Treatment of Multiple Myeloma in the First Relapse

Abstract

The treatment scope for relapsed myeloma has been expanded considerably in the last few years, by virtue of the advent of numerous novel agents with new mechanisms of actions. This has resulted in increasing responses and prolonging survival even in advanced diseases. The wealth of novel regimens comes with the challenges of balancing toxicities and aligning a regimen with the biology of myeloma and the nature of relapse in conjunction with the patient’s treatment history, comorbidities, and personal preference. The second-line treatment in myeloma includes new generation of proteasome inhibitors and immunomodulators, CD38 monoclonal antibodies, Panobinostat, and Elotuzumab. Recent randomized trials have shown that triplet combinations incorporating CD38 monoclonal antibodies, dexamethasone along with either proteasome inhibitor or immunomodulator were superior to doublet combinations in terms of response rate and progression-free survival. The choice of the second-line therapy is determined by lenalidomide/bortezomib exposure and resistance and access to new agents. Furthermore, autologous transplantation should be considered in selected cases. Here, we will be discussing the optimal management of multiple myeloma in the first relapse.

1. Introduction

Multiple myeloma (MM) is a neoplastic proliferation of plasma cells accounting for 10% of hematologic malignancies [1]. An induction regimen using a combination of immunomodulatory drugs, proteasome inhibitors, and dexamethasone followed by autologous stem cell transplantation (ASCT) is considered standard treatment for newly diagnosed myeloma in physically fit patients [2]. In the era of novel therapies, several randomized trials have proved improved progression-free survival (PFS) and overall survival (OS) in favor of use of novel therapies in a combination of ASCT with maintenance therapy [3]. Despite these advances, MM remains an incurable disease and the majority of patients continue to relapse and will require additional treatment [4]. Factors related to poor outcomes include lack of response, high-risk cytogenetics, stage, age, presence of extramedullary disease, and circulating plasma cells, and co-morbidities and functional status are linked to bad prognosis [5].

2. Definitions of relapsed and relapsed/refractory myeloma

The International myeloma working group (IMWG) published and revised the definitions of relapsed MM in 2015. Relapsed MM is defined as a recurrence of disease after prior response on the basis of objective laboratory and radiological criteria:

• ≥25% increase of the monoclonal protein (M-protein) in serum (absolute increase ≥0.5 g/dl) or urine (absolute increase ≥200 mg /d) or

• ≥25% difference between involved and uninvolved serum free light chains (absolute increase >10 g/L) or

• >10% increase of the absolute percentage of the bone marrow plasma cells or

• Development of new (extramedullary) plasmacytomas or hypercalcemia.

Relapsed/refractory MM (RRMM) is defined as a disease that becomes nonresponsive or progressive on therapy or within 60 days of the last treatment in patients who had achieved a minimal response or better on prior therapy [6]. Furthermore, the IMWG consensus defined the relapse of MM based on the clinical aggressiveness as shown in Table 1.

Non-aggressive relapse		Aggressive relapse
Biochemical relapse	Symptomatic relapse
Progression based on increased M-protein; No associated symptoms or myeloma related organ dysfunction	Slowly increasing M protein and slow onset of clinical symptoms; Progressive disease with prominent symptoms	Short duration of response or progression while on therapy; Aggressive clinical progression includes: Rapid onset of symptoms; Extensive disease on radiologic, laboratory, or pathologic findings; Circulatory plasma cells; ISS stage II/III at relapse; Isotype transformation (light chain disease or hypo secretory disease); Adverse cytogenetic abnormalities; t 14;4, del 17p, hypodiploidy; High B2 microglobulin (>5.5 g/L) or low albumin (<3.5 g/ L), high LDH; Presence of extramedullary disease; Disease-associated organ impairment

Table 1.

The IMWG consensus defined the relapse of MM based on the clinical aggressiveness.

3. Diagnosis of relapse

At relapse, the diagnostic assessment should include the full routine workup of MM, including complete blood count and differential, serum electrolyte, renal and liver function, serum and urine electrophoresis with immunofixation, serum free light chain assay, and 24-hour urine for protein. Bone marrow evaluations are highly recommended (especially in non or oligosecretory MM). BM examination should include morphology and fluorescence in situ hybridization (FISH) on CD138 selected plasma cells to detect cytogenetically unfavorable abnormalities that require an intensive approach with a combination of maintenance therapy and other abnormalities that predict response to therapy (Venetoclax) such as t(11;14) [7].

Imaging evaluation is recommended to all patients (Pts) at relapse and this includes low dose whole body computed tomography (CT) scan or whole spine magnetic resonance imaging (MRI) in cases of relapsed smoldering MM to detect any focal lesion or FDG positron emission tomography combined with computed tomography (PET/CT) in cases of suspected extramedullary relapse [8].

4. Predictive factors for early relapse

The result of Pourmoussa et al study in 2019 has shown that achievement of complete response (CR) before transplant may help to prevent early relapse or progression of the disease, which was in accordance with prior observations where achievement of CR or very good partial response before autologous stem cell transplantation translated to a better long-term outcome [9]. There is a strong association between high-risk cytogenetic by FISH results such as del(17p) and/or t(4;14) and/or t(14;16), high lactate dehydrogenase (LDH) and serum albumin (<3.5 g/L) are predictive of early relapse [10]. Furthermore, there was a strong relation between Freiberg comorbidity index (FCI) and early relapse and progression partly due to poor tolerance to treatment [11]. Minimal residual disease (MRD) positivity at the end of induction and post consolidation or transplantation is strongly associated with inferior outcomes and early relapse [12].

5. Prognostic factors at time of relapse

There are several prognostic markers indicative of an aggressive relapse as shown in Table 2. Patients who experienced a primary refractory disease, or relapsed within 112 months of initial diagnosis, usually have a poor prognosis [13]. Relapse with prior lenalidomide exposure usually indicates a poor prognosis and short progression-free survival (PFS) [14]. Patients with extramedullary or secondary plasma cell leukemia (sPCL) tend to have dismal outcomes [15, 16].

Parameters
Disease-related parameters (parameters associated with poor prognosis)	High ISS High risk cytogenetics (t (4;14), t(14;16), 17p del Extramedullary disease Short response to prior therapy (less than 12 months) Aggressive relapse (rapid onset hypercalcemia, renal failure)
Patient and treatment-related	Age Co-morbidities Performance status (EGOG or frailty index) Failure to achieve VGPR or more Detectable MRD Previous ASCT or not Lenalidomide/Bortezomib refractoriness or intolerance Number and toxicity of prior lines of treatment

Table 2.

prognostic markers indicative of an aggressive relapse.

6. Management of early/first relapse

6.1 General considerations

Myeloma treatment has evolved during the past decade to include multiple immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies. The choices of treatment can be guided by disease biology and the nature of relapse (biochemical vs clinically aggressive) and prior lines of treatment.

Autologous stem cell transplantation remains a mainstay for patients who elect to defer transplantation as initial therapy [17]. The main classes of drugs in multiple myeloma include proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies primarily anti CD38 monoclonal antibodies (daratumumab and Isatuximab) and Elotuzumab (targets SLAMF7). The choice of regimen depends on response and prior therapies. It is preferable to class switch if needed or uses next generation of the same class.

Evaluating indolent versus aggressive relapse is critical since patient with mild biochemical relapse might not require switching therapy as discussed before. Patients who experience a biochemical relapse may be treated by increasing the medication dose if they are on maintenance lenalidomide, reintroducing dexamethasone, and/or adding another agent. While patients who develop aggressive relapses, such as extramedullary disease, may require special approach with multiagent chemoimmunotherapy.

Assessing frailty and comorbidities is crucial in deciding the choice of therapy. It is generally recommended to use a triple combination; however, this might not be appropriate in extremely frail patients, therefore, a doublet combination might be used.

Psychosocial issues and access to care are important in the relapsed setting, especially in older patients or with relapsed myeloma with comorbidities. Patients who have no access to transportation can be treated at home with oral treatment whenever possible [18].

6.1.1 Indications of treatment at relapse

The goal of relapse treatment is to relieve disease symptoms, prevent new organ damage, and achieve a second lasting disease remission. Second and later remissions tend to be shorter because the disease may be more aggressive owing to the presence of different clones, which represent refractory disease [19, 20].

Indications to start treatment at relapse have been defined as clinical or significant relapse as defined by the IMWG [21] as shown in Table 3. The choice of salvage regimen is based on lenalidomide/bortezomib resistance, CD38 monoclonal antibody availability, and access. ASCT is done in specific scenarios as per standard recommendations (to be discussed below).

Type of relapse	Indications
Clinical relapse	Development of new soft-tissue plasmacytomas or bone lesions; Definite increase (≥50%) in size of existing plasmacytomas or bone lesions Hypercalcemia (≥11.5 mg/dL; 2.875 mmol/L) Decrease in hemoglobin of ≥2 g/dL (1.25 mmol/L) or of10 g/dL because of myeloma Rise in serum creatinine by ≥2 mg/dL or more (≥177 mmol/L), due to myeloma Hyperviscosity requiring therapeutic intervention
Significant biochemical relapse in patients without clinical relapse	Doubling of the M-component in 2 consecutive measurements separated by 2 months with the reference value of 5 g/L, or; - In 2 consecutive measurements, any of the following increases: The absolute levels of serum M-protein by ≥10 g/L, or An increase of urine M-protein by ≥500 mg per 24 h, or An increase of involved FLC level by $20 mg/dL (plus an abnormal FLC ratio) or a 25% increase (whichever is greater)

Table 3.

Indications to start treatment at relapse.

There are different protocols used in the first relapse refractory cases as summarized in Table 4. Incorporating CD38 monoclonal antibodies into the backbone of salvage therapy has been shown to be superior to historical controls in many clinical trials.

Study (median FU)	Median PFS	Safety	Hazard ratio	Comments
CANDOR (27.8 m); - D-Kd vs Kd	28.6 vs 15.2 mons	HTN: 21 vs 15%; ↓PLT: 25 vs 16%; PNA: 15 vs 9%	HR 0.59; p<0·0001	1–3 lines, HR CG 15% (50% failed CG !!), GFR ≳20, LVEF ≳40%; Len refractory 39%
POLLUX (44.3 m); - D-Rd vs Rd	SR: NR vs 18.6 mons; HR: 26.3 vs 8.3 mons	-	SR: 0.43; P < 0.0001; HR: 0.34; P = 0.0035	≳1 lines (1–11,), GFR > 30,; 1 line (52%), 80% no prior len
CASTOR (40 m); - D-Vd vs Vd	16.7 vs 7.1 mons	-	HR 0.31; P < .0001	1–9 lines (median 2); len refractory 25%,; prior Velcade 65%
IKEMA (20.7 m); - Isa-Kd vs Kd	NR vs 19 mons	-	HR 0·53; p=0·0007	1–3 lines, GFR ≳15, LVEF ≳40%; primary refractory excluded, HR CG 23%; No K or Dara, Len refractory 25%
OPTIMISUM (15.7 m); - P-Vd vs Vd	ITT: 11.2 mons; 1L Rx: 20.7 mons	↑neutropenia; ↑thrombocytopenia; ↑infection	ITT: 0.61; P < 0.0001; 1L: 0.54; P = .0027	≳1 lines, GFR > 30
TOURMALINE; - Ixa-Rd vs Rd	ITT: 20.6 mons; 1L Rx: 20.6 mons	-	ITT: 0.73; 1L: 0.83	≳1 lines, GFR > 30; No G2PN, Exc. Len or PI ref
ELOQUENT-2; - Elo-Rd vs Rd; N=321 pts	19.4 vs 14.9 mons	Lymphocytopenia, neutropenia, fatigue, and pneumonia Infusion-related reactions (IRR) 10% mostly Grade 1/2

Table 4.

Cross trial comparison of different protocols.

Patients who are lenalidomide exposed or sensitive seem to have the best outcomes from daratumumab, lenalidomide, and dexamethasone (D-Rd) combination as shown by POLLUX trial [22], with a median follow-up of 44.3 mons, the median progression-free survival (PFS) not reached and 25.3 months for standard risk and high-risk patients, respectively. In patients with lenalidomide refractoriness, the use of isatuximab (IKEMA, Isa-Kd) [23] and daratumumab (CANDOR trial, Dara-Kd) [24] based combination with carfilzomib and dexamethasone best outcomes. In CANDOR trial, with a median follow-up of 27.8 mons the median PFS was 28.6 mons (Hazard ratio HR 0.59, P < 0.0001%), while the IKEMA trial has shown a median PFS not reached with a median follow up of 20.7 mons. Daratumumab, bortezomib, and dexamethasone (Dara-Vd) as per the CASTOR trial, with a median follow-up of 40 mons, the median PFS was 16.7 months, and HR of 0.31 (P < 0.0001) [25].

Another group of monoclonal antibodies called anti SLAMF7 (signal lymphocyte activation molecule F7) has been evaluated in a phase 3 trial, Elotuzumab, lenalidomide, and dexamethasone (Elo-Rd) vs Rd have shown a median PFS benefit of 19.4 mons vs 14.9 mons (HR 0.70, P<0.001%) [26].

In phase 3 trial, evaluating the use of pomalidomide, bortezomib, and dexamethasone (P-Vd) vs bortezomib and dexamethasone (Vd) at a median follow-up of 15.7 mons, median PFS for patients who had one prior line of therapy was 20.7 mons in favor of P-Vd (HR 0.54, P=0.0027) [27]. TOURMALINE trial, which evaluated Ixazomib, lenalidomide, and dexamethasone (I-Rd) vs Rd showed a median PFS of 20.6 months in favor of I-Rd with an HR of 0.83 [28], although there was no statistically significant difference in overall survival with the addition of ixazomib to the combination, this might be confounded by the subsequent therapies [29].

High-dose chemotherapy and ASCT can be used in the first relapse for fit patients who experienced a prolonged PFS after the first transplant or those who never had a transplant before as summarized in Table 5 [7, 13, 30].

ESMO 2021:

Initial remission duration of ≥ 36 months.

mSMART 2020: if eligible

Consider salvage auto SCT who have not had it before; Consider 2nd auto SCT Remission ≥ 18 months unmaintained or Maintained response to first ASCT of ≥ 36 months

EBMT/ASTCT 2015:

Initial remission duration of ≥ 18 months

Table 5.

Role of autologous stem cell transplant in the first relapse.

7. Treatment of relapse in special scenarios

7.1 Renal failure

Renal failure is commonly seen in patients with multiple myeloma at the first diagnosis, however, it is less common in the relapse if the patient was followed up regularly because antecedent biochemical relapse is seen before clinical relapse. However, If the patient has renal impairment, it is crucial to note that almost all clinical trials have excluded patients with renal impairment (estimated glomerular filtration rate eGFR) [31].

Proteasome inhibitors do not need dose modification except for Ixazomib. Immunomodulators (pomalidomide and thalidomide) do not need dose modification but lenalidomide does. CD38 monoclonal antibodies do not need dose modification. Alkylating agents do need dose modification. In summary, we need to check the dosing schedule as per eGFR for the patient.

7.2 Extramedullary relapse (EMD) or secondary plasma cell leukemia (sPCL)

EMD and sPCL usually indicate an aggressive disease and carry a dismal prognosis with a median overall survival (OS) of 6 mons (EMD) [15] and 4.3 mon (sPCL) [16]. It required incorporating chemotherapy i.e. VTD-PACE followed by ASCT if meets the criteria as discussed before. The use of CD38 monoclonal antibodies such as daratumumab has not shown to improve outcomes in this group of patients [32].

Central nervous system (CNS) involvement at relapse correlates with poor outcomes due to its resistance to several treatments. The frequency of CNS involvement is only approximately 1% [33]. Immunomodulators (IMIDs) and daratumumab have been shown to have a good penetration to the blood-brain barrier (BBB) and are effective in CNS myeloma cases as shown in Table 6 [34]. Use of intrathecal chemotherapy has shown efficacy in combination with anti-myeloma treatment, however, dosing, frequency, and duration of therapy are not well defined [35]. Myeloma cells are usually radiosensitive [36], therefore combining radiotherapy with chemotherapy can be more effective than if used alone [37].

Class of therapy	Agents	BBB penetration	CNS Myeloma
Immunomodulator	Thalidomide; Lenalidomide; Pomalidomide	Good; Good; Good	Effective; Effective; Effective
Proteasome inhibitor	Bortezomib; Carfilzomib; Ixazomib	Poor; Poor; Poor	Ineffective; No data; No data
CD38 monoclonal	Daratumumab; Isatuximab	Good; No data	Effective; No data

Table 6.

Anti-myeloma efficacy in CNS myeloma.

8. Summary and recommendations

• Patients with multiple myeloma at the first relapse should undergo a full clinical, laboratory, and radiological evaluation.

• It is crucial to differentiate between clinical and biochemical relapse and determine the aggressiveness of the relapse.

• The choice of treatment is based on the disease biology, prior treatment, and aggressiveness of the relapse.

• ASCT can be offered to a specific group of patients who are fit and had a prolonged duration of remission with the first transplant or those who are transplant naïve.

• The use of monoclonal antibodies yields the best outcomes in the first relapse of multiple myeloma patients

• For lenalidomide refractory patients, Dara-KD, Isa-KD, KPD, or PVD can be used.

• For lenalidomide sensitive patients: Dara-Rd, Dara-KD, Dara-Pd, Isa-Kd, Isa-Pd, KRd, KPd, or Elo-Rd