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International Journal of Hematology (2020) 111:512–518https://doi.org/10.1007/s12185-020-02841-w

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PROGRESS IN HEMATOLOGY

Latest treatment strategies aiming for a cure in transplant‑eligible multiple myeloma patients: how I cure younger MM patients with lower cost

Kenshi Suzuki1

Received: 6 February 2020 / Accepted: 6 February 2020 / Published online: 3 March 2020 © Japanese Society of Hematology 2020

AbstractThis article presents a practical overview of the treatment of younger, newly diagnosed multiple myeloma patients, focus-ing on novel treatment strategies. With the introduction of effective new agents, multiple myeloma is one of the most active and changing fields in clinical oncology. In addition, monitoring technology has become reliable and practical. Achieving and sustaining minimal residual disease negativity (MRD– ), such as multiparameter flow cytometry (MFC) < 10−5, is one of the goals of therapy. MRD– is significantly associated with prolonged progression-free survival, whereas MRD persis-tence (MRD +) is an independent factor for poor progression-free survival. Evidence from several recent studies evaluating modern therapy has further supported the positive correlation between depth of response and outcomes. Multiple myeloma can become a chronic illness with sustained MRD– in a significant number of patients. Our ultimate hope is to leverage tumoricidal-immunomodulatory sequential therapies and to cure a subset of our patients.

Keywords Multiple myeloma · Autologous stem cell transplantation · Minimal residual disease negativity · Cure of myeloma · Healthcare costs

Introduction

Multiple myeloma (MM) is an incurable disease, and responsiveness to treatment varies among patients due to the high heterogeneity of the disease [1, 2]. The decision on which treatment is best for MM has been a difficult issue. However, treatment of MM has advanced remarkably in the past 10 years (Fig. 1). MM patients can achieve long-term remissions and survival [3–9]. According to an IMWG Research Project, sustaining a complete response (CR) at 1 year was associated with better progression-free survival (PFS) (median 3.3 years vs. 2.6 years, P < 0.0001), as well as overall survival (OS) (median 8.5 years vs. 6.3 years, P < 0.0001) [7]. This article reviews the latest trends and future developments in the treatment of MM.

Induction regimen

Bortezomib‑lenalidomide‑dexamethasone (VRd/VRd‑lite)‑autologous stem cell transplantation (ASCT)

For newly diagnosed, physically fit patients younger than 70 years, ASCT after induction therapy remains stand-ard [10, 11]. Incorporation of novel agents into induction regimens further improves survival outcomes. A three-drug combination that includes immunomodulatory drugs (IMiDs) such as lenalidomide (Len) or pomalidomide (Pom), antibodies, and proteasome inhibitors (PIs) may be optimal. Len/dexamethasone (Dex) (Rd) is the backbone of many triplet regimens (Fig. 2). Bortezomib (Bor)-containing triplet regimens, such as Bor/thalidomide (Thal)/Dex (VTd), Bor/Len/Dex (VRd), and Bor/cyclophosphamide (CPA)/Dex (VCd), are highly active in patients with newly diagnosed MM. Recent studies show that triplet regimens contain-ing IMiDs and PIs offer better response rates, as well as improved PFS compared with doublets. More importantly, a

Recent Advances in Biology and Treatment of Multiple Myeloma

* Kenshi Suzuki ken-suzuki@mtb.biglobe.ne.jp

1 Director of Myeloma and Amyloidosis Center, Japanese Red Cross Medical Center, Shibuya-ku, Hiroo 4-1-22, Tokyo, Japan

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recent phase 3 trial has shown that OS is superior with VRd as initial therapy compared with Rd. In patients over the age of 65 and those who have received more than four cycles of Rd, stem cells must be mobilized with granulocyte colony-stimulating factor (G-CSF) together with plerixafor [12]. In the IFM/DFCI trial, the CR rate was higher in the ASCT group than in the VRd-alone group (59% vs. 48%, P = 0.03), as was the minimal residual disease negativity (MRD–) rate (79% vs. 65%, P < 0.001) [10]. However, OS at 4 years did not differ significantly between the two groups (81% and 82%, respectively). An increasing range of treatment options is available for newly diagnosed and relapsed or refractory MM (RRMM); however, there remains no global standard of care. Despite clinical trials showing benefits of continuous

versus fixed duration therapy, shorter treatment durations are seen in the real world [13].

Autologous stem cell transplantation

High-dose melphalan followed by ASCT improves PFS and OS in MM, with treatment-related mortality (TRM) less than 1%. Hence this treatment should be considered in all eligible patients. Although early ASCT after four cycles of initial therapy is preferred, some randomized trials show similar OS whether ASCT is early or delayed. Recent stud-ies comparing up-front ASCT with a protracted course of novel agents with deferred ASCT at first relapse found that the former approach resulted in superior CR, MRD− rates, and PFS. Furthermore, ASCT can be considered for salvage in fit patients if the interval between the first ASCT and relapse is 18 months or more. The time to progression of disease (PD) (19 vs. 11 months) and OS (67 vs. 52 months) were significantly better with salvage ASCT. ASCT remains important in the era of novel agents [14].

Post transplantation consolidation/maintenance therapy

In general, the term “consolidation” refers to a short course of therapy following definitive initial therapy, while “main-tenance” refers to a more prolonged course of treatment with a lower-intensity regimen. The IMWG Research Project found a statistical cure fraction of 14.3% [15]. This result identifies CR as an important predictor of long-term sur-vival for ASCT-eligible MM patients, and clinical variables reflective of higher disease burden as poor prognostic mark-ers. The study identified achieving CR in the first year of diagnosis as an important landmark associated with superior PFS and OS. After achieving MRD–, sustaining it by various combination strategies including immunological effects may be more important for the cure (Fig. 3).

Multi consolidation/maintenance until sustained MRD‑negativity for 2 years by continuous DRd‑Kd‑EPd‑IRd/PCd

Despite improvements in PFS and OS, relapses are almost inevitable for most MM patients, primarily due to incom-plete eradication of MRD. To improve the outcome of ASCT, it is important to eradicate MM tumor cells through the synergistic immunological effects of ASCT and peri- and post-ASCT treatment (Fig. 4). In retrospective observational studies, prolonged therapy appeared to result in better out-comes. There is a great debate concerning the role of achiev-ing MRD– with multiparameter flow cytometry (MFC) and sustained MRD– as a goal of therapy. Although data show

Fig. 1 Historical perspective: Progress in multiple myeloma treat-ment options. Overall survival has improved from 3 to 7–10 years and beyond. Many powerful new drugs are further increasing the depth and duration of remission

Fig. 2 Many options for initial therapy of multiple myeloma (NCCN Guideline 2020). Choice of initial treatment is complicated by the novel agents. Triplet regimens increase response and improve out-come

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that MRD– has favorable prognostic value, additional trials are needed to determine if changes in treatment need to be made based on MRD status (Fig. 5).

Anti‑CD38 antibodies

A synergistic effect of anti-CD38 antibodies with IMiDs is supposed because the CD38 expression level in MM cell lines is substantially up-regulated by Pom and Len [16–19]. A global, ongoing phase 3 clinical trial (the MAIA trial) is comparing the clinical benefit of daratumumab (Dara)-Rd versus Rd in patients with newly diagnosed MM. In MAIA, Dara-Rd treatment significantly reduced the risk of PD or death by 44%.

Isatuximab (Isa) is another antibody that targets CD38. Single-agent Isa had an overall response rate (ORR) of 24.3%, with a median PFS and OS of 3.7 and 18.6 months, respectively, in patients with RRMM [20]. Several stud-ies are currently ongoing, including one of Pd with or without Isa in RRMM (ORR 62%, with a median PFS of 17.6 months) and another of VRd with or without Isa in patients with newly diagnosed MM [21].

Fig. 3 Imaging for cure by combined tumoricidal and immunomodu-latory sequential therapies. After achieving minimal residual disease negativity (MRD–, sustaining it by various combination strategies including immunological effects may be more important for the cure

Fig. 4 Strategy of treatment of multiple myeloma in transplant-eligi-ble patients in our institute (plan). For the induction and consolida-tion phases, agents with deep and quick response should be selected; however, for the maintenance phase, agents with high safety and immunological power should be considered. We divided treatment into four phases. The initial therapy consisted of four courses of VRd-lite followed by PBSC-harvest. In cases of under partial response, an additional two cycles of KRd therapy may be performed with the use of plerixafor (a phase). In our clinical practice, up-front ASCT is per-formed, followed by continuous multi consolidation/maintenance reg-imens until minimal residual disease negativity (MRD–) is sustained for 2 years with DRd-Kd-EPd-Rd every 6 months (b phase). Patients with confirmed MRD– at 2 years will be actively monitored for resur-gence of MRD or clinical relapse. After that, the treatment is stopped, with careful watching. Progression of disease (PD) is defined as (1) > 25% elevation in M-protein, (2) hypercalcemia, (3) progres-sion of anemia, (4) bone pain, (5) β2-MG elevation, (6) additional chromosomal abnormalities, or (7) elevation of bone marrow (BM) myeloma cells. After PD, problem-oriented ASCT may be performed after two cycles of VTD-PACE therapy (c phase). In patients under 60  years of age whose families agree to allo-SCT, we choose allo-SCT with ERd-R maintenance (d phase). BM aspiration for evalua-tion of depth of response and MRD before ASCT, after DRd therapy, and at 6 months between regimens

Fig. 5 Minimal residual disease-driven decision making at consoli-dation/maintenance periods. Monitoring of minimal residual disease (MRD) kinetics not only can predict prognosis more precisely, but also can be helpful to guide treatment decisions, particularly when deciding when to start retreatment of relapsed patients. MRD nega-tivity (MRD–) guides treatment modification. MFC is currently con-sidered a sensitive co-adjuvant test, not only for diagnostic screening but also as a surrogate marker of multiple myeloma. Bone marrow aspiration is performed for evaluation of depth of response and MRD before and after ASCT with 6-month intervals between each regi-men. Our optimal responses are VGPR at harvest periods, CR at after ASCT, and MRD– at the end of DRd. MRD-driven decision-making should be done at consolidation/maintenance periods

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KRd/Kd

In Japan, KRd was approved for RRMM by the phase 3 ASPIRE trial and Kd by the phase 3 ENDEAVOR trial [22–24]. In addition, once-weekly administration of Car was submitted for RRMM by the phase 3 ARROW trial. Once-weekly KRd (carfilzomib 56 mg/m2) showed prom-ising activity with an acceptable safety profile in patients with newly diagnosed MM and reduce the burden on elderly patients and those living far from hospitals. These results merit additional evaluation of a convenient wKRd regimen in patients with newly diagnosed MM.

Anti‑SLAMF7 antibody

Signaling lymphocytic activation molecule family member 7 (SLAMF7) is expressed on myeloma cells [25]. Elotu-mumab (Elo) in combination with Rd (ERd) was approved for RRMM according to the results of the ELOQUENT-2 study. The ELOQUENT-3 study showed promising efficacy of Elo in combination with Pd (EPd). EPd had good ORR (53%) compared with Pd (26%). The most remarkable fea-ture of Elo is its high safety. Interestingly, adding Elo to Pom-Dex improved Pom-induced neutropenia [26–29].

IRd

Ixazomib (Ixa) was approved in Japan as the first oral PI in combination with Rd (IRd) for RRMM (TOURMALINE-MM1 [30–33]). In the TOURMALINE-MM3 trial, patients after ASCT were randomly assigned to receive Ixa main-tenance therapy or placebo. A 28% reduction in the risk of progression or death with Ixa versus placebo (median PFS, 26.5 vs. 21.3 months) was reported. No increase in second malignancies was noted with Ixa therapy compared with placebo.

PVd/PCd

Pd is approved in Japan for patients with RRMM [34]. In the phase 3 OPTIMISMM trial, Bor + Pd (PVd) prolonged PFS compared with Vd in RRMM patients who had received one to three prior regimens including Len (median 11.2 vs. 7.1 months, P < 0.0001) [35–37]. An oral regimen of Pom/CPA/Dex (PCd) in the first relapse after exposure to Len and Bor is efficacious and safe. PCd maintenance may be useful for sustained MRD–. The importance of an IMiD-free interval until the start of Pd was reported. OS, PFS, and PFS2 were improved in patients who had an inter-val of ≥ 18 months from the last dose of Len to the first dose of Pom compared with those who had an interval of < 18 months (PFS, 10.5 vs. 4 months, P = 0.002). This result suggests that the Len-free interval may prolong PFS

and shows the possibility of the emergence of IMiD-sensi-tive clones after an IMiD-free interval.

Ongoing clinical trials of four‑drug combinations (quad induction)

I believe that we are moving toward using quadruplet treat-ment regimens, based on data from the CASSIOPEIA trial and others. In CASSIOPEIA, at 100 days after ASCT, 39% of patients in the Dara-VTd group versus 26% in the VTd group achieved CR or better, and 64% versus 44% achieved MRD– (both P < 0.0001) [38]. In a trial of Dara + VRd (GRIFFIN), 16 patients were enrolled and completed nine or more cycles of Dara-VRd [39]. By the end of consoli-dation, all patients had reached VGPR or better, and 63% achieved CR (including 25% sCR and 50% MRD–). Twelve patients developed infections. No deaths due to serious adverse events were reported, and no patients discontinued treatment due to adverse events. Based on this study, a phase 3 study of Dara-VRd was initiated. In this study, patients in the Dara-VRd group who achieve sustained MRD– for 12 months after ≥ 24 months of maintenance will stop Dara but continue Len maintenance until PD; upon loss of CR or MRD–, patients will restart Dara treatment. The results of this study will address how MRD– guides treatment modi-fication. A phase 2 trial of the combination of Dara with KRd is ongoing.

Experimental maintenance strategy

Some studies are ongoing to aim to improve response. The duration of maintenance and the stopping rule differ among the protocols. It is too early to estimate how much the MRD– rate would increase during maintenance. In the Dara-VRd safety-run in cohort (n = 16), the response contin-ued to deepen during maintenance (sCR, 25% at the end of consolidation, 63% during maintenance). It is anticipated the more patients with MRD– will be seen after longer follow-up times.

Anti‑B‑cell maturation antigen (BCMA) chimeric antigen receptor‑T (CAR‑T)

BCMA has been targeted for CAR-T cell approaches against MM, and preclinical studies showed regression of BCMA-expressing MM cells. The first phase 1 study of CAR-T cell therapy targeting BCMA in 33 patients with a median of 7 prior regimens was reported [40]. The data cutoff date was 6.2 months after the last infusion date. Twenty-five patients had cytokine release syndrome, which was grade 3 in two patients. Neurologic toxic effects occurred in 14 patients and

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were grade 1 or 2 in 13 patients. One patient had a revers-ible grade 4 neurologic toxic effect. The ORR was 85%, including 45% CR. Six of the 15 patients who had a CR have had a relapse. CAR-T cell expansion was associated with responses, and CAR-T cells persisted up to 1 year after infusion. In the future, we should consider early introduction of CAR-T therapy for high-risk patients, such as those who relapse within a year after ASCT.

VTD‑PACE

In addition to the regimens discussed above, another option is multiagent combination chemotherapy, such as VTD-PACE (Bor/Thal/Dex, cisplatin, doxorubicin, CPA, and etoposide). VTD-PACE is particularly useful in patients with aggressive disease, such as plasma cell leukemia or multiple extramedullary plasmacytomas [41]. The efficacy of VTD-PACE-like regimens in the treatment of RRMM may be based on the combination of PACE for 4 days of continuous drip infusion with an interval of 4–6 weeks.

Allo‑SCT

Previous studies suggested that allogeneic stem cell trans-plantation (allo-SCT) can overcome high-risk cytogenet-ics associated with poor outcome in MM. Despite having the potentially curative therapy for MM, the use of allo-SCT remains controversial due to the unacceptable high non-relapse mortality (10–15%), extensive morbid chronic graft-versus-host disease (50–80%), and high relapse rates (50–60%) [42]. Allo-SCT is not recommended as part of initial therapy. There are conflicting data about its clinical benefit, and the TRM rate (10–20%) remains a concern. For patients who survive the first year, the high GVHD rate and the likelihood of relapse remain formidable issues. It would be reasonable to consider allo-SCT in selected young patients with high-risk disease who are willing to accept high TRM for a chance of better long-term survival [43].

Supportive care

Although our previous consensus for adjunctive manage-ment of vascular thrombosis, skeletal complications, infec-tions, and peripheral neuropathy remains valid, emerging concerns pertaining to specific new drugs will need to be addressed. Hepatitis B virus infection is highly endemic in Asia, and a major concern is the risk of its reactivation after the use of anti-CD38 therapy. Hence, it is mandatory to screen for both HBsAg and anti-hepatitis B virus core antibody.

Financial impact

With all myeloma therapies given as combinations, three major considerations for the practicing hematologist are combined toxicities across agents, decision making for ther-apeutic strategies offered to patients, and total costs, includ-ing traffic fees. Several other factors should be considered when planning treatment strategy, such as logistics, drug availability, social considerations, comorbidities, and patient preference, as each may influence treatment choice. There-fore, biomarker-driven or other decision support tools for precision medicine would be of significant utility in guiding myeloma practice to match each patient (Fig. 6). The thera-peutic progress in MM has come with a significant financial impact on both patients and society. Most of the new drugs approved for MM in recent years cost more than $100,000 per year of therapy. With a shifting paradigm toward con-tinuous therapy, the cumulative cost of treatment can be as high as $500,000 for initial therapy, including induction, consolidation, and maintenance. Since most patients who achieve remission with initial therapy eventually relapse, the cost of newer agents creates an unsustainable financial burden for patients and the society. A study in the US state of Washington reported that the rate of financial bankruptcy was 2.65 times higher in cancer patients than in those with-out cancer. We present data to argue that these medications and associated expenses are of direct benefit to patients and society. Long-term studies have shown that, even with trans-plantation, a small minority of patients can be cured now.

Fig. 6 Future treatment strategy. Evidence of future treatment strat-egy will come from Japan. Future treatment will be like Total Ther-apy X, which consists of a triplet (or quadruplet treatment regimens) and two to four regimens every 6 months. New myeloma treatments are evaluated for efficacy, cost, and safety. Admission periods maybe 2–3  months (including ASCH + ASCT, Dara-induction, and any infections). Total healthcare costs should be 0.5 million dollars, over 10 years survival with good QOL

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Perhaps an optimal strong induction (e.g., Dara-KRd) fol-lowed by consolidation with ASCT and CAR-T will cure more patients. If so, the future will be not only brighter, but also more economical.

Conclusion

As mentioned above, the therapy and treatment strategy of MM have largely changed in recent years. Ongoing efforts to improve the treatment paradigm even further include using oncogenomics to better characterize molecular pathogenesis and to develop refined patient stratification and personalized treatment of MM using immune-based therapies, including antibodies, cytokines, and novel immunocytic strategies. Understanding the profile of oncogene and tumor suppres-sor gene mutations with their interactions and impact on the prognosis of MM can improve the definition of disease subsets and identify pathways important in disease patho-biology. At the same time, it is becoming more important to control the disease over the long term while maintaining the quality of life of the patient. The increased number of treatment options enables us to select personalized medicine according to the systemic condition of the patient. Moreover, understanding the characteristics of novel agents and using them in combination with existing drugs appropriately for the individual patient is critical. Finally, we should consider how we can help patients to live long, active lives throughout the treatment.

Compliance with ethical standards

Conflict of interest K. Suzuki received honoraria from Celgene, Take-da, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen, and consulted for Amgen, Janssen, Takeda, and Celgene; received research funding from Bristol-Myers Squibb, Celgene and Amgen.

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