5.1. Validated Therapy for Relapsed/Refractory Multiple Myeloma
The duration, the quality, and the depth of response to previous therapy represent fundamental principles to take into account for the choice of the relapse/refractory treatment program. Moreover, a complete RRMM framework needs to consider high relapse risk clinical features (systemic symptoms, organ damage, EMD, circulating plasma cells increase LDH), acquired high-risk FISH cytogenetics lesions (17p deletion, chromosome 14 translocations, alterations involving chromosome 1), and residual therapy-related toxicity derived from previous treatments [154
Anti-angiogenic drugs such as lenalidomide and pomalidomide represent the back-bone of the treatment schedules; in particular, lenalidomide was firstly approved in combination with bortezomib and dexamethasone [155
] in 2015 and one year later with the second-generation proteasome inhibitor carfilzomib (Figure 4
Bortezomib in combination with dexamethasone (bortezomib-dexamethasone—VD) [157
] or the triple-therapy with also liposomal doxorubicin (bortezomib, doxorubicin and dexamethasone—PAD) [157
] and lenalidomide-dexamethasone (lenalidomide-dexamethasone—RD) schedule [67
] have showed significant prolongation of PFS in phase 3 clinical trials, becoming standard salvage therapy schemes.
More recently, randomized clinical trials demonstrated a greater efficacy of triplets retaining a tolerability profile similar to that of the two-drug regimens.
The Aspire study has compared, in the MM pretreated setting, patients who underwent a combination triple therapy with carfilzomib lenalidomide and dexamethasone (carfilzomib with lenalidomide and dexamethasone KRD) to an RD schedule group. The authors reported that in the KRD cohort, there was a significant increase in responses (87% vs. 67%, p
< 0.001) and in survival rates at two years (median PFS 26.3 months vs. 17.6 months, 95% CI: 0.57–0.83, p
= 0.0001; OS 73% vs. 65%, 95% CI: 0.63–0.99, p
= 0.04). KRD is associated with a slight increase in the incidence of infections and cardiac events, characterized by hypertension and seldom by heart failure and ischemic heart disease compared to KRD [156
The Eloquent study showed that the combination of the anti-SLAMF7 monoclonal antibody elotuzumab with lenalidomide and dexamethasone induces a significant increase in median PFS (19.4 months vs. 14.9 months, 95% CI: 0.57–0.85; p
< 0.001) and treatment time (TNT) (33 vs. 21 months) compared to RD in pre-treated patients. Elotuzumab-RD was very well tolerated, and infusion reactions after monoclonal antibody occur in 20% especially after the first infusion and are predominantly Grade I–II [160
]. Clinical studies and the toxicity profile identify KRD as a possible choice for patients with first or second recurrence with well-controlled hypertension, without severe cardiologic comorbidities, and with adequate compliance to an intravenous treatment twice a week. Elo-RD is indicated in patients with first or second recurrence without high-risk clinical and biological features.
KRD is also indicated as a pre-transplant re-induction treatment in fit patients younger than 70 years who achieved a lasting response after autologous transplantation and who still have viable cryopreserved hematopoietic stem cells (CD34+ cells >2 × 106/kg).
Salvage autologous transplantation seems well tolerated, not very toxic, and more effective if the response of the first autologous transplant lasts longer than 18–24 months [161
In the poor-responder/refractory patient setting, allogeneic hematopoietic stem cell transplantation (allo-HSCT) needs to be taken into account after a 4–6 KRD induction therapy. Scientific evidence indicates that heavily-pretreated patients who have failed several lines of treatment should no longer undergo allo-HSCT, as it is burdened by high transplant-related and high relapse rates. In contrast, an allo-HSCT in first recurrence for patients considered to be at high risk could maximize the advantages of the procedure, reducing toxicity and increasing the efficacy of the graft-versus-myeloma effect, although prospective studies in this patient setting are still ongoing [162
]. Moreover, in RRMM, bendamustine can be used alone or in association with bortezomib in patients with preserved bone marrow reserve [163
]. In more advanced stages of disease (i.e., after second relapse) pomalidomide in combination with dexamethasone represents a good treatment option [27
]. Pomalidomide in combination with dexamethasone has been shown to increase PFS and OS compared to dexamethasone alone (4.1 vs. 1.9 months, 12.7 vs. 8.1 months, respectively) in RRMM patients. In terms of adverse events, a modest neutropenia and an increase rate of infections compared to the conventional arm were reported. Immunotherapy represents a novel chance for MM treatment since daratumumab [164
], a specific CD38 monoclonal antibody, was added to the therapeutic armamentarium in MM. The CD38 represents a suitable antigen to target at the same time the plasma cell compartment, but also the immune-microenvironment with depletion of T and B regulatory cells and myeloid-derived suppressor cells enhancing T cell-mediated cytotoxicity [133
]. The anti-CD38 monoclonal antibody daratumumab [164
] has been shown to be efficient and well tolerated. In RRMM, daratumumab in monotherapy achieved at least 36% partial responses, with a PFS and OS at one year of 65 and 77%, respectively. The most important toxicity concerns infusion reactions, which are limited to the first administrations and adequately prevented by premedication with steroids and anti-H1 antihistamines. Patients with third or subsequent relapse, already exposed to proteasome inhibitors and lenalidomide, are suitable to be treated with pomalidomide and dexamethasone or to undergo salvage treatment with daratumumab.
As also mentioned above, MM is being explored in the field of the new T cell immunotherapies, as well, with the chimeric antigen receptor T cell program already targeting B-cell maturation antigen (BCMA ) [165
] and with new bi-specific antibodies still in clinical trials (Figure 4
5.2. Novel Target in Relapsed/Refractory Multiple Myeloma
The biology of RRMM patients is characterized by an acquisition of genetic lesions such as 1q amplification and deletion 17p, 1p, or 13q, usually associated with poor prognosis (Figure 4
]. Moreover, oncogenes mutations such as BRAF, NRAS, and KRAS, as well as tumor suppressor genes as TP53 are enriched in the RRMM setting [108
]. Moreover, changes in the tumoral microenvironment and the angiogenesis enhancement represent key regulators in tumor progression and refractoriness development [95
]. Given the biological background, in the last few years, major improvements have been made in the treatment of this peculiar patient group. New targeted therapies are emerging in MM, such as combinations of BRAF and MEK inhibitors [177
] in RAS pathway-mutated patients and BCL2 inhibitors [175
]. Additionally, based on peculiar genomic features, clinical trials targeting the FGFR3, CDK, and PI3K pathways are ongoing [180
] (Figure 4
B). Despite encouraging pre-clinical results [181
], FGFR3 inhibitors in the MM setting failed to show an effectiveness as monotherapy [174
]. CDK inhibitors are the more advanced drugs in clinical trials for MM: results from a phase 1/2 study reported objective responses in 20% of patients and a stable disease maintenance in 44% [173
]. These approaches are able to block the proliferative and survival advantages acquired by resistant cells during the progression of the disease and to induce deep responses also in heavily pre-treated patients [95
]. Nevertheless, these new targeted approaches seem to be effective, but only in selected cases and for a limited timeframe that fit with the selection over the subclonal “underwood” that usually molecularly characterizes MM. Indeed, the association strategy will be mandatory in order to limit the overgrowth of resistant cell populations.