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How to achieve the best results in patients with high-risk MM

Nov 9, 2020

This month, the Multiple Myeloma Hub has been exploring the theme of high-risk multiple myeloma (MM). Treatment of patients with high-risk MM is the focus of this final article, in particular, what agents to use to achieve measurable residual disease (MRD) negativity. In a talk at the 25th European Hematology Association (EHA) Virtual Congress 2020, Jesús San Miguel spoke about how he treats patients with high-risk MM.1

The main goal of treatment should be to eradicate MRD cells, as discussed in the previous editorial theme article on the Multiple Myeloma Hub, which can be found here. These cells are very aggressive and act as a reservoir for clonal evolution and disease relapse. To achieve this, it is necessary to be able to measure MRD effectively, including both extramedullary sites and bone marrow, and have effective therapies. A combination of different treatments with various modes of action may be the most successful method.

Identification and analysis of patients with high-risk MM

As the MRD positive cells act as a reservoir for disease relapse, Jesús San Miguel and colleagues investigated the transcriptome of cells from 40 patients with MM at diagnosis and following treatment with bortezomib, lenalidomide, and dexamethasone (VRD). Using flow cytometry and massive parallel single-cell RNA sequencing, they found 672 genes significantly deregulated. Surprisingly, it was found that when patients with standard-risk disease were compared, they had a 9-fold greater number of deregulated genes than patients with high-risk disease.

Jesús San Miguel postulated that the cells from the patients with high-risk disease were already more likely to be resistant to treatment, and therefore, did not experience the same selection pressure when treated with VRD. In the standard-risk patients, the cells that altered their transcription profile underwent clonal selection and presented a greater number of deregulated genes in the analysis. 

How to improve outcomes for high-risk MM patients

Jesús San Miguel gave these general recommendations:

  • Aim for sufficient dose density rather than intensity when treating this group
  • How to sequence therapies and whether multiple short treatments with different agents may be the best method warrants further consideration
  • Early rescue intervention may be needed in patients with a suboptimal response or early biochemical progression

Next, we will consider group-by-group, how best to manage patients with high-risk MM.

Transplant-eligible patients

Role of induction therapy

To improve patient outcomes, every stage of the treatment process must be optimized, starting with induction therapy. Originally, the two main options were VRD or bortezomib, thalidomide and dexamethasone (VTD). However, with the advent of monoclonal antibodies (mAbs), it is now necessary to investigate whether a quadruplet treatment strategy is beneficial for patients.

The CASSIOPEIA trial (NCT02541383) investigated daratumumab (dara) + VTD against VTD alone. The results from this trial:

  • Dara + VTD treatment arm, 64% MRD negative
  • VTD arm, 44% MRD negative

Despite this positive result, patients with high-risk disease showed a reduced improvement with treatment than the standard risk patients. It is interesting to note that dara-VTD in high-risk patients achieve a similar progression-free survival (PFS) at 18 months to standard-risk patients treated with VTD only, although the outcome is still inferior to standard-risk patients in the dara arm (HR 0.67 vs 0.41).

Philippe Moreau discussed this subject further when speaking to the Multiple Myeloma Hub during the 46th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT).  He talked about whether dara + VTD might not be the best quadruplet induction treatment for newly diagnosed patients with high-risk MM, and this video can be seen below.

Is dara + VTd the best induction treatment for high-risk patients with newly diagnosed MM?

The GRIFFIN study (NCT02874742) investigated dara + VRD in patients with newly diagnosed MM and again found that the addition of the mAb improved MRD negativity rates compared with VRD alone (51% vs 20.4%) and stringent complete response (42.4% vs 32.0%). However, patients with high-risk cytogenetics (odds ratio 0.52 [0.09−2.90]) or International Staging System stage III (odds ratio 0.64 [0.14−2.94]) disease did not experience such favorable results with respect to stringent complete response rates.

Other quadruplets with different combinations involving elotuzumab, isatuximab, or carfilzomib are being investigated at the frontline setting in this patient population. Find a summary of the latest data in this previous review published on the Multiple Myeloma Hub.

Role of transplant

Following induction, patients may be offered a hematopoietic stem cell transplant. The relative benefits and drawbacks of single autologous transplants compared with tandem auto-transplants for patients with high-risk disease has been covered previously by the Multiple Myeloma Hub and can be found here.

The role of allogeneic transplant at relapse remains controversial with some studies showing a benefit when used in patients with specific cytogenetic abnormalities, as shown in Table 1. In patients with del(13q), a non-deleterious mutation, allogeneic transplant significantly increases PFS (p = 0.005). However, for patients with t(4;14), there was no difference between autologous-allogeneic transplant compared with tandem autologous. For del(17p) there was a significant improvement in PFS and OS when using auto-allo transplant (p = 0.0002 and 0.011, respectively).

Table 1. Survival outcomes and cytogenetic risk for auto vs allo transplant in a German multicenter study2

Allo, allogeneic; auto, autologous; CA, cytogenetic abnormalities; OS, overall survival; PFS, progression-free survival.

Survival factor months [CA]



p value

Median PFS [del(13q)]




Median PFS [del(13q) & t(4;14)]




Median PFS [del(13q) & del(17p)]




Median OS [del(13q) & del(17p)]




What is the role of consolidation in high-risk patients?

This factor has been investigated in the EMN02/HO95 trial (NCT01208766), which compared patients treated with VRD consolidation against the outcome of the untreated patients. In this study, consolidation was shown to increase PFS in standard-risk patients, but there was no clear benefit in high-risk patients.

These results indicate that it may be necessary to rethink the consolidation strategy: in patients that during VRD induction start to show a plateauing of response, it does not make sense to treat again with VRD at consolidation. Agents with different modes of action may be more effective in this situation.

Is maintenance therapy valuable for high-risk patients?

In the Myeloma XI study (NCT01554852), lenalidomide (lena) maintenance therapy was compared with observation alone. A clear benefit was seen in the patients treated with maintenance therapy; an increase of PFS by 18 additional months compared with the observational group in the whole study population (p < 0.0001). A benefit in PFS was also seen in the high-risk and ultra-high-risk patients (HR of 0.45 and 0.42, respectively).3

Bortezomib as a maintenance agent has been studied in different trials, including the HOVON-65/GMMG-HD4 trial, in which patients received either:

  • vincristine, doxorubicin, dexamethasone (VAD) induction followed by high dose melphalan and thalidomide maintenance or,
  • bortezomib, doxorubicin, dexamethasone (PAD) followed by high dose melphalan and bortezomib maintenance

Looking at specific cytogenetic anomalies within the high-risk population, patients with del(17p) receiving bortezomib induction and maintenance showed a significantly increased PFS (p = 0.024) and overall survival (p = 0.028). As previously reported, the outcome for the standard-risk patients on the two different treatment arms was significantly improved compared with the high-risk patients.

Summary – for transplant eligible candidates the recommendations are:

- Quadruplet induction therapy

- Tandem autologous stem cell transplantation (ASCT)

- Consolidation therapy that considers the kinetics of the induction therapy and switches agent if the disease stabilizes during treatment

- Maintenance therapy with lena and a proteasome inhibitor

Transplant ineligible patients

The phase III ALCYONE trial (NCT02195479) investigated the current standard of care, bortezomib, melphalan and prednisone (VMP) against VMP + dara in elderly patients. As in the transplant eligible patients, the addition of the mAb significantly improved the rate of MRD negativity in the dara arm (27% compared with 7%; p < 0.0001); however, this improvement was less evident in patients with high-risk disease compared with standard in terms of PFS (HR 0.78 vs 0.39). These results were echoed by the MAIA trial (NCT02252172), evaluating dara + lenalidomide and dexamethasone (Rd) (PFS in high-risk, HR 0.85 vs 0.49 in standard-risk MM).

Relapsed patients

This group of patients can be divided into patients who relapse under treatment with lena (refractoriness) and those who relapse when not currently on lena. In this latter cohort, the standard of care was to treat with Rd; however, recent evidence has shown that triplet therapy is superior to the Rd doublet, as shown in Table 2. In the POLLUX trial, the addition of a mAb resulted in a marked increase in PFS, from 17.5 months to 44.5 months (Rd vs dara-Rd, respectively).

Table 2. PFS in clinical trials examining triplet therapy compared with doublet in the relapsed setting

d, dexamethasone; Dara, daratumumab; E, elotuzumab; I, ixazomib; K, carfilzomib; PFS, progression-free survival; R, lenalidomide.


POLLUX (N = 569)

ASPIRE (N = 792)

ELOQUENT-2 (N = 646)


Treatment regimen

DaraRd vs Rd

KRd vs Rd

ERd vs Rd

IRd vs Rd

PFS HR (months)

0.44 (44.5 vs 17.5)

0.67 (26.3 vs 17.6)

0.71 (19.4 vs 14.9)

0.74 (20.6 vs 14.7)

High-risk HR (months)

0.37 (26.8 vs 8.3)

0.70 (23.1 vs 13.9)

N/A (18.5 vs 14.8)

0.66 (17.5 vs 11.1)

For the lena-refractory group of patients, a modified approach is required. Kd has been shown to almost double PFS compared with Vd in the ENDEAVOR trial (NCT01568866; 18.7 months vs 9.4 months, respectively). Dara+Vd vs Vd was analyzed in the CASTOR trial (NCT02136134) and showed a favorable result with the addition of the mAb:

  • PFS 16.7 months vs 7.1 months in standard-risk patients
  • PFS 12.6 months vs 6.2 months in high-risk patients

The outcome of patients with high-risk disease can be improved with novel agents, however, to date, this has not been enough to overcome the adverse prognosis.

What is the future of high-risk MM treatment?

While progress has been made, many questions still need to be addressed. For example:

  • How best to manage patients who relapse early in treatment or are primary refractory without the presence of high-risk features
  • Are the novel agents effective against extramedullary sites of disease?  

There remains a need to develop new strategies and therapeutic agents to control MM in these patient groups. The two following topics may add to the arsenal of tools at the disposal of clinicians treating MM:

  • Early rescue intervention: treating biochemical relapse results in improved survival outcomes rather than waiting until a clinical relapse is seen.
  • Novel immunotherapies and cell-based therapies: a promising area that may play a key role in treating patients with high-risk MM in the future.


The new therapeutics that have been developed are changing the landscape for the treatment of patients with MM, especially those with standard-risk disease. Real improvements have been seen in this cohort. The benefit is not so marked for high-risk patients, and further investigation into their management is required. The ideal management strategy for these patients remains unclear, but the continued progress achieved by researchers and clinicians in the field is encouraging.

The importance of MRD as an endpoint has been highlighted in recent years and may indicate that the definition of a patient's risk needs to be updated. Patients who achieve MRD negativity despite the presence of high-risk cytogenetic features may overcome their poor prognosis. The converse is also true; patients who remain MRD positive following treatment should now be considered as high-risk.

Immunotherapy shows great promise for the treatment of high-risk patients, and early rescue intervention may help treat appropriately and, ultimately, improve these patients’ survival.

Jesús San Miguel summarized, for the Multiple Myeloma Hub, the take-home messages of his educational talk on high-risk MM management during the 25th EHA Annual Congress, and can be watched below.

How to decide between bispecific antibodies or CAR T-cell therapies

  1. San Miguel J. Management of high-risk multiple myeloma patients. EHA25 Annual Congress. Jun 12, 2020. Virtual.
  2. Knop S, Liebisch P, Hebart H, et al. Autologous followed by allogeneic versus tandem-autologous stem cell transplant in newly diagnosed FISH-del13q myeloma. Blood. 2014;124(21):43. DOI: org/10.1182/blood.V124.21.43.43
  3. Graham JH, Davies FE, Pawlyn C, et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol., 2019;20(1);57-73. DOI: S1470-2045(18)30687-9