Sequencing treatments for relapsed/refractory multiple myeloma

Front-line treatment of patients with newly diagnosed multiple myeloma (MM) depends on their eligibility for autologous-hematopoietic stem cell transplantation (auto-HSCT). Patients who are transplant-eligible receive induction therapy followed by auto-HSCT and maintenance; while those who are not eligible receive initial therapy followed by maintenance. Despite remission after first-line treatment, many patients eventually relapse, and the duration of response decreases with subsequent therapies. Treatment becomes more challenging after each relapse as multiple therapies enrich for resistant malignant clones. Additionally, following each relapse, the cumulative toxicity of therapies increases while the bone marrow function decreases.¹ With a wide range of novel treatment options approved or in late stages of clinical development, the optimal sequencing of therapies in relapsing patients requires thorough consideration.

On May 16, during the 6th World Congress on Controversies in Multiple Myeloma (COMy), which was held virtually, Jean Luc Harousseau from the Institut de Cancérologie de l’Ouest and Saad Usmani from Levine Cancer Institute, discussed optimal therapies for patients in first and later relapse. This article provides a summary of those presentations.²

Management of MM in the first relapse

Most first-line treatments used today consist of triplet combinations like bortezomib/lenalidomide/dexamethasone or bortezomib-cyclophosphamide-dexamethasone, and doublets, i.e., lenalidomide/dexamethasone (Rd); followed by auto-HSCT when feasible. Additionally, most patients receive maintenance therapy with lenalidomide or bortezomib. Despite the different therapeutic pathways, all patients eventually relapse, and a decision on the best subsequent regimen has to be individualized considering several factors, such as age, fitness, comorbidities, and prior treatment response and tolerability.

Before bortezomib and lenalidomide were used as front-line treatments, bortezomib/dexamethasone (Vd), and Rd were considered standard treatment options for patients with MM in the first relapse. However, with the increasing incidence of resistance to those agents in earlier stages of the disease, new therapies are needed. 

Clinical studies demonstrated significantly improved clinical outcomes with triple regimens with a second generation agent compared to double combinations (Table 1). The superior response rates and progression-free survival (PFS) results with the triple combinations compared to Rd and Vd doublets, are seen across all age groups, regardless of the International Staging System score, prior lines of treatment, transplantation status, and cytogenetic risk. In particular, the addition of daratumumab to both, lenalidomide or bortezomib-based regimens, reduces the risk of progression or death significantly and a high proportion of patients with relapsed or refractory (RR) MM achieve negative measurable residual disease status.

Table 1. Efficacy of triple combinations with lenalidomide or bortezomib with a second generation agent

 Multiple factors should be considered when deciding on the best treatment option, like patients’ age, frailty, and comorbidities.

Frail/older patients

In frail and older patients especially, the treatment during the first relapse should induce a response without adding too much toxicity. The decision regarding optimal treatment is mainly based on factors including:

• Age
• Comorbidities
• Performance status
• Tolerance of previous therapies

Compared to younger and fitter patients, elderly patients are usually frail, have an increased number of comorbidities, poor performance status, and higher risk of infection, venous thromboembolism, neuropathy, and treatment failure. Diagnosing symptomatic myeloma in older patients is also more challenging. Therefore, these patients are often not included in clinical trials, making it difficult to compare different treatment options. However, some of the novel agents are well tolerated by older/frail patients, including:

• Daratumumab
• Elotuzumab
• Ixazomib

Additionally, reduced dosing of lenalidomide or bortezomib might be preferred in this setting.

Fitter and younger patients

In fit /younger patients, the main goal of treatment is to achieve the best possible PFS. The key factors driving treatment choice are:

• Sensitivity/resistance to lenalidomide and bortezomib
• Whether a patient had a transplant
• Prognostic factors such as International Staging System score and cytogenetics
• Duration of response to previous therapy
• The aggressiveness of the relapse 
• Treatment availability

In these patients, triple combinations are superior independent of disease-related prognostic factors. Since head-to-head comparative studies between triple regimens are currently not available, Jean Luc Harousseau recommends making decisions depending on sensitivity to lenalidomide and bortezomib, as well as treatment availability.

 Lenalidomide-refractory disease

As lenalidomide is used as frontline treatment in most patients, the ones defined as refractory (progressed during treatment or < 60 days after the end of treatment) are often excluded from triple combination studies. To add to the challenge, the results in trials without lenalidomide are suboptimal (Table 2).

Table 2. Efficacy of some of the approved lenalidomide-free regimens for RRMM

 Other combinations with second generation agents are being investigated to improve those outcomes:

• Pomalidomide (P)-based
  • P- cyclophosphamide- dexamethasone
  • P-carfilzomib-dexamethasone (KPd)
  • P-ixazomib-dexamethasone
• Daratumumab (D)-based
  • D-Kd vs Kd (CANDOR)
  • D-pomalidomide-dexamethasone (DPd)
• Elotuzumab (E)-based
  • E-Pd vs Pd (ELOQUENT-3, 3^rd line)
• Isatuximab (isa)-based
  • isa-Pd vs Pd (ICARIA, 3^rd line)
  • isa- Kd vs Kd (IKEMA)

In CANDOR, ELOQUENT-3, and ICARIA trials, patients with lenalidomide refractory disease achieved better clinical outcomes with a triple combination compared with doublet therapies. The most promising results in this group of patients were reported with daratumumab-carfilzomib-dexamethasone, which significantly improved PFS compared with Kd (not reached vs 11.1 months; HR = 0.45).

The treatment options for patients in the first relapse based on the sensitivity to lenalidomide and bortezomib are presented in Table 3, with Jean Luc Harousseau's favored options highlighted in bold.

Table 3. Proposed treatment options for patients with MM in first relapse depending on lenalidomide and bortezomib sensitivity

Prior transplant

If auto-HSCT was not performed during the initial therapy, it should be considered as a part of salvage therapy. However, transplantation should not be considered for patients in the first relapse after front-line auto-HSCT.

Management of MM beyond the first relapse

The therapeutic landscape for patients after ≥ 2 lines of prior therapy is rapidly changing, with many clinical trials evaluating various treatment combinations. Similarly, to the first relapse, the decision on the optimal next line treatment needs to consider disease biology and prior therapy exposure. Saad Usmani provided an overview of large clinical trials exploring different treatment options in this setting (Table 4). 

Table 4. Clinical trials in RRMM

 Although triple combinations show improvement in response rates and PFS compared with double regimens in RRMM, they may also contribute to significant toxicity in some cases. For instance, the venetoclax-bortezomib-dexamethasone trial was initially partially halted due to safety concerns, but later data analysis revealed that using presence of t(11;14) and high BCL2 expression as biomarkers may help to identify patients who would benefit the most from the venetoclax-bortezomib-dexamethasone  therapy.

The recommended treatment regimens for patients with RRMM in second relapse and beyond are presented in Table 5, with Saad Usmani’s favored options in each category highlighted in bold.

Table 5. Treatment options for patients with RRMM in second relapse and beyond

 Other promising options for patients with RRMM mentioned by Saad Usmani were:

• Selinexor (S), an inhibitor of exportin-1 inhibitors, which is being tested in various combinations, including carfilzomib-dexamethasone (SKd) and pomalidomide-dexamethasone (SPd). The overall response rate (ORR) achieved with SPd was of 83%
• TAK-079, an antibody against CD38, currently investigated in phase Ib study demonstrated ORR of 45% (56% in daratumumab-naïve patients) in patients with a median of 3 prior lines of therapy
• CC-93269, a bispecific anti-B-cell maturation antigen antibody, which in a phase I study showed ORR of 43% in patients with a median of 5 prior lines of therapy
• JNJ-4528, a chimeric antigen receptor (CAR) T-cell therapy, in CARTITUDE-1 phase Ib/II study showed ORR of 100%, including very good partial response of 86%
• bb21217, a CAR T-cell therapy

In the last part of the presentation, the speaker listed a few novel small molecule inhibitors in early stages of development that might be soon incorporated into RRMM treatment, including the following:

• Cereblon E3 ligase modulators or CELMoDs (CC122, CC220 and CC480)
• Myeloid cell leukemia 1 inhibitors (AMG176, AZD5991 and MIK665)
• Bromodomain inhibitors (CPI-0610, RO6870810 and ARV825)
• Mouse double minute 2 homolog inhibitors (AMG232, DS3032b and idasanutlin)
• New proteasome inhibitors (marizomib and oprozomib)

Conclusions

The treatment landscape of RRMM is constantly evolving, with some established therapies moving into earlier settings and novel agents entering clinical development. Triple combination regimens, with second generation agents, have demonstrated superior activity over double combinations. Newer agents are more target-specific and often administered orally. Both the CAR T-cell therapies and bispecific antibodies are likely to play an important role in the treatment of patients with RRMM. However, access to these novel agents can be restricted due to high costs.

The speakers highlighted the need for careful consideration when deciding on the next line of treatment for patients with RRMM. Further data on patients with high-risk RRMM and optimal sequence of combinations with new and existing treatments, will improve the chances of patients receiving the best treatment option and move forward into a personalized treatment of MM.

Further Resources

The full oral abstracts session is currently available via this link [Correct as of May 27, 2020].