anderson, discussed immune therapy trials in SMM, focusing on single-agent trials of the monoclonal antibodies Darzalex, Sarclisa (both anti CD-38 antibodies), Empliciti (anti-CS-1 antibody), and Keytruda (anti PD-L antibody)
- The Darzalex monotherapy CENTAURUS trial had 41 patients per arm, with intermediate or high risk SMM. Patients received either long (20 8-week cycles) high intensity therapy, medium (20 8-week cycles) lower intensity therapy, or short (one 8-week cycle) therapy. Both the long and medium duration regimens showed a 55% overall response rate, while the short therapy duration arm demonstrated a 38% response rate. The percentage of patients surviving without biochemical progression at 24 months after the end of therapy was 78% for high intensity, 70% for medium intensity, and 27% for the low intensity arm.
- In a Sarclisa monotherapy trial, 24 patients received either Sarclisa weekly for 1 month, Sarclisa every 2 weeks for 5 months, or Sarclisa monthly for 2 yrs. The overall response rate was 50% at 6 months after end of therapy, similar to what was seen with Revlimid monotherapy and Dara monotherapy.Only 2 of 24 patients had progressed to MM at 2 yrs post treatment, which translates to a 92% PFS.
- An Emplicit monotherapy trial in 31 high risk SMM patients demonstrated a 10% overall response rate; 69% of patients had not progressed at 2 years post therapy.
- Empliciti in combination with Revlimid and dex in 50 high risk SMM patients demonstrated that 95% of patients had not progressed at 3 years post therapy, and overall response rate of 84%, which is higher than that seen with Revlimid/dex, indicating that there may be some synergy in this combination.
- A Keytruda monotherapy trial in 13 patients showed an 8% overall response rate, however one of the patients went into a CR (complete response), which has lasted 2 years so far, after only 3 infusions of Keytruda. The researchers also noted extensive T cell activation, which will be investigated in future studies.
In conclusion Dr. Manasanch noted that monoclonal antibodies are an excellent choice for SMM patients on clinical trials and are well tolerated. Darzalex and Sarclisa are effective as monotherapy, and are an excellent choice for combination therapy. She encouraged the audience to treat SMM patients only within the structure of clinical trials so that necessary data can be gathered for FDA approval.
The next speaker was Dr. Shaji Kumar of Mayo Clinic Rochester who discussed ongoing curative trials in SMM.
- The DETER-SMM phase 3 trial enrolled 288 patients who received Darzalex/Revlimid/dex (active MM type therapy) or Revlimid/dex (low intensity therapy) for 1 year, after which dex was discontinued and other therapy continued for another year; if patients progress, they go off therapy, but if they respond, therapy is continued for the full 2 years.
- GEM-CESAR (discussed above)
- The ASCENT trial for high risk SMM regimen includes Kyprolis/Revlimid/Darzalex/dex for 4 cycles of induction, 4 cycles of consolidation, 4 cycles of intensification (total 1 year of therapy), and then Kyprolis/Revlimid/Darzalex maintenance for an additional 1 year, with a follow-up of observation only for 5 years.
Dr. Kumar concluded his talk with a decision tree for treatment of high risk SMM vs. standard risk SMM vs. MM-like SMM:
- First confirm SMM diagnosis, including high resolution imaging required to detect bone lesions and extramedullary (outside the bone) disease
- If patient has multiple high risk features, treat as MM
- If patient has high risk SMM, go to a clinical trial or very close observation
- If patient has standard risk SMM, follow up every 3 months and go to a clinical trial if disease evolves to high risk
The final speaker of the session was Dr. Omar Nadeem of the Dana-Farber Cancer Institute, who discussed 3 and 4 drug regimens in SMM. He noted several current unknowns:
- does adding a 3rd or 4th drug in SMM help as much as it does in newly diagnosed MM?
- some high risk SMM patients are essentially MM patients, so will deeper response lead to better outcomes?
- high intensity therapy upfront can be shorter but is it still effective?
- what is the best intervention? There are many choices.
Dr. Nadeem went into detail on 2 trials that are ongoing at DFCI. The first is a phase 2 trial of Ninlaro/Revlimid/dex in high risk SMM. In this trial, 61 patients received the triplet regimen for 9 months, then had stem cell collection, then Ninlaro/Revlimid maintenance for a total of 2 years of therapy on this trial. They saw
- an overall response rate of 94%, with 69% patients achieving MRD negativity (9 of 13 patients in a CR were tested)
- No progression of any patients at 15 months
The second trial is a phase 2 trial of Empliciti/Revlimid/dex in 50 high risk SMM patients. It includes 8 months of induction with Empliciti/Revlimid/dex or Empliciti/dex, then 16 months of maintenance with Empliciti/Revlimid with a total of 2 years of therapy. So far they have seen an 84% overall response rate, and at 3 years follow-up, 95% of patients have not progressed.
Dr. Nadeem concluded by noting that:
- The ideal SMM intervention is evolving, and more data is needed
- The phase 2, 3 drug regimens are encouraging so far, but phase 3 trials are needed
- Immunotherapeutic approaches also warrant study
The day ended with a spirited panel discussion of data presented and next steps, and a look forward to the second annual Precursors meeting to be convened in 2021.
