Key concepts when talking about cure of multiple myeloma

The use of the term ‘cure’ in the field of multiple myeloma (MM) remains controversial. There has been great debate over whether a cure is possible and what it would look like if achievable. The Multiple Myeloma Hub has chosen the fascinating subject of ‘Should cure be the goal for multiple myeloma?’ to be the focus of its first Satellite Symposium, which will be held on May 7, 2021. During this symposium, four international experts will discuss different approaches for trying to achieve a cure in different disease settings.

As an introduction, this article will review material presented by Jean-Luc Harousseau at the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), in which he discusses the requirements for a functional cure in MM.¹

Defining ‘cure’

What would a cure look like in MM? In 2000, an article was published that was the first to use the term ‘operationally cured’. This term was used when a patient remained in complete remission (CR) for >10 years. However, since this was defined, it has been demonstrated that achieving CR is not sufficient.

Further investigation showed that patients who lost the CR status within the first 3 years had a poorer prognosis compared with patients in CR and patients who had only achieved a partial response.

Measurable residual disease

In recent years, measurable residual disease (MRD) has become a goal of treatment for several hematologic malignancies. In MM, MRD negativity was shown to be associated with longer progression-free survival (PFS) compared with MRD positivity at the level of 10⁻⁵ in the IFM 2009 trial (NCT01191060 and NCT03679351) (p < 0.001).

Another analysis performed by the Spanish PETHEMA group compared the strength of CR with MRD on prolonging the PFS. They found that patients in CR who were MRD negative demonstrated good outcomes, whilst those in CR but who were MRD positive did not fare better than those reaching only a partial response.

The impact of MRD negativity on PFS can be modified by several factors, including:

• MRD sensitivity level and duration
• type of treatment
• age of the patient
• cytogenetic abnormalities

Sensitivity level

A subanalysis of the IFM 2009 trial showed the value of achieving MRD at different sensitivity levels: patients reaching MRD at 10⁻⁶ demonstrated significantly increased PFS compared with patients that were MRD negative at 10⁻⁴ only (p < 0.001). These results were confirmed in the Spanish PETHEMA GEM2012 trial (NCT01916252), which reached an MRD negative sensitivity level up to 2×10⁻⁶ and showed a dramatically increased PFS vs persistent MRD (p < 0.001).

The duration of MRD negative status also affects long-term prognosis. Analysis from the POLLUX trial (NCT02076009) showed that patients who remained MRD negative for ≥12 months, even in the relapsed setting, had a better PFS than those who achieved MRD negativity then subsequently relapsed within ≤6 months.

Type of treatment

In the updated analysis of the IFM 2009 trial, it was found that even when patients achieved MRD at the level of 10⁻⁶, those who had received an autologous stem cell transplant exhibited a better PFS than those who were treated with VRd (bortezomib + lenalidomide + dexamethasone) only.

Following this analysis, the question now becomes how to increase the proportion of patients eligible for transplant who can achieve an operational cure. At the moment, >50% of patients who reach MRD negativity at 10⁻⁶ will not have progressed by 8 years after treatment with a triplet induction therapy, such as VRd (3–6 cycles), and transplant followed by lenalidomide maintenance.

The GRIFFIN trial (NCT02874742) investigated the addition of daratumumab (dara) to the induction regimen of VRd vs VRd alone. In this trial, dara-VRd increased the proportion of patients achieving MRD negativity at both 10⁻⁵ (62.5% dara-VRd vs 27.2% VRd alone) and 10⁻⁶ (26.9% dara-VRd vs 12.6% VRd alone).

Further investigation of how to increase the proportion of patients achieving an operational cure will be addressed in the IFM 2021 trial, which will compare two consolidation regimens (with or without transplant) and two maintenance therapies (lenalidomide alone or in combination).

Treatment at earlier stages

Treating patients with high-risk smoldering MM was shown to produce very positive outcomes with a 35-month PFS of 92% and a 35-month overall survival of 96% in the GEM-CESAR trial (NCT02415413), which used KRd (carfilzomib + lenalidomide + dexamethasone). However, some adverse events and fatalities were recorded. Therefore, the question remains whether it is best to treat asymptomatic patients. It will be key to identify high-risk patients with smoldering MM so that treatment can be given only to those with a significant risk of disease progression.

Prognostic factors, including cytogenetic risk

The presence of specific cytogenetic risk factors greatly impacts whether a patient is likely to achieve MRD negativity. Del(17p) confers a much lower probability of reaching MRD negative status than t(4;14). In an analysis of the IFM 2009 trial, patients with t(4;14) achieved an MRD negative rate (10⁻⁶) of 40%, similar to that of standard-risk patients. On the other hand, patients with del(17p) only demonstrated an MRD negativity rate of 11%.

An improved PFS was seen for both high-risk and low-risk patients achieving MRD negativity. Patients with low-risk disease who did not achieve MRD negative status had a poorer prognosis than those with high-risk disease and who were MRD negative.

In the Spanish PETHEMA trial, no difference in PFS was shown between the high- and low-risk group if MRD negativity was achieved. This result confirms that the objective for high-risk patients should be to reach MRD negativity.

Age

The majority of work investigating the impact of MRD negativity has been carried out in patients eligible for transplant, who tend to be younger. Therefore, the question of whether age has an effect had yet to be fully addressed.

In the MAIA trial (NCT02252172), dara + RD (lenalidomide + dexamethasone) was tested against RD alone in older patients who were ineligible for transplant. These elderly patients were able to reach MRD negativity in this study, which was associated with longer PFS. It is hoped that dara with other triplet combinations will increase MRD negativity rates for these patients going forward.

PET/CT also has a role in MRD assessment. Bone marrow sampling can miss the extramedullary disease; samples taken in this way can also show false negatives as a result of heterogeneous infiltration through the marrow and dilution of samples. PET/CT can be used to confirm the presence or absence of residual disease alongside next-generation sequencing and flow cytometry techniques.

Conclusion

The requirement for long-term remission (10 years) is achieving MRD negativity at ≤10⁻⁵. At 10⁻⁶ the probability of achieving long-term PFS is highest. MRD negativity should be durable and last for ≥1 year for the best chance of prolonged overall survival. While patients with high-risk MM achieve MRD negativity less frequently, MRD negative status can still be associated with longer PFS.