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How I Treat In Brief: Treatment of High-Risk Multiple Myeloma

January 31, 2022

February 2022

Elena Zamagni, MD, Simona Barbato, PhD, and Michele Cavo, MD, review current definitions of high-risk multiple myeloma, the results of available trials with high-risk patients, and how to use risk-adapted treatment strategies in difficult-to-treat patients. This material is repurposed from “How I treat high-risk multiple myeloma,” published in the November 2, 2021, edition of Blood.

Fast Facts

  • About 15-20% of patients with MM are considered high risk and have a predicted OS of less than three years.
  • Ultra-high-risk patients, with an OS of less than two years, have co-occurring high-risk features, such as cytogenetic/genetic abnormalities or relapse within one year of AHCT.
  • Among MM risk factors, genetic-molecular alterations and response to treatment are the most robust predictors of outcomes.
  • More than half of patients newly diagnosed with MM are considered elderly (i.e., >65 years), and this population is extremely heterogeneous, with comorbidities and frailty increasing with age.
  • Current data show that the best way to overcome high-risk disease is to sustain MRD negativity, with the prognosis of high-risk patients achieving sustained MRD negativity getting very close to that of patients with standard risk.

The overall survival (OS) rate of patients with multiple myeloma (MM) has significantly improved during the past decade and is currently close to a median of 10 years for newly diagnosed, fit patients. However, the improvement has not been uniform, and 15-20% of all patients have a predicted OS of less than three years. This subgroup is identified as having high-risk MM and represents a challenge to diagnose and treat with unsatisfactory disease control and early relapse, despite using the newest therapies. Patients with co-occurrence of high-risk features – particularly cytogenetic/genomic abnormalities – or early relapse (<1 year) after autologous hematopoietic cell transplantation (AHCT) are included in an ultra-high-risk category, with an expected median OS of less than two years. For these patients, innovative treatment strategies are warranted.

With the increased availability of highly active classes of new drugs and innovative treatment strategies, the time has come to design prospective risk-tailored studies aimed at offering the most effective approaches to high-risk patients to achieve and sustain measurable residual disease (MRD) negativity. Here, we review clinical cases of difficult-to-treat patients, focusing on various risk aspects that might be applicable throughout different treatment phases.

Clinical Case 1: Treatment of Newly Diagnosed, High-Risk, Transplant-Eligible MM

A 62-year-old woman was referred because of moderate anemia and a suspected serum M protein. She underwent a workup that established the diagnosis of active IgA/K MM, International Staging System (ISS) stage III. High-risk characteristics included histologically proven involvement of hyper­meta­bolic lymph nodes determined using positron emission tomography–computed tomography (PET-CT), 3% of circulating clonal plasma cells (PCs) determined by flow cytometry, and positivity for del(13q) at conventional karyotype combined with amp(1q21) determined by fluorescence in situ hybridization (FISH) analysis.

The patient was classified as high risk for the presence of cytogenetic aberrations, ISS stage III, circulating PCs, and extramedullary disease (EMD). She was treated according to national guidelines with four cycles of VTD (bortezomib-­thalidomide-dexamethasone) induction, achieving stringent complete response (sCR), followed by double AHCT (conditioned with 200 mg/m2 melphalan) and, thereafter, two cycles of VTD consolidation. After the consolidation phase, the patient’s disease was still in an sCR, and assessment of MRD status by next generation sequencing (sensitivity level of 10-5) was negative. Maintenance therapy with lenalidomide was started following consolidation and was ongoing 18 months after diagnosis.

Case 1 Commentary

The optimal choice of new agent combinations and their most effective incorporation into treatment strategies for patients with high-risk MM who are candidates to receive AHCT are not well defined. According to the International Myeloma Working Group (IMWG), the optimal induction therapy for patients with high-risk cytogenetics should include a proteasome inhibitor (PI), like bortezomib, plus an immunomodulatory drug (IMiD), preferentially lenalidomide, and dexamethasone (VRd), with between four and six cycles, according to the maximal response.

Results from several phase II studies of carfilzomib plus Rd (KRd), with or without AHCT, have supported the inclusion of KRd in the latest National Comprehensive Cancer Network guidelines. VTD, VRd, or KRd have more recently represented the backbone to which to add daratumumab or isatuximab to further increase the activity. The addition of polychemotherapy to triplet induction regimens, even though not supported by phase III trials, may be considered in patients with EMD and plasma cell leukemia.

The use of double AHCT in newly diagnosed MM was introduced before the availability of newer agents, and more recently, several studies have readdressed its role for patients with newly diagnosed MM, particularly those at high risk. Although the debate is still open, double AHCT is recommended for patients at high risk in IMWG and European Myeloma Network guidelines.

Consolidation therapy typically includes the same combination of agents used as induction therapy before AHCT. Many phase II and III studies comparing three- versus two-drug consolidation regimens, as well as quadruplet versus triplet therapies, have been performed so far, supporting the value of consolidation therapy in increasing sCR and MRD negativity. The role of consolidation therapy with VRd versus no consolidation was prospectively evaluated in two randomized studies with conflicting findings. Assessment of MRD status at the highest sensitivity level achievable with modern techniques may help the physician make clinical decisions in the high-risk setting.

Clinical Case 2: Treatment of Newly Diagnosed,  High-Risk, AHCT-Ineligible MM

A 78-year-old man with a prior history of prostatectomy for adenocarcinoma, atrial fibrillation in oral anticoagulant therapy, hypercholesterolemia, and type II diabetes was admitted to the hospital due to worsening lumbar pain and laboratory evidence of moderate renal failure (serum creatinine = 2.6 mg/dL, estimated glomerular filtration rate [eGFR] = 35 mL/min). The workup led to a final diagnosis of immunoglobulin G kappa (IgG-K) MM, per the Revised ISS stage III, because of a beta2-mic level of 15 mg/L and presence of t(4;14) determined by FISH; immediate therapy was needed because of extensive skeletal disease documented by fluorodeoxyglucose PET-CT and axial magnetic resonance imaging.

After an evaluation of the patient’s age, frailty status (renal failure, hypomobility), and comorbidities, he was categorized as intermediate/unfit with intermediate cytogenetic risk and started on reduced-dose Rd plus daratumumab. This allowed him, after the first eight weeks, to receive most of the treatment at home. His disease was in a partial response (PR) after two cycles, very good PR after five cycles, and complete response (CR) at cycle nine. Renal function improved to an eGFR of 45 mL/min. The patient is currently receiving monthly daratumumab with lenalidomide 10 mg and stopped dexamethasone in light of the optimal response, underlying diabetes, and the COVID-19 pandemic.

Case 2 Commentary

Improvements in outcomes for elderly patients with high-risk features have not been as evident as in transplant-eligible patients. In fit patients, the combination of first-generation agents, PI- or IMiD-based, have improved the response rate in the high-risk subset, although OS remained significantly shorter. Even in the recent phase III trials evaluating the addition of daratumumab to Rd or VMP (bortezomib, melphalan, prednisone), the advantage in survival outcomes seen for the general population was less clear, probably related to the fact that the high-risk population was under-represented (approximately 10%). However, a meta-analysis of six phase III trials comparing backbone regimens with the same regimen plus daratumumab showed that incorporation of daratumumab may be associated with improved progression-free survival (PFS) among patients with high-risk MM.

In patients with poor performance status or frailty, the goal of therapy should be safety and quality of life rather than depth of response. The new standards of care, including frontline daratumumab and VRd, turned out to be feasible in patients older than 75 years, without a detrimental effect of age, and even in frail patients. However, dose-modification guidelines are available to adjust treatment based on patient fitness, considering both limited induction duration, lower drug doses, steroid-sparing regimens, and more tailored treatments.

Clinical Case 3: Dynamic Risk Evaluation and Treatment of Relapsed/Refractory High-Risk MM

A 68-year-old man with a previously established diagnosis of ISS stage III IgG/λ MM and high risk characterized by the co-segregation of t(4;14), with del(17p) and P53 mutation (double-hit MM), was referred because of a persistent MRD-positive CR after first-line treatment with VTD induction plus AHCT plus VTD consolidation and lenalidomide maintenance. Given the high-risk status and MRD positivity, a complete re-evaluation of the disease was performed, detecting bone marrow plasma cell infiltration of 20%, FISH unchanged, small serum M protein (1 g/dL), PET-CT and axial MRI positive for diffuse bone marrow involvement, without new lytic lesions. Biochemical early relapse was established.

At the time the patient was referred for treatment, the CARTITUDE-4 phase III study comparing B-cell maturation antigen (BCMA)–targeting CAR-T therapy (cilta-cel) with daratumumab-based triplet combinations in patients with early relapse after AHCT was open to enrollment. The patient was screened and randomized in the CAR-T arm. He is currently in CR and sustained MRD negativity 18 months after CAR-T infusion.

Case 3 Commentary

Randomized controlled trials showed the superiority of triplet combinations of PIs, IMiDs, monoclonal antibody therapies (MoAbs), and new classes of agents over the doublet backbone, both in lenalidomide-naïve or sensitive, and lenalidomide-refractory patients. The survival outcome superiority of the triplets has been confirmed in high-risk patients, though it is less pronounced than in standard-risk patients. For this reason, no regimen is more uniquely suited than another in high-risk patients.

Among the triplets in lenalidomide-naïve patients, the longest PFS is afforded by daratumumab-lenalidomide-dexamethasone (26.8 months), especially in patients achieving sustained MRD negativity; however, the PFS in high-risk patients was almost half that reported for the general population. In lenalidomide-refractory patients, several PI- or pomalidomide-based triplets, combined with each other or with MoAbs, are available and showed benefit for high-risk patients, despite less mature data than the lenalidomide-based therapies. Also, the addition of chemotherapeutic agents may help patients who are experiencing a rapid, aggressive relapse, particularly with characteristics of para-skeletal or EMD.

Little information is available on the efficacy of newer drugs in the high-risk population, such as the oral inhibitor of exportin-1 selinexor, immunotherapy-directed anti-BCMA, bispecific MoAbs, or CAR-T cell therapy. Nevertheless, the capability of these newer approaches to induce relatively high rates of MRD negativity, make them attractive and potentially a better way to pursue the goal of eradicating all malignant cells required in the context of aggressive disease.

Conclusion

Fifteen to 20% of cases of MM are considered high risk, which is characterized by reduced survival as a result of tumor biology, some form of frailty, or suboptimal or no response to therapy. Identification of different risk factors for aggressive disease is crucial to managing this difficult-to-treat population. In biologic high-risk MM, the goal of treatment should be to achieve and sustain MRD negativity, inside and outside the bone marrow. In patients with frailty, therapy should be adapted to reduce toxicity and improve quality of life. The combination of a risk- and MRD-adapted treatment strategy may represent the optimal approach.

 

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