Multiple myeloma: treatment evolution

Abstract

Melphalan–prednisone (MP) was introduced for the treatment of MM in late 1960s. In the subsequent 30 years, the treatment improvements remained stagnant, since more complex chemotherapy combinations, such as vincristine, doxorubicin, and dexamethasone (VAD), or with the addition of BCNU (VBAD) or melphalan and cyclophosphamide (VCMP), only led to small increases in the overall response rate but without differences in survival, as assessed in a large meta-analysis that included over 6000 patients. The next step forward was the use of high-dose melphalan followed by stem cell support (autologous stem cell transplant – ASCT) for young myeloma patients, which resulted in a significant improvement in disease free survival and overall survival. However, for elderly patients MP remained as the standard of care. From year 2000, a revolution in the treatment armamentarium of MM has emerged with the availability of new agents with singular mechanism of action such as thalidomide and lenalidomide (Revlimid®), both immunomodulatory drugs and the proteasome inhibitor bortezomib (Velcade®).

Keywords:

• Autologous transplant
• Proteasome inhibitors
• Immunomodulatory drugs
• Allogeneic transplant

Treatment of Newly Diagnosed Transplant Candidate Patients

Currently, treatment in this setting usually includes 3–6 cycles of induction therapy, consolidation with autologous stem cell transplant (ASCT) and the possibility of maintenance therapy.

Induction

The combination of vincristine, doxorubicin, and dexamethasone (VAD) has long been the gold standard as a preparatory regimen for young newly diagnosed MM patients candidates for ASCT, with partial response rates around 60%, and <10% complete response (CR). However, novel drug combinations are significantly superior to VAD. Triple drug combinations based on thalidomide (T) (TAD or TCD) induce 80% responses although the CR usually is <15%; by contrast the TD combination is suboptimal. Regarding lenalidomide (Len), in combination with dexamethasone (Dex) the majority of patients (>85%) respond, but probably a minimum of 4–6 cycles would be required to achieve >10% CRs. With bortezomib (Bz) based regimens, particularly triplets such as BzAD, BzCD or even better BzTD or BzLenD the response rate (RR) is around 90% with up to 30%CR. Thalidomide or Bz combinations did not affect stem cell collection, while for Len it is recommended to harvest stem cells after no more than 3–4 cycles.

Autologous stem cell transplant

High dose therapy (usually based on melphalan 200 mg/m²) followed by ASCT is currently considered as standard of care for younger patients with multiple myeloma, mainly based on the benefit on RR and event-free survival (EFS) observed in several randomized trials as compared to standard dose therapy although not all studies demonstrated benefit in overall survival (OS). In the setting of novel agents it is also important to define whether or not ASCT enhances the RRs obtained with these new induction regimens. Several randomized trials have shown that the CR rate was improved following ASCT suggesting that induction with novel agents and ASCT are complementary rather than alternative treatment approaches. Nevertheless, some investigators argue that this approach may be challenged by the optimal results obtained with ‘long-term’ treatment with novel combinations (i.e. Len+Dex). Randomized trials comparing early versus late transplant are underway, but until these results become available we recommend the upfront transplant because it induces a high CR rate (a goal in all haematological malignancies), patients enjoy a long-term period free of treatment with excellent quality of life and we know that at relapse usually respond to rescue therapies, while we do not yet know the efficacy of high dose therapy after long term exposure to novel agents. Regarding tandem ASCT, its use has significantly decreased in favour of consolidation or maintenance therapies. By contrast, second transplant at relapse may be increasingly used, providing that the duration of the response to first transplant has lasted for more than 2–3 years.

Maintenance

The third step in this sequence of treatment is maintenance. Interferon and/or corticosteroids have shown little benefit and have been abandoned. The availability of novel agents (particularly those in oral formulations: T and Len) has renewed the concept of maintenance in an attempt to prolong the duration of the responses after transplant. Six randomized trials based on T or TD have shown a significant prolongation in progression-free survival (PFS), but only three in OS as compared to Pamidronate, corticosteroids or interferon. However, the toxicity and possibility of inducing more resistant relapses is an important concern. Two randomized trials have recently reported a significant benefit for Len maintenance in terms of PFS (42 vs 24 months in the placebo arm) but only in one there is so far benefit in OS. Moreover, a higher incidence of second primary malignancies was detected which requires close follow-up before it is recommended as a standard of care.

Allogeneic transplant

Allogeneic transplantation remains as the only curative therapeutic approach in MM patients. However, it is associated with a high transplant related mortality (TRM up to 20–40%) and morbidity (mainly due to chronic graft-versus-host disease). Accordingly, it should be used in carefully defined situations and, preferably, within the context of clinical trials. In order to decrease TRM, different reduced intensity conditioning regimens (RIC) have been developed (allo-RIC), mainly based on fludarabine and melphalan or fludarabine plus radiotherapy (2 Gy). The TRM decreases to 10–25% but this is associated with a higher incidence of relapses. Six randomized trials have compared the use upfront of double ASCT versus ASCT followed by allo-RIC; only in two of them the allo approach was superior in terms of PFS and OS. Differences in patient characteristics, chronic graft-versus-host disease prophylaxis and conditioning regimens could explain these discrepant results. Moreover, unfortunately, a high proportion of patients develop extramedullary relapses without bone marrow involvement indicating that, although the disease may be under control in the bone marrow milieu, extramedullary spread may occur. Regarding the use of Allo-Trx as rescue therapy, a prerequisite is to obtain a complete remission or very good partial response before the transplant since most patients with active disease will not benefit from this procedure. Once again these transplants should be performed by experienced groups and within clinical trials. Moreover, the role of Allo transplant needs to be revisited integrating novel agents.

Treatment of Newly Diagnosed Elderly and Non-transplant Candidate Patients

Melphalan–prednisone (MP) has been the gold standard for over 40 years; however, recent results based on the combination of MP with either T or Bz, and probably also with Len, indicate that there are now new standards of care for elderly MM patients.

Six randomized trials have compared T+MP (MPT) vs MP showing significantly higher RR in the MPT arm (59 vs 37%) (CR 10 vs 2·5%) as well as longer PFS/TTP (prolongation in PFS of 5·4 months). However, only in the three studies, MPT treatment was associated with a significant prolongation in OS. The toxicity associated with the high dose of T used in some of these trials may explain the survival discrepancies. Preliminary data from the MRC myeloma IX trial show that the combination of Cyclophosphamide+Thalidomide+Dexamethasone is superior to MP in terms of RR (82 vs 49%) but not in OS. MP has also been compared with thalidomide+dexamethasone (TD) and although the RR was higher in the experimental arm the OS was shorter. It should be noted that in this last trial TD treatment was associated with higher rate of early discontinuations, due to toxicity, and higher mortality particularly during the first year.

Lenalidomide has also been combined with MP. A large randomized trial comparing MP vs Len+MP using Len only as part of the induction or also as maintenance has recently been completed; the initial results show a significantly longer PFS for the maintenance approach (31 vs 14 and 12 months, respectively). Nevertheless, these MP combinations are being challenged by the results reported with Len+Dex, particularly using low dose Dex with a 2-year survival probability of 82% in patients >65 years and a very good tolerability.

The proteasome inhibitor Bz has been tested in combination with MP in a pilot study conducted by the Spanish group; the positive results were confirmed in a large randomized study that has compared BzMP vs MP. The RR for BzMP vs MP were 71 vs 35% with 30 vs 4% CR. BzMP treatment was associated with a longer TTP (24 vs 16·6 months) and OS at 3 years of 72 vs 59%. In an attempt to optimize the treatment of elderly untreated MM patients with BzMP, the Spanish and Italian Myeloma groups (GEM/PETHEMA and GIMEMA) have activated two randomized trials. Instead of the twice-weekly dose, bortezomib is administered only once weekly. Results indicate that efficacy is maintained with the reduced dose bortezomib schedule, while tolerability is increased substantially. Notably, grade 3/4 PN was only 2 or 5% with the reduced dose BzMP regimen in the two studies. Moreover, the rate of treatment discontinuations was low in both studies (8% and 10%).

A controversial issue is whether there is any preference for one of the three novel MP combinations. An individualized treatment approach would probably be valuable: (1) for patients with antecedent or risk of deep venous thrombosis, BzMP could be the preferable option; (2) in patients with antecedent peripheral neuropathy, Len-MP should be the choice; (3) in patients with renal insufficiency, BzMP is safe; (4) in patients living long distances from hospital, oral treatment (MPT or Len-MP) would be preferable; and (5) in patients with poor compliance with treatment, BzMP could be better.

In patients >75 years or with fragile condition it would be recommended to use modified regimens, with a lower dose of T (100 mg); Len (15–20 mg) (or Bz 1 mg/m² or a weekly schedule). One additional possibility in these patients is to substitute melphalan by cyclophosphamide (50 mg/day or 1 g/21 days), since this latter agent is less myelotoxic. In very elderly patients, special attention must be paid to infectious episodes (require active treatment) and renal function (appropriate hydration), particularly during the first three months of treatment when they are responsible for the high incidence of early deaths. Ongoing studies will establish optimal dosing and treatment schedules for different populations with the aim of maximizing efficacy and improving tolerability.

Treatment at Relapse

In this setting it is important to separate the young from the elderly patients. In patients relapsing after transplant, we should discriminate three cohorts of patients: early relapse (<1 year), intermediate relapse (1–3 years), and late (>3 years) relapse. If the relapse occurs within the first year after transplant, the patients should be considered as a high risk and, in order to overcome drug resistance, rescued with either a combination of all potentially effective drugs such as BzTD-PACE or BzLenDex. If CR is achieved, the patient could proceed to an allo-transplant with reduced intensity conditioning regimen (RIC-Allo), although this must be still considered as an investigational approach. An alternative to RIC would be to consolidate the response with maintenance therapy with immunomodulatory drugs.

If relapse occurs between 1 and 3 years after ASCT, we would favour rescue with novel agents used in a sequential (not simultaneous) manner: first one line of treatment, (different from the one used as induction), and shifting to the second and subsequent lines only when disease progression occurs. Within this category of patients, for those that are young (<55 years) with an HLA–identical sibling and who had suboptimal response to the first line of treatment, the possibility of a RIC-Allo-Trx can be re-considered.

Finally, if the relapse has occurred >3 years after the first ASCT, an attractive possibility is re-induction with the initial treatment or other novel agent combination, followed by a second ASCT.

In the elderly patients treatment decisions at relapse must take into account the general condition of the patient. Once the patient relapses, after up-front treatment, the durations of subsequent responses to rescue therapies are progressively shortened. Therefore, the current goal in relapsed MM is to optimize the efficacy of the novel drugs through their most appropriate combinations, to establish optimal sequences of treatment and to promote active clinical research on experimental agents that have already shown promising activity in in vitro and animal models.

At first relapse a scheme based on novel drugs (T, Len or Bz) different from that used as induction, should be given. The most widely used schemes at relapse includes: T-Dex or T-Cyclo-Dex; Len-Dex or Len-Dex+Doxorubicin; and Bz-Dex or Bz-LiposomalDoxorubicin+/-Dex or Bz-Cyclo-Dex. At second or subsequent relapse, usually after having been already failed to Bz and at least one IMID, a clinical trial with experimental agents should be encouraged. If the patient is not a candidate for active therapy, palliative treatment with oral cyclophosphamide (50 mg on alternating days) and prednisone (30 mg/day) can be considered.

New Drugs

Some of the molecular events responsible for the transformation of a normal into a malignant plasma cell (PC) represent potential therapeutic targets. Thus, the t(4;14) translocation generates a constitutive activation of the oncogenic tyrosine kinase receptor FGFR3 with subsequent phosphorylation of the antiapoptotic STAT3 signalling pathway. Moreover, several IgH translocations lead to Cyclin D deregulation, and represent a common pathogenic event in MM. Therefore, the use of inhibitors of cyclin dependent kinases as well as inhibitors of the FGFR3 tyrosine kinase could be attractive therapeutic targets against MM. The second area of MM pathogenesis that has important implications for treatment intervention is the interaction between the malignant cell and the bone marrow microenvironment that promotes MM cell growth and proliferation. In this area several targeted oriented drugs are already at early phases of clinical investigation, and these includes: (1) agents against receptors present in PCs which can be targeted by specific drugs or monoclonal antibodies: cell death receptors (such as DR4-6, FAS and BCL2); TK receptors, VEGFR; TACI, IL6-R, IGF-1R or the CD56 or CS1 antigens; (2) inhibitors directed to signalling pathways including Farnesil Transferase (Tipifarnib), RAF (RAF 265), STAT3 (Atiprimod), mTor (RAD001) or AKT (Perifosine); and (3) drugs that interfere with the interactions between PC and microenvironment such as new Proteasome inhibitors (Carfilzomib), novel IMIDs (Pomalidomide), and HDAC inhibitors.